Zometa Zoledronic Acid Protocol No SPCG Protocol No Effectiveness of

Zometa® (Zoledronic Acid, CGP42446) Protocol No. CZOL446G DE08 SPCG Protocol No. 11 Effectiveness of Zometa® treatment for the prevention of bone metastases in high risk prostate cancer patients. A randomized, open-label, multicenter study of the European Association of Urology (EAU) in Cooperation with the Scandinavian Prostate Cancer Group (SPCG) and the Arbeitsgemeinschaft Urologische Onkologie (AUO). Steering Committee: Prof. Georg Bartsch / University of Innsbruck Prof. Frans Debruyne /University Medical Center Nijmegen Prof. Peter Iversen / University of Copenhagen Prof. Kurt Miller / University Clinic Benjamin Franklin, Berlin Prof. Anup Patel / St. Mary’s Hospital, London Prof. Teuvo Tammela /Tampere University Hospital Prof. Andrea Tubaro / "La Sapienza" University of Rome Prof. Manfred Wirth / University Clinic Dresden Dr. Valter Torri/Mario Negri Institute, Milano Dr. Ulrike Haus / Novartis Pharma GmbH, Nürnberg Prof. Dr. Manfred Wirth University Clinic Carl Gustav Carus Dresden, Germany Phone: +49 351 458 2447 e-mail: urologie@mailbox.tu-dresden.de Study Chairman Study Statistician Country Local study group Local Study Chairman Document type: Document status: Release date: Number of pages: Clinical Study Protocol Final, including Amendment 1 11. November 2003 56 Confidential AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 2 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Signature Page Compound name / number : Protocol number: Approved by the following: Zometa® (zoledronic acid, CGP42446) CZOL446G DE08 Prof. Dr. Manfred Wirth Principal Investigator Signature Date type/print name Local Study Chairman Signature Date type/print name Dr. Valter Torri, Study Statistician Signature Date AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 3 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Study Declaration/Confidentiality Agreement Protocol Number: Date of protocol: Country: CZOL446G DE08 I understand that this protocol contains confidential information property of the EAU. I have received and read this protocol and I agree that it contains all the necessary details for carrying out the study described herein. I shall direct this protocol in the manner described herein and I shall make all reasonable efforts to complete the study within the designated time. I will provide copies of this protocol and access to all information furnished by the EAU to the staff participating in the study and who are under my supervision. I will discuss this material with them to ensure that they have all the information for carrying out the study. I agree to conduct this trial in accordance with all stipulations of the protocol and in accordance with the Declaration of Helsinki. type/print name Name of Investigator Signature Date AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 4 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Table of contents Signature Page .....................................................................................................................2 Study Declaration/Confidentiality Agreement ....................................................................3 List of tables ........................................................................................................................5 List of abbreviations ............................................................................................................6 1. Introduction .........................................................................................................................7 2. Study objectives.................................................................................................................12 3. Investigational plan ...........................................................................................................12 3.1. Overall study design ..............................................................................................12 3.2. Discussion of design ..............................................................................................12 3.3. Study population....................................................................................................13 3.3.1. Patient population..................................................................................13 3.3.2. Inclusion and exclusion criteria ............................................................13 3.3.3 Randomization .............................................................................................14 3.3.4. Interruption or discontinuation of treatment .........................................15 3.4. Treatments .............................................................................................................16 3.4.1. Investigational therapy and reference therapy ......................................16 3.4.2. Treatment assignment ...........................................................................17 3.4.3. Blinding.................................................................................................17 3.4.4. Treatment compliance ...........................................................................18 3.4.5. Concomitant therapy .............................................................................18 3.4.6. Treatment of HCM occurring during the course of the trial ................19 3.5. Visit schedule and assessments .............................................................................20 3.5.1. Visit schedule ........................................................................................20 3.5.2. Efficacy assessments .............................................................................22 3.5.3. Safety assessments ................................................................................25 4. Protocol amendments, other changes in study conduct.....................................................27 4.1. Protocol amendments.............................................................................................27 4.2. Other changes in study conduct.............................................................................27 5. Data management ..............................................................................................................27 5.1. Data collection .......................................................................................................28 5.2. Database management and quality control ............................................................28 6. Statistical methods.............................................................................................................28 6.1. Statistical methods to be employed .......................................................................28 6.1.1. Populations............................................................................................29 6.1.2. Background and demographic characteristics.......................................29 6.1.3. Study medication...................................................................................29 6.1.4. Concomitant therapy .............................................................................29 6.1.5. Efficacy evaluation................................................................................29 6.1.6. Safety evaluation...................................................................................31 AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 5 ® Zometa (Zoledronic Acid) / CZOL446G DE08 6.1.7 Interim analyses ....................................................................................31 6.2. Sample size and power considerations ..................................................................31 7. Notable laboratory value criteria, special methods and scales ..........................................32 7.1. Criteria for clinically notable laboratory abnormalities.........................................32 8. Reference list .....................................................................................................................33 9. Procedures and instructions ...............................................................................................35 9.1. Special safety-related procedures ..........................................................................35 9.1.1. Instructions for rapid notification of serious adverse events ................35 9.1.2. Delay in Zometa® (zoledronic acid) administration after increased serum creatinine values .........................................................................36 9.1.3. Instructions for completing adverse event case report forms................36 9.2. Administrative procedures.....................................................................................37 9.2.1. International Inter-group Steering Committee ......................................37 9.2.2. Scientific Committee.............................................................................38 9.2.3. Changes to the protocol.........................................................................38 9.2.4. Monitoring procedures ..........................................................................38 9.2.5. Recording of data and retention of documents .....................................39 9.2.6. Handling of study medication ...............................................................40 9.2.7. Publication of Results ...........................................................................40 9.2.8. Disclosure and confidentiality...............................................................41 9.2.9 Discontinuation of study .......................................................................41 9.3 Ethics and Good Clinical Practice .........................................................................41 9.3.1. Institutional Review Board/Independent Ethics Committee.................41 9.3.2 Informed consent...................................................................................41 9.3.3. Insurance policy ....................................................................................42 9.3.4. Declaration of Helsinki .........................................................................42 10. Appendices .........................................................................................................................45 Appendix 1: Performance status - ECOG .........................................................................45 Appendix 2: New York State Heart Association functional classification ......................46 Appendix 3: Staging of Prostate Cancer ...........................................................................47 Appendix 4: NCIC Common Toxicity Criteria .................................................................49 Appendix 5: Gleason Grading ...........................................................................................54 Appendix 5: Novartis Contact Person for SAE reporting .................................................55 List of tables Table 1: Evaluation schedule .................................................................................... 20 AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 6 ® Zometa (Zoledronic Acid) / CZOL446G DE08 List of abbreviations AE BMD CRF CS&E CR CBC CRO DPD DXA ECG ECOG EOD FACT-G FDA HCM ICH IRB/IEC LPLV NS NCI PE PSA o,d. p.o. REB SAE SOP SRE TIH WHO Adverse event Bone mineral density Case report/record form Clinical Safety and Epidemiology Clinical Research Complete Blood Count Contract Research Organization Deoxypyridinoline (crosslinks) Dual-energy x-ray absorptiometry Electrocardiogram Eastern Cooperative Oncology Group Extend of Disease in Bone Scan Functional Assessment of Cancer Therapy-General Food and Drug Administration Hypercalcemia of malignancy International Conference on Harmonization Institutional Review Board/Ethics Committee Last patient last visit Normal saline National Cancer Institute Physical examination Prostate specific antigen Omnia die / once a day Per os / by mouth / orally Research Ethics Board Serious adverse event Standard Operating Procedures Skeletal Related Event Treatment induced hypercalcemia World Health Organization AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 7 ® Zometa (Zoledronic Acid) / CZOL446G DE08 1. Introduction Prostate cancer is the most common single cancer in men. Although there has been a clear trend in the past decade to improved prognosis associated with earlier detection, mortality from prostate cancer remains high at 11% of cancer deaths in men, second only to lung cancers. In the US, the overall 5-year survival rate at diagnosis is 47% (blacks), 56% (whites) and this falls to less than 30% for men with metastases already at diagnosis.1-3 The primary treatment of prostate cancer depends largely on the tumor stage and the patient’s age, with age 70 years as the watershed. Before that, stage A patients receive radiation therapy in about 50% of cases and no intervention in the others. Between 70% of stage A and almost all stage B and C patients undergo prostatectomy and/or radiation therapy, and this falls to approximately 50% at stage. In the elder patients surgery and radiotherapy are carried out much less frequently.4 With more than 85% of advanced disease patients responding to medical or surgical castration this treatment has become the current standard. Orchiectomy is still practiced but nowadays therapy consists more frequently of administration of LHRH analogues. Anti-androgen drugs are associated initially to block the temporary increase in testosterone levels at the start of LHRH treatment but their continuous association may also provide a small survival advantage over orchiectomy or LHRH treatment alone. Response is both symptomatic and objective with regression of primary and metastatic tumors, relief of bone pain, reduction in urinary obstructive symptoms, a fall in PSA levels and improved well-being. The median duration of response to hormone therapy is 15-18 months, the loss of response being characterized by a rising PSA level and the reappearance of symptoms. At this stage, treatment consists usually of second-line hormone therapy, cytotoxic drugs and/or radiolabelled strontium. Although this can achieve temporary responses it must be considered as palliative with no consistent evidence of prolonged survival allowing consensus on a standard approach. The median survival at the hormone-refractory stage ranges from 6 -12 months. Overall, after the initiation of hormone therapy for advanced disease, the median survival is approximately 2.5 years.5-8 Hormone therapy is also frequently given as a short-term adjuvant to primary therapy. But evidence is gathering to indicate that prolonged hormone therapy, initiated at the time of diagnosis may increase the time to progression and eventual survival in patients with nonmetastatic but locally-advanced prostate cancer. Although the outcomes of a number of large collaborative group trials are awaited to categorically establish the value of early hormone therapy, preliminary results from the Medical Research Council trial have already been in favor of early treatment. Currently, early hormone therapy is frequently practiced on the basis of prognostic factors such as clinical stage, pathology, PSA levels, performance status and others but the advantage must offset its side-effects which include loss of libido and impotence, osteoporosis, as well as fatigue and impaired quality of life in the pre-metastatic stage.5,9-12 The skeleton is the most frequent target for prostate cancer metastases. Bone metastases are present in 65-75% of patients with advanced disease. On radiography these appear as 'sclerotic' lesions typically ascribed to osteoblastic, regenerative activity although changes in biochemical markers of bone metabolism demonstrate osteoclastic activity to be as great. Bone metastases result in considerable morbidity. Loss of bone integrity leads to pathological fractures with secondary complications depending on fracture location: immobilisation in load-bearing long bones, neuralgia and neurogenic dysfunction in vertebral collapse with AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 8 ® Zometa (Zoledronic Acid) / CZOL446G DE08 spinal cord and nerve root compression. Bone pain resulting from metastatic cell activity is common. It responds to hormone therapy at the hormone-sensitive stage and to localized radiotherapy when resistant. Analgesic treatment will vary from minor analgesics to opiates as bone pain becomes difficult to control. A different sort of pain is the severe mechanical pain and neuralgia, which can accompany fractures. Hypercalcaemia secondary to malignant osteolysis can be life-threatening if left unchecked leading to CNS and renal complications and cardiac arrhythmias. Paradoxical hypocalcemia (the so-called 'bone hunger' syndrome) has been reported as associated with hyperparathyroidism, secondary to the calcium sequestration associated with increased bone-regeneration.13,14 Skeletal integrity in these patients is further compromised by generalized osteoporosis secondary to hormone therapy which compromises osteoblastic in relation to osteoclastic activity. Studies of bone mineral density (BMD) in men undergoing androgen-deprivation show a decrease of approximately 6% over the first two years of drug hormone-therapy and of 10% after orchiectomy. Subsequent loss is directly proportional to the duration of therapy. This results in an increase in the risk of fractures due to osteoporosis with one retrospective study, in orchiectomised men, suggesting a cumulative incidence rate of osteoporotic fractures as high as 10% after three years compared to none in non-orchiectomised men with prostate cancer.15,16 Bisphosphonates are compounds characterized chemically by two C-P bonds giving them an affinity for bone through rapid and strong binding to hydroxyapatite crystals with preferential localization in areas of increased bone resorption and regeneration. In bone chelated with bisphosphonates there is a reduction in the number and activity of osteoclasts which appears to be the result of a direct effect on osteoclasts as well as an indirect effect through interrelating osteoblasts and possibly macrophages. The intimate mechanism of action is complex and still uncertain in many respects but the net effect, at specific concentrations, is a reduction in excessive bone turnover with preservation of bone structure and materialization in otherwise osteopenic states. The decrease in bone resorption is also accompanied by increased intestinal absorption of calcium in the presence of raised 1,25-(OH)2 vitamin D which contributes further to the increased calcium balance, and this, in addition to the need to counter the effects of secondary hyperparathyroidism, is the reason associating calcium and vitamin D supplementation to these patients when receiving bisphosphonates. In addition to their effect on bone metabolism, there is evidence that bisphosphonates can inhibit the potential of tumor cells to metastase to, and develop in, bone through reduced adhesion, reduced metalloproteinase-mediated bone-matrix degradation and other mechanisms entering into the metastatic cascade. Side effects of bisphosphonates differ according to whether administration is oral or intravenous. Bisphosphonates are poorly bioavailable reaching only a few percent even with oral bisphosphonates such as clodronate, the result of their low lipophilicity and chelation by calcium. Gastrointestinal side-effects are frequent with nausea, dyspepsia, vomiting, gastric pain, diarrhea and even ulceration. These can be alleviated by taking water and remaining upright to minimize esophageal reflux. The major risk with intravenous bisphosphonate administration is that of renal failure consequent to the formation of deposits after an over-rapid injection. Renal side-effects can be avoided by slow intravenous infusion with adequate fluid volumes. A transient low-grade fever accompanied sometimes by flu-like symptoms can initially accompany the parenteral administration of nitrogen-containing bisphosphonates. Given in excessive amounts bisphosphonates will inhibit normal calcification. The therapeutic window and modalities of administration are an important feature defining the use of the different bisphosphonates.17,18 There is an increasing amount of clinical evidence confirming the value of bisphosphonates in metastatic bone disease. Long term studies have shown that bisphosphonates can reduce AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 9 ® Zometa (Zoledronic Acid) / CZOL446G DE08 skeletal morbidity, pain and improve the quality of life in patients with multiple myeloma and bone metastases due to breast cancer. With metastatic prostate cancer, short-term studies have demonstrated improved symptoms with oral etidronate, clodronate and intravenous pamidronate. Pamidronate has been shown to prevent androgen deprivation-related osteoporosis in patients with locally-advanced but pre-metastatic prostate cancer as shown by changes in BMD after 48 weeks of leupolide treatment. Currently though, there is no long term evidence demonstrating that clodronate or pamidronate can prevent skeletal complications or improve survival. Currently, the outcome is awaited for two large, placebocontrolled studies investigating the value of initiating long term clodronate therapy in patients with prostate cancer to prevent (1.) skeletal complications in patients commencing hormone therapy because of bone metastases, and (2.) progression to bone metastatic disease in patients with only localized tumor.19-21 Zoledronic acid (Zometa®) is a third-generation nitrogen-containing bisphosphonate which is being developed because of its improved therapeutic window in animal models of benign and malignant bone disorders and increased potency relative to other bisphosphonates including the direct inhibition of prostate cancer cells22. It has been approved in Europe and the US for the treatment of bone metastases in a broad range of tumors and for the treatment of malignancy-related hypercalcemia.23-30 A double-blind, randomized, placebo-controlled phase 3 study (study 039) has been completed recently investigating the value of zoledronic acid as an adjuvant to antineoplastic drugs in patients with prostate cancer and bone metastases becoming hormone-refractory. Patients were randomized to zoledronic acid (4 mg via 15-minute infusion) or placebo every 3 weeks for up to 24 months.31 Zoledronic acid gave a significant reduction (38% vs 49%, p = .028) in the overall incidence of patients with skeletal-related events (SRE), prolongation in the time to these (median 488 days vs 321 days, p = .009), and a reduction in the skeletal morbidity rate i.e. the annual frequency of SREs per patient (mean, 0.77 vs 1.47 events/year for placebo (p = .005). The multiple event analysis showed that zoledronic acid reduced the risk of developing an SRE by 36% (hazard ratio = 0.64; 95% confidence interval, 0.49, 0.85: p = .002). Zoledronic acid also significantly reduced Brief Pain Inventory composite pain scores relative to placebo at 24 months (p = .024). Median survival was 546 days in the zoledronic acid group and 469 days in the placebo group, however this difference did not reach statistical significance. Zoledronic acid (4 mg via 15-minute infusion) demonstrated an overall safety profile similar to that of other intravenous bisphosphonates. Renal deterioration was more frequent in the zoledronic acid group but a change in the duration of infusion (from 5 to 15 minutes) during the study reduced the risk relative to placebo from 2.0 before, to 1.14 thereafter. (A third arm in this study with 8mg zoledronic acid infused over 5 mins was modified to 4mg over 15 mins because of excessive renal toxicity). Adverse events observed with other bisphosphonates such as fever, arthralgia, myalgia and electrolytic abnormalities were also more frequent in the zoledronic acid patients but with no significant consequence on the ability of patients to remain on treatment. The patients in study 039 had had a median duration of hormone therapy of 25 months at the time of recruitment, during which 34% of them had already experienced a first SRE. Administered at the time of initiation of hormone therapy, there is clear scope for zoledronic acid to prolong the time to, and the incidence of, SREs through an effect on the evolution of metastases as well as the prevention of skeletal metastasis. In animal models, bisphosphonates have been shown to reduce and even to prevent the development of bone metastases. The hypothetical mechanism for this antitumor effect by AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 10 ® Zometa (Zoledronic Acid) / CZOL446G DE08 bisphosphonates is that the inhibition of osteoclastic bone resorption prevents the release of tumor-promoting growth factors from the bone matrix.32 In addition, preclinical studies have indicated that nitrogen-containing bisphosphonates may also inhibit the adhesion of tumor cells to bone matrix and induce tumor cell apoptosis.33-38 These studies showed that these antitumor effects were both potent and dose dependent. Several clinical trials have been reported using the relatively low potency oral bisphosphonate, clodronate. In the largest study, 1079 women with primary operable breast cancer were randomized to either clodronate 1600mg daily or placebo for two years in addition to standard adjuvant systemic treatment. Recent data presented with a median follow-up time of 5 years revealed a non-significant reduction in the frequency of bone metastases in the clodronate treated patients (63 (12%) v 80 (15%) patients, p=0.127)39. During the two years on active treatment there was a reduction in bone metastases but this disappeared on discontinuation of the study drug, suggesting that adjuvant bisphosphonate treatment trials in the future should test a longer duration of treatment. There was no effect on non-bone recurrence (112 (21%) v 128 (24%) patients, p=0.26) but, despite little effect on the primary endpoint (bone recurrence), patients randomized to the clodronate arm had a better survival (p=0.047). In a second study, Diel et al. studied 302 breast cancer patients randomly allocated to either oral clodronate 1600mg daily (n=157) for 3 years or a control group (n=145). These women had no overt evidence of metastatic disease, but were selected for the trial on the basis of immunocytochemical detection of tumor cells in the bone marrow, a known risk factor for the subsequent development of distant metastases40. Patients received appropriate adjuvant chemotherapy and endocrine treatment. There were no discernable prognostic or treatment imbalances between the two groups and the follow-up schedules were similar. The median observation period was 36 months. The incidence of osseous metastases was significantly lower in the clodronate group (11 (7%) versus 25 (17%) patients, p < 0.002). There was also an unexpected large reduction in the incidence of visceral metastases in the clodronate group (19 (13%) versus 42 (29%) patients, p < 0.001). These results have subsequently been updated41 and show similar results although the striking effect on extraskeletal visceral relapse seen in the earlier report is less and no longer statistically significant. The exciting findings of the Diel study must, however, be viewed in the light of a further trial which produced conflicting results. Saarto et al42 randomized 299 women with primary nodepositive breast cancer to oral clodronate 1600mg daily (n=149) or a control group (n=150). The median follow-up was 5 years. Treatment with clodronate in this study did not lead to a reduction in the development of bone metastases (29 (19%) v 24 (16%) patients, p=0.27 for the clodronate and control groups respectively). Additionally the development of non-skeletal recurrence was significantly higher in the clodronate group (60 (40%) versus 36 (24%) patients, p = .0007) and, most importantly, the overall five year survival was significantly lower in the clodronate group (70% versus 83%, p = .009). It is possible that there were some prognostic imbalances favoring the control group but the safest assumption is to consider that the Diel and Saarto studies cancel each other out and probably reflect the usual heterogeneity of results seen in relatively small adjuvant studies. In patients with locally advanced breast cancer (n=33) or with extraskeletal metastases (n=91) no preventive efficacy of supportive oral pamidronate treatment (300 mg daily) could be demonstrated with respect to the incidence of bone metastases when compared to a control group with freely allowed tumor therapy. Radiologic evidence of bone metastases was AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 11 ® Zometa (Zoledronic Acid) / CZOL446G DE08 detected in 36% of patients on pamidronate and in 27% of patients in the control group.43 Interpretation of these results has to consider that an oral dose of 300 mg daily pamidronate seems to be too low to effectively reduce the incidence of bone metastases since oral bioavailability is only 1%. Furthermore, breast cancer patients of the pamidronate study were in an advanced cancer stage. Therefore, differences in study populations might have contributed to controversial results of the oral bisphosphonate prevention studies. The zoledronic acid preclinical and preliminary clinical data favor this new bisphosphonate over clodronate and pamidronate, and intravenous infusion therapy with zoledronic acid appears promising in the prevention of bone metastases and shall therefore be investigated in the present study. This protocol contains a substudy measuring bone mineral density in men with high risk prostate cancer starting with hormone therapy. In a recently completed trial (Zometa Protocol 705), Zometa®4 mg given as a 15-minute intravenous infusion every 12 weeks for one year (5 treatments) significantly increased lumbar spine and hip bone mineral density compared to placebo in 106 men with prostate cancer who were beginning androgen deprivation therapy.44 Men who received the Zometa® infusions had an increase in lumbar spine bone mineral density (BMD) of 5.16% (p<0.001 vs. placebo). BMD increased by 1.08% in the total hip, 1.64% at the femoral neck, 2.37% at the trochanteric region, and 3.39% at Ward’s triangle, and decreased by 2.62%, 1.85%, 2.45%, and 0.58%, respectively, at these sites in the placebo group (p<0.001 for difference between zoledronic acid and placebo at the total hip, femoral neck, and trochanteric regions, respectively). It is expected that in the present study Zometa® in addition to the prevention of bone metastases will show its potential in preventing hormone therapy induced bone loss. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 12 ® Zometa (Zoledronic Acid) / CZOL446G DE08 2. Study objectives It is the aim of this prospective, randomized, open label, two-arm, parallel group clinical study to assess the efficacy and tolerability of 4 mg zoledronic acid every 3 months in high risk prostate cancer patients as compared to control in preventing bone metastases. Primary study objective: The primary objective of this study is to show superiority of zoledronic acid as compared to control in the proportion of patients with at least one bone metastasis after 48 months of treatment. Bone metastases are assessed due to the occurrence of symptoms (i.e. pain) or PSA > 10 ng/ml. Assessment of bone metastases due to bone pain will be done by x-ray of the affected site(s). In case of PSA > 10 ng/ml a bone scan followed by x-ray of the sites showing high uptake of radioactive substance will be done to confirm metastases. After the treatment phase of 48 months all patients will receive a bone scan. Secondary study objectives are • • • • to evaluate the effect of zoledronic acid on the time to the first bone metastasis irrespective whether symptomatic or not to evaluate the effect of zoledronic acid on overall survival. to evaluate the effect of zoledronic acid on serum PSA doubling time to evaluate the effect of zoledronic acid on bone mineral density at two years after randomization in patients receiving hormonal therapy at study entry (substudy in selected centers) to evaluate the effect of zoledronic acid on biochemical markers of bone turnover (selected centers only) • 3. 3.1. Investigational plan Overall study design This is a prospective, multi-center, randomized, open-label, two-arm study in parallel groups. 3.2. Discussion of design Patients will receive intravenous study treatment (zoledronic acid) for a total duration of 48 months or no treatment (control group). After the development of bone metastases in the control group, it is recommended to treat all patients with 4 mg zoledronic acid. At an assignment ratio of 1:1 patients will be randomized within each center. Randomization will be stratified according to the individual prior local treatment (non-curative versus curative) and hormone therapy (hormone therapy starting within 6 months prior to study entry or together with study medication versus no hormone therapy). The study is open label because it would be impractical and not ethical to propose a blinding method that would require 3-monthly intravenous infusion of a placebo for a total duration of 48 months in patients randomized to the control arm. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 13 ® Zometa (Zoledronic Acid) / CZOL446G DE08 The following scheme illustrates this design: Study Design 48 months treatment period N = 650 Prostate no history Cancer of bone disease R In case of bone metastasis treatment with a bisphosphonate every 4 weeks is recommended (e.g. Zometa 3.3. Study population 3.3.1. PATIENT POPULATION Patient population will consist of hormone-naïve male patients with non-metastatic prostate cancer. 3.3.2. INCLUSION AND EXCLUSION CRITERIA Inclusion criteria • • Male patients aged 18+, ECOG = 0 (Karnofsky performance status > 90). M0 prostate cancer patients who previously received local curative treatment (e.g. surgery, radiotherapy) or no local curative treatment. Duration between local curative treatment and starting of the study drug must not be longer than 6 months. At least one of the following conditions must be present: Gleason Score 8-10 pN+ PSA ≥ 20 at diagnosis • • Patients receiving androgen deprivation by orchiectomy or administration of GnRH analogue ± anti-androgens or no androgen deprivation. Hormone therapy regimen will depend on standard medical management of prostate cancer patients, i.e. when corresponding to standard medical management, patients on hormone treatment at study entry can later be withdrawn and patients not on hormone treatment at study entry can later start with androgen deprivation. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 14 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Intermittent hormone treatment is allowed when corresponding to standard medical management. Patients should not be under hormonal ablation for longer than 6 months before the first study drug infusion. Neoadjuvant androgen deprivation is allowed as long as the duration between start of androgen deprivation and start of study drug is no longer than 6 months. • • • Hormone naïve patients starting androgen deprivation by orchiectomy or administration of GnRH analogue ± anti-androgens. Life expectancy of > 6 months Signed informed consent prior to initiation of any study procedure. Exclusion criteria • • • • • • • Patients with known visceral metastasis or bone metastases in bone scan. prior treatment with bisphosphonates chemotherapy to treat prostate carcinoma Anti-androgen monotherapy is not allowed. use of other investigational drugs (drugs not marketed for any indication) within 6 months before start of study history of noncompliance to medical regimens and patients who are considered potentially unreliable or incapable of giving informed consent as judged by the investigator. Patients with abnormal renal function as evidenced by either a serum creatinine determination 1.5 x or greater above the upper limit of normal or by a calculated creatinine clearance of 60 ml/minute or less. If one of these two criteria is fulfilled the patient has to be excluded. Serum creatinine > 3 mg/dl (265 µmol/L) history of other malignant neoplasm within previous five years with exception of nonmelanomatous skin cancer which has been satisfactorily treated other known concurrent, severe medical disorder jeopardizing the life of the patient in the immediate future (myocardial infarction in previous six months, angina pectoris despite treatment, uncontrolled severe arterial hypertension, progressive cardiac or respiratory failure) • • • 3.3.3 RANDOMIZATION All patients meeting the study entry criteria will be randomly assigned in a ratio of 1:1 to receive either: • Zometa® 4 mg in 100 ml of calcium-free solution (e.g. 0.9% sodium chloride or 5% glucose) administered intravenously as a 15-minute infusion every 3 months for a treatment period of 48 months and a supplement of calcium 500 mg and 400-500 I.U. vitamin D a supplement of calcium 500 mg and 400-500 I.U. vitamin D alone or • AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 15 ® Zometa (Zoledronic Acid) / CZOL446G DE08 The Central Data Management Center will prepare randomization lists stratified by center and prior local treatment (non-curative versus curative) and hormone therapy (hormone therapy starting within 6 months prior to study entry or together with study medication versus no hormone therapy). A validated system that automates the random assignment of treatment groups to randomization numbers will be used. Randomization will be performed by fax. 3.3.4. INTERRUPTION OR DISCONTINUATION OF TREATMENT It will be documented whether or not each patient completed the clinical study. If for any patient either study treatment or observations were discontinued the reason will be recorded. Patients who fail to receive an infusion of trial medication (e.g., in case of an intercurrent illness) for a period exceeding 12 weeks do not have to be permanently discontinued from study medication. These patients may be restarted on study medication as soon as clinically advisable at the discretion of the investigator. The reason for postponement, and the date when the postponed infusion of Zometa® was administered, will be recorded in the CRF. In addition, if a treating physician determines that a study patient’s medical condition (e.g. osteoporosis) requires the use of an inhibitor of osteoclastic bone resorption, then the subject is to be discontinued from the whole study. Patients have to be withdrawn from the study as soon as the first bone metastasis (irrespective whether symptomatic or not) is confirmed by x-ray. Progression of malignant disease in nonskeletal sites should not be seen as a reason that a patient discontinues trial. During ongoing monitoring of the phase II trials with Zometa® the safety monitoring boards noted a possibly higher frequency of increases in serum creatinine and AEs associated with the use of Zometa® and recommended that serum creatinine should be measured prior to each dose of study drug. A two weeks window for checking creatinine is allowed prior to the next dose. The local serum creatinine result must be evaluated according to the following criteria: • If the patient’s baseline serum creatinine was < 1.4 mg/dl at the time of study entry, an increase of 0.5 mg/dl or more will require the delaying of the dose of study drug until the patient’s serum creatinine returns to no higher than 10% above the baseline value. • If the patient’s baseline serum creatinine was > 1.4 mg/dl, then any increase in the serum creatinine of 1.0 mg/dl or more will require that the study drug be delayed until the patients serum creatinine returns to no higher than 10% above the baseline value. • Any doubling of the baseline serum creatinine value will require that the study drug be delayed until the patient’s serum creatinine returns to no higher than 10% above the baseline value. • Should the study drug need to be delayed, the patient’s serum creatinine will continue to be followed at intervals according to the Investigator’s clinical , but at least at the regularly scheduled study visits until full recovery (i.e., return to no higher than 10% above the baseline value). Other study procedures should be followed according to the protocol schedule even if study drug continues to be held. As much information as possible should be collected regarding withdrawals. Reasons that a patient may discontinue participation in a clinical study are considered to constitute one of the following: AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 16 ® Zometa (Zoledronic Acid) / CZOL446G DE08 1. 2. 3. 4. 5. 6. 7. 8. 9. clinically relevant adverse event(s) clinically relevant abnormal laboratory value(s) clinically relevant abnormal test procedure result(s) subject’s condition no longer requires study treatment protocol violation subject withdrew consent administrative problems death Lost to follow-up 3.4. 3.4.1. Treatments INVESTIGATIONAL THERAPY AND REFERENCE THERAPY All patients will be treated with hormone therapy or androgen deprivation by orchiectomy or administration of GnRH analogue ± anti-androgens, by the choice of the investigator. Antiandrogen monotherapy is not allowed. According to randomization, patients will receive: Group A: Zometa® 4 mg in 100 ml of calcium-free solution (e.g. 0.9% sodium chloride or 5% glucose) administered intravenously as a 15-minute infusion every 3 months for a treatment period of 48 months No investigational treatment or Group B: Patients receive study drug (group A) or observation (group B) until month 48 or until first documented evidence of bone metastases, whichever is shorter. After the development of bone metastases, patients should receive bisphosphonates according to local treatment guidelines (e.g. Zometa every 4 weeks). Zometa® (zoledronic acid) will be provided in plastic vials containing 4 mg zoledronic acid in 5 mL concentrate solution for infusion. Each zoledronic acid plastic vial contains 4 mg zoledronic acid (anhydrous). The zoledronic acid 4 mg/5 mL concentrate solution is not for direct infusion and has to be further diluted prior to the use. Prior to administration, the 5ml of the concentrate solution must be diluted with 100 mL calcium-free infusion solution (0.9% sodium chloride solution or 5% glucose solution). The appropriate volume of the reconstituted zoledronic acid solution is 105 ml. The necessary infusion bags/bottles containing either 100ml calcium free 0.9% sodium chloride or 5 % dextrose solution have to be used for the set up of the infusion and will be provided by the study center. Zometa® (zoledronic acid) 4 mg/5 mL concentrate solution must not be mixed with calciumcontaining solutions such as Ringer’s solution. If not used immediately after dilution with infusion media, for microbiological integrity, the final solution must be placed in a refrigerator with a temperature between 2-8 0C. The refrigerated solution should then be equilibrated to room temperature prior to administration The total time between dilution, storage in a refrigerator and end of administration of the infusion must not exceed 24 hours. Reconstituted zoledronic acid solutions must be administered in no less than a 15-minute intravenous infusion in a line separate from all other drugs. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 17 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Patients must be evaluated prior to and following the administration of the zoledronic acid infusion to ensure that they are adequately hydrated. Since no data are available on the compatibility of zoledronic acid with other intravenously administered substances, zoledronic acid must not be mixed with other medications or substances and should always be given through a separate infusion line. Stability studies using diluted zoledronic acid 4 mg/5 mL concentrate solutions in glass bottles and infusion bags made from polyvinylchloride (PVC), polypropylene (PP) and polyethylene (PE) prefilled with 0.9% sodium chloride solution or 5% dextrose solution and with infusion lines made from PVC and PE showed no incompatibility. Medication Total # Vials Calcium-free Infusion solution Volume Added 100 mL Total Volume Infused 105 mL Zoledronic Acid 4 mg I.V. every 3 months 1 vial of 4.0 mg/vial in 5 ml concentrate solution Serum creatinine is to be measured prior to each dose of study drug. The local laboratory serum creatinine result must be available prior to administration of the dose of study drug but a two weeks window for checking creatinine is allowed prior to the next dose (see section 3.3.4 of this protocol). Study drug supplies will be shipped to each study center. Drug will be packaged in an openlabel fashion. Medication labels will comply with the local legal requirements in each country. Medication labels will supply no information about the subject. The storage conditions for study drug will be described on the medication label and will be maintained at all times and expiration periods will be strictly complied with. The clinical investigator will keep the clinical supplies in a secure place and protected against access by unauthorized persons. The study drug is to be used for the study outlined in this protocol, only. Any other usage is explicitly forbidden. The clinical investigator also undertakes to operate a complete system of drug accounting to record dispensing and return of study drugs. The per-patient consumption must be recorded on the study drug administration CRF and on a drug dispensing log. Clinical supplies that are not required must be stored at the study center, recorded and returned at study closure. The study center will confirm the receipt and complete return of clinical supplies. 3.4.2. TREATMENT ASSIGNMENT After a screening period of up to 4 weeks all patients who fulfill the admission criteria will start a treatment according to randomization. Prior to any screening the patient has to have signed the informed consent. 3.4.3. BLINDING This is an open-label trial; no blinding will be performed. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 18 ® Zometa (Zoledronic Acid) / CZOL446G DE08 3.4.4. TREATMENT COMPLIANCE Study drug is administered as intravenous infusions by a physician. All study infusions will be recorded by visit and date on the relevant CRF. The number of Zometa® (zoledronic acid) vials will be counted and compared with pharmacist's/investigator's records. Drug accountability will be noted by the field monitor during site visits and at the completion of the trial. Treatment compliance will be displayed as number of vials administered versus prescribed. If patients do not attend protocol examinations or infusion dates underlying reasons have to be elucidated as far as possible. 3.4.5. CONCOMITANT THERAPY Calcium and Vitamin D supplementation: Patients have to take 500 mg of calcium supplements and a multi-vitamin tablet (containing 400-500 IU of vitamin D), orally, once daily, for the duration of administration of study medication. Patients should begin taking calcium supplements and multi-vitamin tablets prior to the administration of study medication and should receive at least one dose prior to the first administration of study medication. Patients should be instructed to take one dose of calcium supplements (500 mg) daily in with food. The daily dose of multi-vitamin tablets (containing 400-500 IU of vitamin D) should be taken with food. The formulation of the tablets is at the discretion of the investigator. Combination tablets can be used as long as the tablet does not contain any mineral that might affect absorption of calcium or vitamin D and may be taken either in the morning or in the evening with food. These supplements will be discontinued if the patient develops HCM and when the patient discontinues study medication. Allowed concomitant therapy: Depending on individual findings the concomitant treatment options listed below may be administered: Antineoplastic therapy is allowed in case of metastases except bone metastases (patients with bone metastases have to be withdrawn from the study). Hormonal manipulations may be given as follows: Withdrawal of non-steroidal anti-androgens, if applicable, is considered as a hormonal manipulation. Ketoconazole or aminoglutethamide and prednisone; DES or other estrogens may be given. Neoadjuvant hormone therapy may be given as long as the duration between start of neoadjuvant androgen deprivation and first Zometa treatment is no longer than 6 months. Zometa treatment is started at the same time. Standard radiation therapy to treat non-skeletal tumor sites is allowed (patients with skeletal tumor sites have to be withdrawn from the study). .Prohibited concomitant therapy: • Treatment with bisphosphonates other than the study medication is prohibited. If such treatment is deemed necessary, the subject should be withdrawn from the study. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 19 ® Zometa (Zoledronic Acid) / CZOL446G DE08 • Anti-androgen monotherapy is not allowed. Therapy of concomitant diseases Whenever possible, necessary treatment of concomitant diseases should not be changed during the study. Any concomitant treatment given to the patient during the entire study has to be recorded on the CRF. 3.4.6. TREATMENT OF HCM OCCURRING DURING THE COURSE OF THE TRIAL HCM occurring during the course of the trial is defined as a corrected serum calcium ≥ 12 mg/dL (3.00 mmol/L), or a lower level of hypercalcemia which is symptomatic and which requires active treatment other than rehydration. Patients developing HCM should be treated as follows: if it is known that HCM occurred > 14 days after an infusion of trial drug, patients should receive their next infusion of study medication as treatment for the episode of HCM even if this means giving the infusion earlier than scheduled. These patients should remain on study following this episode provided that there is no recurrence of HCM. However, the patient is to be discontinued from trial treatment if HCM continues or recurs. Patients should immediately be discontinued from trial treatment if HCM to the knowledge of the investigator develops ≤ 14 days after an infusion of study medication. The episode of HCM should then be treated at the discretion of the physician. After the administration of study medication, episodes of HCM should be recorded as adverse events on the Adverse Events CRF page. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 20 ® Zometa (Zoledronic Acid) / CZOL446G DE08 3.5. Visit schedule and assessments 3.5.1. VISIT SCHEDULE Table 1: Evaluation schedule Screen -ing Week -4-0 Visits Inclusion / exclusion criteria, informed consent Study drug administration Medical history, a pretreatment Bone Scan X-ray/CT/MRI Bone metastases Serum testosterone Serum PSA Serum Creatinine only treatment arm Biochemistry Hematology c Study period Infusions with zoledronic acid every 3 months Months 0 2 3 3 6 4 9 5 12 6 15 7 18 8 21 9 24 10 27 11 30 12 33 13 36 14 39 15 42 16 45 17 48 18 Follow -up 1 x x x x x x x x x x x x x x x x x x x In case of PSA > 10ng/ml b x In case of symptoms (e.g. bone pain) or bone metastases in bone scan appropriate radiologic confirmation of bone metastases (X-rays, MRI or CT) are to be done x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 3-monthly before application of zoledronic acid, only treatment arm x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x Physical d examination Adverse events Concomitant medication DXA Scan e Continously Continously x x x h x x x x x x x x x x X x x x x x x x x x g Markers of bone f turnover Survival Study phase completion a b c d e f g h Continously Includes prior treatment, staging etc. if no bone metastases are diagnosed bone scan will be repeated after 12 months or when symptoms (i.e. bone pain) occur More frequently if chemotherapy is used Includes questioning patient regarding symptoms of their prostate cancer and ECOG Performance Status. Selected patients/centers only Selected patients/centers only Until last patient finished visit 15 samples are to be taken before administration of study drug Visit 1 (-4/-0 weeks) Baseline 1. 2. Patient signs informed consent A complete physical examination and medical history including stage of prostate cancer at initial diagnosis (see Appendix) will be performed. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 21 ® Zometa (Zoledronic Acid) / CZOL446G DE08 3. 4. 5. 6. Fulfillment of in- and exclusion criteria will be checked. Concomitant medications/therapies will be recorded. Antineoplastic history and medications will be recorded. If necessary the diagnosis of malignant disease will be confirmed and tumor measurements will be performed. If clinically required, appropriate radiologic studies are to be done. The presence of metastatic bone disease will be excluded. Within 3 months prior to start of study drug treatment, a radionuclide bone scan will be obtained. Abnormal findings have to be reexamined by appropriate radiologic methods (X-ray, CT, MRT) to exclude bone metastasis. ECOG Performance Status (Appendix) will be recorded. Venous blood will be drawn for serum chemistry, CBC, serum testosterone, creatinine and PSA. 7. 8. 9. 10. Venous blood serum for bone TRAP, skeletal alkaline phosphatase, osteoprotegerin, Ntelopeptide and creatinine will be collected and frozen at –20oC (selected centers only). 11. Bone mineral density measurements (by DXA scan) will be performed at selected centers. Visit 2 – Visit 17 1. Venous blood will be drawn for serum chemistry, CBC, and PSA. Venous blood needs to be drawn for creatinine analysis prior to dosing. See the required serum creatinine criteria which must be satisfied prior to dosing, as described in Protocol section 3.3.4. 2. Study drug administration. 3. Venous blood serum for parameters of bone turnover bone TRAP, skeletal alkaline phosphatase, osteoprotegerin, N-telopeptide and creatinine will be collected and frozen at –20°C (selected centers only). 4. Adverse events since the previous visit will be recorded. Adverse events are to be recorded on the Adverse Event CRF log if they occurred after administration of the study drug on Visit 2. Adverse events between Visit 1 and Visit 2 will be recorded on the Relevant Medical History/Current Medical Condition CRF (Visit 1) if they occurred prior to administration of the study drug. 5. Concomitant medications/therapies since the previous visit will be recorded. 6. Antineoplastic medications since the previous visit will be recorded. 7. Interim physical examinations will be performed, ECOG Performance Status will be recorded (see appendix). 8. Bone metastases since the previous visit will be recorded. Additional examinations: Visit 6, 10, 14 Venous blood will be drawn for serum testosterone. Visit 10 Bone mineral density (by DXA scan) will be performed at selected sites. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 22 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Visit 18 (final visit) 1. Venous blood will be drawn for serum chemistry, CBC, serum testosterone and PSA. 2. A complete physical examination will be performed, ECOG Performance Status will be recorded (see appendix). 3. Adverse events since the previous visit will be recorded. 4. Concomitant medications/therapies since the previous visit will be recorded. 5. Antineoplastic medications since the previous visit will be recorded. 6. A radionuclide bone scan will be obtained. Abnormal findings have to be reexamined by appropriate radiologic methods (X-ray, CT, MRT) to confirm bone metastases. 7. Venous blood serum for parameters of bone turnover bone TRAP, skeletal alkaline phosphatase, osteoprotegerin, N-telopeptide will be collected and frozen at –20°C (selected centers only). 8. Bone metastases since the last visit will be recorded. 9. Bone mineral density (by DXA scan) will be performed at selected sites. 10. A study completion page will be completed 3.5.2. EFFICACY ASSESSMENTS The following efficacy parameters will be measured and recorded: Primary efficacy variable: • Number of patients who develop at least one bone metastasis after 48 months of treatment Bone metastases are assessed due to the occurrence of symptoms (i.e. pain) or PSA > 10 ng/ml. Assessment of bone metastases due to bone pain will be done by x-ray of the affected site(s). In case of PSA > 10 ng/ml a bone scan followed by x-ray of the sites showing high uptake of radioactive substance will be done to confirm metastases. After the treatment phase of 48 months all patients will receive a bone scan. Secondary efficacy variables: • Effect of zoledronic acid on the time to first bone metastasis irrespective whether symptomatic or not Time to first bone metastasis will be defined as time from visit 2 until confirmed diagnosis of bone metastasis. • Overall survival Survival will be assessed until the last patient has finished visit 18 and is defined as time from visit 2 until death. • Serum PSA doubling time PSA doubling time is defined as the time until the PSA level is increased by 50% as compared to baseline, whereby baseline is defined as the first point in time when the PSA level is above zero, i.e. the first time the PSA level shows an exponential increase. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 23 ® Zometa (Zoledronic Acid) / CZOL446G DE08 • Bone mineral density A Bone mineral density (BMD) measurement by dual energy x-ray absorptiometry (DXA) will be performed at Visit 1 and repeated at Visit 10 as well as at last visit (Visit 18, month 48) in patients receiving hormone therapy at study entry. Primary scanning site is the lumbar spine (L1 to L4) and the secondary scanning site is the total hip (including femoral neck, trochanteric region and Ward’s triangle, femoral shaft). DXA will be assessed in selected centers in selected patients only. • Parameter of bone turnover (measured in treatment and control group) Prostate cancer is the most frequent malignancy in men and is characterized by the occurrence of skeletal metastases in about 65-75% of patients with advanced disease. Bone metastases alter the balance between bone formation and bone resorption by influencing the involved bone cells, the osteoblasts and osteoclasts, through a local release of cytokines and growth factors. To detect and monitor this metastatic bone involvement, bone scintigraphy is the widely applied standard method. Bone turnover markers that reflect either bone formation in consequence of osteoblast proliferation and analytes indicating bone resorption as the opposite bone remodeling activity have been recommended as tools in the assessment of bone metastasis in prostate cancer. The balance between osteoblastic and osteoclastic activity in bone is essentially determined by osteoclastogenesis. Osteoclastogenesis is regulated by three proteins, namely receptor activator of nuclear factor-κB (RANK), its ligand RANKL, and osteoprotegerin. Osteoprotegerin and RANKL as osteoclastogenesis marker could be, in addition to bone formation and resorption markers, potential biomarkers to detect bone metastases and to monitor the behavior of metastases during therapy especially bisphosphonates. The aims of this substudy is: 1. to measure serum markers of bone formation, bone resorption, and osteoclastogenesis as noninvasive, easy-to-determine analytes of bone metastases in the same serum samples 2. to evaluate the ability of the serum markers to detect an early progression of bone metastases 3. to verify whether bone markers could be used for predicting prognosis in PCa patients 4. to use bone markers as indicators for the changed bone turnover under the treatment with bisphosphonates (zoledronic acid) Patients and samples Patients in the treatment and the control group should be included. Serum samples (10 ml) should be taken from fasting patients before 8.30 in the morning by phlebotomy puncture at the following regimen: Zero serum sample before the first Zometa application (visit 2) Every three month, during the visits (3., 4., 5., … ) Blood samples should be collected in evacuated Monovette plastic tubes for serum and will be centrifuged at 2000g for 10 min at 4°C within 2 h after venipuncture. The supernatants will be frozen at –20 C (or better at –80°C) and not thawed before analysis. The samples should not be stored at –20 °C longer than 8 weeks, otherwise they should be transferred to a –80 °C refrigerator. Bone formation markers The following analytes should be measured: • Total alkaline phosphatase (tALP; enzyme activity measurement, e.g. Roche Diagnostics) • Bone-specific alkaline phosphatase (bALP; Beckman-Coulter) AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 24 ® Zometa (Zoledronic Acid) / CZOL446G DE08 • Procollagen I aminoterminal propeptide P1NP (total P1NP-Assay; Roche Diagnostics) Bone resorption markers The following analytes should be measured: • Bone sialoprotein (BSP; Immunodiagnostik) • β-cross-linked C-terminal telopeptides of type I collagen (CTX; Crosslaps, Roche) • The active isoform 5b of the tartrat-resistant acid phosphatase47, 48 (TRAP, Metac, Wedel) Osteoclastogenesis markers • Osteoprotegerin45, 46 (OPG; Immundiagnostik, Bensheim, Germany) which equally detects both monomeric and homodimeric forms of OPG The parameters of bone turnover will be analyzed in a central laboratory: PD Dr. Michael Lein Department of Urology Charité University Hospital Humboldt University Berlin Schumannstrasse 20/21 10117 Berlin Germany michael.lein@charite.de phone: +49 30 450 515052 fax: +49 30 450 515915 Healthy bone is remodeled continuously, requiring a balance of bone formation and bone resorption. Bone metastases in prostate cancer patients show distinctive osteoblastic reactions. Thus, analytes identified during osteoblast proliferation (e.g., skeletal alkaline phosphatase; sALP) have been reported to be useful serum markers. The balance between osteoblastic and osteoclastic activity in bone is essentially influenced by osteoclastogenesis. This process is regulated by the three proteins RANK (receptor activator of nuclear factor-KB; expressed on osteoclast precursor cells), its ligand (RANKL; expressed on the surface of pre-osteoblastic and stromal cells) and osteprotegerin. The interaction of RANKL with RANK stimulates the differentiation of osteoclasts whereas osteprotegerin blocks this process by functioning as a decoy receptor for RANKL. This novel cytokine system apparently plays an important role in the establishment of bone metastases in PCa patients. Collagen type I is the most abundant protein in bone. Increased production of collagen formation and collagen resorption markers have been observed in patients with bone metastases. Following markers of bone turnover are suggested to be analyzed in selected centers only: 1. Skeletal alkaline phosphatase (sALP) - Bone isoenzyme of alkaline phosphatase - is consistent with the osteoblastic reactions seen in skeletal metastases - reflect osteoblast proliferation - unspecific bone formation marker - (possible determination by the Tandem-MP Ostase Immunoenzymetric Assay, Beckman Coulter) 2. Osteoprotegerin - it has recently been found to be overexpressed in bone metastases45 AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 25 ® Zometa (Zoledronic Acid) / CZOL446G DE08 - - overexpression in such patients could indirectly favor osteoblastic reactions by inhibiting osteoclasteogenesis and might explain the so far unknown reason for this typical kind of bone lesion in PCa patients increased serum osteoprotegerin could be a marker of bone metastatic spread in prostate cancer patients46 (possible determination by the ELISA of Immundiagnostik, Germany) 3. N-terminal propeptide of type I procollagen - Measures type I collagen formation in bone metastases - (possible determination by the Orion diagnostica’s UniQ test, Matritech, Germany) 4. C-terminal telopeptide of type I collagen - Specifically reflects matrix metalloproteinase-mediated pathological degradation of bone collagen - Clearly increased in response to skeletal metastatisation of breast, prostate and lung cancer - Can be used for early detection of bone metastases of cancer - (possible determination by the Orion diagnostica’s UniQ test, Matritech, Germany) 5. Cross-linked N-telopeptides of type I collagen (NTx) - represent a osteoblastic and osteoclastic marker - higher levels of NTx could be demonstrated in metastatic prostate cancer patients47 - (possible determination by the Osteomark NTx Assay, Ostex International) 6. Tartarte-resistant acid phosphatase 5b (TRAP) - osteoclasts release both isoformes (5a and 5b) of TRAP - is a possible new bone resorption marker - is a marker of osteoclast activity48, 49 - (possible determination by the Bone TRAP Assay, Medac Diagnostika, Wedel) Urine chemistry: After rising in the morning, the initial urine sample passed by the patient is discarded. The subsequent ‘second void’ urine is collected. The patient need not remain fasting but to reduce diurnal variation, the sample should be collected in mid-morning whenever possible. Blood chemistry: 5 ml blood will be taken from fasting patients before 8.30 in the morning. The parameters of bone turnover will be analyzed in a central laboratory. 3.5.3. SAFETY ASSESSMENTS Safety assessments will consist of regular monitoring and recording of the following parameters: • • Blood biochemistry: serum creatinine (to be evaluated prior to each administration of Zometa® (zoledronic acid)) Adverse events / serious adverse events (including new or, compared to baseline, worsened significant findings in physical examination or routine laboratory assessments). The NCI Common Toxicity Criteria (CTC) (National Cancer Institute, 1999 http://ctep.cancer.gov/forms/CTCManual_v4_10-4-99.pdf) will be used for grading the severity of adverse events, except for assessment of cardiac toxicity for which the New York Heart Association (NYHA) criteria is suggested). AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 26 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Laboratory evaluations A local laboratory will be used to perform the measurements. Blood should be drawn prior to every Zometa® (zoledronic acid) infusion for measurement of serum creatinine. The result of the local laboratory must be received before any infusion of Zometa®. Hematology WBC, RBC, thrombocytes, hemoglobin. Hematology results will be stored in the patient file. Only values beyond the normal values will be documented in the AE-pages of the CRF. Blood chemistry (“Complete Biochemistry”) Serum creatinine, bilirubin, calcium, serum albumin, bone alkaline phosphatase, alkaline phosphatase will be analyzed and documented in the CRF if clinically relevant. Serum sodium, potassium, SGPT, SGOT will be analyzed, values will be stored in the patient file and documented in the AE-pages of the CRF if values are beyond normal values. Physical examination A complete physical examination including general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, chest, lungs, heart, abdomen (liver, spleen), back, external genitalia, pelvis, rectum, lymph nodes, extremities and nervous system (including a cerebellar examination) will be performed. The physical examination information will not be collected in the CRF. Documentation of the physical examination must be included among the source documentation at the site. Significant findings occurring after the start of study drug which meet the definition of an adverse event must be recorded on the Adverse Event CRF page. Interim physical examinations will be performed and will include general appearance and follow-up of previous findings. Adverse events Information about all adverse events (AEs), whether volunteered by the patient, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, will be collected and recorded on the Adverse Event Case Report Form and followed as appropriate. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study treatment, even if the event is not considered to be treatmentrelated. Disease progress is not an AE. Medical conditions/diseases present before starting study treatment are only considered adverse events if they worsen after starting study treatment. Clinical events occurring before starting study treatment but after signing the informed consent form are recorded on the Medical History/Current Medical Conditions Case Report Form only if the patient receives study treatment. Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or symptoms or require therapy, when they are recorded on the Adverse Events Case Report Form under the signs, symptoms or diagnosis associated with them. As far as possible, each adverse event will also be described by: 1. 2. 3. 4. its duration (start and end dates), the severity grade (grade 1 - 4), its relationship to the study drug (suspected / not suspected), the action(s) taken AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 27 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Serious adverse events Information about all serious adverse events will be collected and recorded on the Serious Adverse Event Report Form. To ensure patient safety each serious adverse event must also be reported to Novartis within 24 hours of learning of its occurrence. A serious adverse event (SAE) is defined in general as an untoward (unfavorable) event which: 1. is fatal or life-threatening, 2. required or prolonged hospitalization, 3. was significantly or permanently disabling or incapacitating, 4. constitutes a congenital anomaly or a birth defect, 5. may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above. Events not considered to be serious adverse events are hospitalizations occurring under the following circumstances: were planned before entry into the clinical study; are for elective treatment of a condition unrelated to the studied indication or its treatment; occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the criteria above); are part of the normal treatment or monitoring of the studied indication and not associated with any deterioration in condition. Any serious adverse event occurring in a patient after providing informed consent and until 4 weeks after stopping the trial must be reported. The period after discontinuing study drug may be extended if there is a strong suspicion that the drug has not yet been eliminated. All serious adverse events must also be reported for the period in which the study protocol interferes with the standard medical treatment given to a patient (e.g. treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant medication). 4. 4.1. 4.2. Protocol amendments, other changes in study conduct Protocol amendments Other changes in study conduct Changes to the protocol will be made in the form of an amendment. Changes in study conduct are not permitted. Any unforeseen changes in study conduct will be recorded in the clinical study report. 5. Data management In this study data management will be performed centrally. The Investigators will enter the information required by the protocol onto appropriate Case Report Forms (CRFs) prepared by the Data Center. Each participating Cooperative Group or single participating institutions will be responsible for ensuring data quality. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 28 ® Zometa (Zoledronic Acid) / CZOL446G DE08 5.1. Data collection Investigators must enter the information required by the protocol onto the Case Report Forms (CRFs) that are printed on 3-part, no carbon required (NCR) paper. Monitors will review the CRFs for completeness and accuracy, and instruct site personnel to make any required corrections or additions. The CRFs are forwarded to the Data Center by field monitors, one copy being retained at the investigational site and one copy being a working copy for the monitor. Once the CRFs are received by the Data Center, their receipt is recorded and they are reviewed prior to data entry. The CRFs will be forwarded to the responsible medical data management staff for data entry. 5.2. Database management and quality control Data items from the CRFs are entered into the study database using double data entry with verification upon second entry. Text items (e.g. comments) are entered once and checked manually against the CRFs. Subsequently, the information entered into the database is systematically checked by the Data Manager, using error messages printed from validation programs and database listings. Obvious errors will be corrected by the data management personnel. Other errors or omissions will be entered on Data Query Forms, which will be returned to the investigational site for resolution. A copy of the signed Data Query Form is to be kept with the CRFs, and once the original is received at the Data Center the resolutions will be entered into the database. If necessary trial specific handling for DQF resolution and archiving will be defined in a separate document. Concomitant medications entered into the database will be coded using WHO-DRL. Coexistent diseases and adverse events will be coded using MedDRA™ (Medical Dictionary for Regulatory Activities™. When the database has been declared to be complete and accurate, the database will be locked. Any changes to the database after that time can only be made by joint agreement between the Principal Investigator, the Study Statistician and the Data Manager. 6. 6.1. Statistical methods Statistical methods to be employed This is a randomized, open-label, parallel-group clinical study to show superiority of Zometa in the proportion of patients with at least one bone metastasis in high risk prostate cancer patients as compared to a control group. Data of all centers will be pooled to reach an adequate sample size. Data will be summarized with respect to demographic and baseline characteristics, efficacy observations and measurements as well as safety observations and measurements. If it deem to be useful, summaries will be done in addition for each stratum separately. Number of valid observations and summary statistics (mean, standard deviation, median, maximum, minimum) will be presented for continuous variables. Absolute and relative frequencies will be tabulated for categorical data. In addition to the p-value for the testing procedure the corresponding confidence intervals will be computed. The comparison will be done on the two-sided 5%level. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 29 ® Zometa (Zoledronic Acid) / CZOL446G DE08 6.1.1. POPULATIONS Safety and tolerability analyses will be performed on the safety sample which comprises all patients who received at least one dose of study medication. Analysis of bone metastases (primary parameter) will be performed for the intent-to-treat population which contains all patients of the safety population for whom the status concerning bone metastases can be determined. This population will also be used for analyzing the secondary parameters. In addition analyses will be performed for the per-protocol population which comprises all intent-to-treat patients who did not show major deviations from the protocol procedures that may have an impact on the study outcome. Criteria that are assumed to have such an impact will be defined before analysis in a blinded team. 6.1.2. BACKGROUND AND DEMOGRAPHIC CHARACTERISTICS Demographic and background information will be described using simple location and dispersion measures for continuous variables and relative and absolute frequencies for categorical variables. No formal statistical testing is planned. 6.1.3. STUDY MEDICATION The drug exposure will be summarized by the number of treatment days on study and the cumulative doses of study medication received. 6.1.4. CONCOMITANT THERAPY Concomitant therapies, i.e. any medication other than the study medication taken by a subject concurrently with the study medication during the treatment period, will be summarized by frequency tables. The frequency tables will summarize the number of subjects receiving concomitant therapy, classifying the concomitant medications according to the WHO-DRL preferred term. 6.1.5. EFFICACY EVALUATION 6.1.5.1. Primary efficacy variables The primary parameter is the proportion of patients who develop bone metastases during the study. The absolute and relative number of patients suffering from at least one metastasis will be presented by treatment as well as by treatment and stratum. The logit for developing at least one bone metastasis will be modeled using the logistic regression including treatment, country, prior local treatment, hormone therapy, Gleason score, PSA level at diagnosis and nodal status as prognostic factors (prior local treatment: non-curative vs. curative; hormone therapy: yes vs. no; Gleason score: <8 vs. ≥ 8; PSA-level at diagnosis: <20 vs. ≥ 20; nodal status: pN+ vs. pN-). For comparing treatment and control the likelihood ratio test will be performed. The odds and probabilities for bone metastases will be estimated as well as the odds ratio for the treated group relative to the control group including the two-sided 95%- confidence intervals. 6.1.5.2. Secondary efficacy variables Analysis of secondary parameters will be done in an explorative manner only. Test results will be interpreted only descriptively. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 30 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Time to first bone metastasis Time to first bone metastasis will be defined as time from first application of study medication (i.e. visit 2) until confirmed diagnosis of bone metastasis. Patients for whom no bone metastases were observed but who died due to prostate cancer will be handled as worst case, i.e. bone metastasis at day of death. Patients who died due to any other reason will be censored with day of death. Patients who are alive and did not develop a bone metastasis will be censored with the last available date. Time to first bone metastasis will be presented using the Kaplan-Meier curve for each treatment group. For testing and estimation of the treatment effect in terms of the HR Hazard Ratio (Zoledronat vs. control) - a Cox proportional hazard model will be fitted including treatment, country, prior local treatment, hormone therapy, Gleason score, PSA level at diagnosis and nodal status (prior local treatment: non-curative vs. curative; hormone therapy: yes vs no; Gleason score: <8 vs. ≥ 8; PSA-level at diagnosis: <20 vs. ≥ 20; nodal status: pN+ vs. pN-). The corresponding 2-sided confidence interval for the HR will be provided. The Wald test will be used for comparison of Zoledronat vs. control. Overall survival Survival time will be calculated as time from first application of study medication (i.e. visit 2) until death. Patients who are alive at the end of the study will be censored with last contact date. Overall survival will be presented using the Kaplan-Meier curve for each treatment group. For testing and estimation of the treatment effect in terms of the HR - Hazard Ratio (Zoledronat vs. control) - a Cox proportional hazard model will be fitted including treatment, country, prior local treatment, hormone therapy, Gleason score, PSA level at diagnosis and nodal status (prior local treatment: non-curative vs. curative; hormone therapy: yes vs no; Gleason score: <8 vs. ≥ 8; PSA-level at diagnosis: <20 vs. ≥ 20; nodal status: pN+ vs. pN-). The corresponding 2-sided confidence interval for the HR will be provided. The Wald test will be used for comparison of Zoledronat vs. control. Time to PSA doubling The PSA doubling time is defined as the time until the PSA level is increased by 50% as compared to baseline, whereby baseline is defined as the first point in time when the PSA level is above zero, i.e. the first time the PSA level shows an exponential increase. Because PSA will be assessed every three months only, the (theoretical) time at which the doubled PSA level would have been observed will be determined for each individual patient by fitting an exponential function. Using the log-transformation, the exponential function will be transferred into a linear function and for each patient a linear regression on the log-PSA-level reveal the time of doubled PSA. For both groups Kaplan-Meier curves will be performed for graphical presentation of time to PSA doubling. Comparisons will be performed using the logrank test. In addition the stratified logrank test will be performed to take into account prior treatment (curative vs. noncurative) and hormone therapy (yes vs no). Parameters of bone turnover Parameters of bone turnover will be measured at each visit in selected centers only. For each timepoint the percent change from baseline of these parameters will be compared between the treatment groups using the Wilcoxon rank sum test. Summary statistics will be AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 31 ® Zometa (Zoledronic Acid) / CZOL446G DE08 provided for the biochemical variables at each evaluation visit and the endpoint (the last measurement observed on study drug for each patient). As an explorative approach subgroup analyses will be performed for overall survival using parameters of bone turnover. Additionally, parameters of bone turnover will be evaluated with respect to their predictive value on survival using Cox proportional hazards regression model. Bone Mineral Density DXA will be assessed at baseline, at visit 10 and at visit 18 in selected centers only. For both visits an analysis of variance (ANCOVA) will be performed with factors treatment and type and of hormone therapy and including the covariate DXA at baseline. Adjusted (=LS-) means will be presented for the treatment contrast together with its confidence interval and p-value. 6.1.6. SAFETY EVALUATION The assessment of safety and tolerability will be based on the number of serum creatinine measurements that fall outside of pre-determined ranges and/or requires a delay in the administration of Zometa® (zoledronic acid) as well as on the frequency of adverse events and serious adverse events. Serum creatinine Serum creatinine as well as other laboratory data will be summarized by presenting for each treatment group shift tables, by presenting summary statistics of raw data and changes from baseline values (means, medians, standard deviations, ranges) and by flagging of notable values in data listings. Frequencies and percentages of patients with serum creatinine values of = 0.5 mg/dl rise from the value at baseline will be presented by visit. Similarly, frequencies and percentages of patients with serum creatinine values of = 1.0 mg/dl rise from the value at baseline will be presented by visit. The frequency of increased serum creatinine values which require a delay in the administration of the next Zometa® (zoledronic acid) dose will be reported per treatment interval and for the total treatment period. The duration of such delays will be summarized in descriptive statistics and presented for treatment intervals and the whole treatment period. Adverse events Adverse events will be summarized by presenting for each treatment group the number and percentage of patients having any adverse event, having an adverse event in each body system and having each individual adverse event. Any other information collected (e.g. severity or relatedness to study medication) will be listed as appropriate. 6.1.7 INTERIM ANALYSES No interim analyses are planned for this study. 6.2. Sample size and power considerations This study is designed to show superiority of Zometa in the relative number of patients suffering from bone metastases as compared to control. Assuming an event rate in high risk prostate cancer patients not treated with Zometa of 25%, which is based on expert opinion, 270 patients per group are required to have 80% chance to detect a difference in the event rate AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 32 ® Zometa (Zoledronic Acid) / CZOL446G DE08 between patients receiving Zometa and patients not receiving Zometa of at least 10% points at the two-sided 5% significance level (nquery®, continuity corrected Chi²-test). To allow for drop outs 650 patients will be randomized in total. 7. 7.1. Notable laboratory value criteria, special methods and scales Criteria for clinically notable laboratory abnormalities Notable values for serum creatinine need to be commented on and are as follows: Serum creatinine multiplying the upper limit of normal cited by the measuring laboratory by the factor 1.15 (standard unit: > 2.0 mg/dl; SI unit: > 177 µmol/L). AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 33 ® Zometa (Zoledronic Acid) / CZOL446G DE08 8. Reference list 1 Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer Statistics 2001. CA Cancer J Clin (2001); 51: 15-36 2 Dennis LK, Resnick MI. Analysis of recent trends in prostate cancer incidence and mortality. Prostate (2000); 42: 247-252 3 Wingo PA, Gloeckler Ries LA, Parker SL, Heath CW. Long-term cancer patient survival in the United States. Cancer Epidemiology, Biomarkers and Prevention (1998); 7: 271-282 4 Meltzer D, Egleston B, Abdalla I. Patterns of prostate cancer treatment by clinical stage and age. Am J Public Health.(2001); 91: 126-128 5 Galbraith SM, Duchesne GM. Androgens and prostate cancer: biology, pathology and hormonal therapy. European J Cancer (1997); 33: 545-554 6 Harris KA, Small EJ. Hormonal therapy for prostate cancer. Exp Opin Invest Drugs (2001); 10: 493510 7 Small EJ. Prostate cancer: incidence, management and outcomes. Drugs and Aging (1998); 13: 71-81 8 Culine S, Droz J-P. Chemotherapy in advanced androgen-independent prostate cancer 1990-1999: a decade of progress? Annals Oncology. (2000); 11: 1523-1530 9 Prostate Cancer Trialists` Collaborative Group. Maximum androgen blockade in advanced cancer: an overview of the randomised trials. Lancet (2000); 355: 1491-1498 10 Newling D. Advanced prostate cancer: immediate or deferred hormone therapy? European Urology (2001); 39 (Suppl 1): 15-21 11 Herr HW, O’Sullivan M. Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy. J Urology (2000); 163: 1743-1746 12 The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostate cancer: initial results of the Medical Research Council trial. Br J Uro (1997); 79: 235-246 13 Skeletal complications of malignancy. Cancer (1997); 80 (Suppl): 1588-1594 14 Berutti A,Piovesan A, Tiorta M et al. Biochemical evaluation of bone turnover in cancer patients with bone metastases: relationship with radiographic appearances and disease extension. Br J Cancer (1996); 73: 1581-1587 15 Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Uro (1997); 157: 439-444 16 Daniell HW. Osteoprosis due to androgen deprivation therapy in men with prostate cancer. Urology (2001); 58 (Suppl 2A): 101-107 17 Fleisch H. Bisphosphonates: mechanisms of action. Endocrine reviews (1998); 19: 80-100 18 Clézardin P, Gligorov J, Delmas P. Mechanisms of action of bisphosphonates on tumor cells and prospects for use in the treatment of malignant osteolysis. Joint Bone Spine (2000); 67: 22-29 19 Coleman RE. Should bisphosphonates be the treatment of choice for metastatic bone disease? Seminars in Oncology (2001); 28 (4Suppl 11): 35-41 20 Olson KB, Pienta KJ. Use of bisphosphonates in the treatment of prostate cancer. Oncology (Huntington) (2001); 15: 1361-1367 21 Smith MR, McGovern FJ, Zietman AL et al. Pamidronate to prevent bone loss during androgendeprivation therapy for prostate cancer. N Engl J Med. (2001); 345: 948-955 22 Lee MV, Fong EM, Singer FR, Guenette RS. Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Research. (2001); 61: 2001 23 Major P, Lorthdary A, Hon J et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignany: a pooled analysis of two randomized, clinical trials. J. Clin. Oncol. 2001; 19 (2): 558-567 24 Saad F, Gleason DM, Murray S, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goad JA, Chen B. A randomized placebo-controlled trial of zoledronic acid in patients with hormone refractory metastatic prostate carcinoma. J Nat Cancer Inst (2002); 94: 1458-1468 25 Rosen LS, Gordon D, Kaminski M et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma. A phase III, double-blind comparative trial. Cancer J. 2001; 7: 377-387 26 Gordon D, Rosen L, Coleman RE et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate in treatment of skeletal complications in patients with advanced multiple myeloma or breast cancer. American Society of Clinical Oncology, Chicago, USA, 2003, Abstract 188 27 Major P, Cock R, Chen BL et al. Multiple event analysis of zoledronic acid in patients with cancer metastatic to bone. American Society of Clinical Oncology, Chicago, USA, 2003, Abstract 3062 AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 34 ® Zometa (Zoledronic Acid) / CZOL446G DE08 28 Rosen L., Gordon D, Tchekmedyian S et al. Zometa significantly increased the median time to first skeletal event (SRE) in patients with osteolytic bone metastases from non-small cell lung cancer (NSCLC) and other solid tumors (OST). Lung Cancer 2001, 34 (suppl. 1), 67 Abstract 29 Tchekmedyian S, Rosen L, Gordon D et al. Long-term efficacy and safety of zoledronic acid in reducing skeletal complications in patients with bone metastases from solid tumors. American Society of Clinical Oncology, USA, 2003, Abstract 2532 30 Saad F, Lipton A, Colombo A et al. Zometa (zolderonic acid) is effective in preventing and delaying skeletal events in patients with bone metastases secondary to urologic malignancies. Can J. Urol. 2002, 9, 1666 31 Saad F, Gleason D, Murray R et al. Zoledronic acid is well tolerated for up to 24 months and significantly reduces skeletal complications in patients with advanced prostate cancer metastatic to bone. J Urology 2003, 167, abstract 1472 32 Green J, Gschaidmeier H, Yoneda T et al. Zoledronic acid potently inhibits tumour induced osteolysis in two models of breast cancer metastasis to bone. Ann. Oncol. 2000; 11 (suppl.4): 14. Abstract 50P 33 Shipman CM, Rogers MJ, Apperley JF, Graham R, Russell G, Croucher PI. Anti-tumour activity of bisphosphonates in human myeloma cells. Leuk Lymphoma 1998; 32:129-38. 34 Derenne S, Amiot M, Barillé S, et al. Zoledronate is a Potent Inhibitor of Myeloma Cell Growth and Secretion of IL-6 and MMP-1 by the Tumoral Environment. J-bone-miner-res 1999; 14:2048-56. 35 Senaratne SG, Pirianov G, Mansi JL, Arnett TR, Colston KW. Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer 2000; 82:1459-68. 36 Boissier S, Magnetto S, Frappart L, et al. Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res 1997; 57:3890-4. 37 van der Pluijm G, Vloedgraven H, van Beek E, van der Wee Pals L, Lowik C, Papapoulos S. Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 1996; 98:698-705. 38 Lee VM, Fong EM, Singer FR, Guenette. Bisphosphonate treatment inhibits growth of prostate cancer cells. Cancer Research 2001, 61:2602-2608. 39 Powles T, Paterson S, Kanis JA, et al: Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20:3219-3224, 2002 40 Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357-63. 41 Diel IJ, Solomayer E, Gollan C, Schutz F, Bastert G. Bisphosphonates in the reduction of metastases in breast cancer – results of the extended follow-up of the first study population [abstract]. Proc ASCO 2000; 82a: abs 314. 42 Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5 year results of randomised controlled trial. J Clin Oncol 2001: 19: 10-17 43 Van Holten-Verzantvoort, A.T., Hermans, J., Beex, L.V. et al. (1996) Does supportive Pamidronate treatment prevent or delay the first manifestation of bone metastases in breast cancer patients? Eur J Cancer 32A (3): 450-454 44 Smith MR, Mansour R, Gleason DM, et al. Randomized, placebo-controlled trial of zoledronic acid for prevention of bone loss in M0 prostate cancer patients receiving initial androgen deprivation therapy. Proceedings of the American Urological Association, 2002. 45 Brown JM, Corey E, Lee ZD, True LD, Yun TJ, Tondravi M, Vessella RL. Osteoprotegerin and rank ligand expression in prostate cancer. Urology 2001; 57: 611-6. 46 Jung K, Lein M, Hösslin K, Brux B, Schnorr D, Loening SA, Sinha P. Osteoprotegerin in serum as a novel marker of bone metastatic spread in prostate cancer. Clin Chem 2001; 47: 2061-3. 47 Kylmälä T, Tammela TLJ, Risteli R, Risteli J, Konttari M, Elomaa I. Type I collagen degradation product (carboxyterminal cross-linked telopeptide of type I collagen) gives information about the nature of bone metastases and has prognostic value in prostate cancer. Br J Cancer 1995; 71: 1061-4. 47 Halleen JM, Suominen H, Heikkinen JE, Väänänen HK. Tartrate-resistant acid phosphatase 5b is a promising new serum marker of bone resorption. Calcif Tissue Int 1999;64 (Suppl 1):106. 48 Janckila AJ, Takahashi K, Sun SZ, Yam LT. Tartrate-resistant acid phosphatase isoforme 5b as serum marker for osteoclast activity. Clin Chem 2001, 47: 74-80. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 35 ® Zometa (Zoledronic Acid) / CZOL446G DE08 9. 9.1. Procedures and instructions Special safety-related procedures 9.1.1. INSTRUCTIONS FOR RAPID NOTIFICATION OF SERIOUS ADVERSE EVENTS Reporting responsibility Any serious adverse event occurring in a patient after providing informed consent, whilst receiving study treatment and until 4 weeks after stopping it must be reported. The period after discontinuing study drug may be extended if there is a strong suspicion that the drug has not yet been eliminated. All serious adverse events must also be reported for the period in which the study protocol interferes with the standard medical treatment given to a patient (e.g. treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant medication). Each serious adverse event must be reported by the investigator to Novartis within 24 hours of learning of its occurrence, even if it is not felt to be treatment-related. Follow-up information about a previously reported serious adverse event must also be reported to Novartis within 24 hours of receiving it. If the serious adverse event has not been previously documented (new occurrence) and it is thought to be related to study drug, the Medical Safety Expert of the Clinical Safety & Epidemiology Department may contact the investigator to obtain further information. If warranted, an investigator alert may be issued, to inform all investigators involved in any study with the same drug that this serious adverse event has been reported. Reporting procedures The investigator must complete the Serious Adverse Event Report Form in English, assess the relationship to study treatment and send the completed form by fax within 24 hours to the local Novartis Clinical Safety and Epidemiology (CS&E) Department. The original and the duplicate copies of the Serious Adverse Event Form, and the fax confirmation sheet must be kept with the case report forms at the study site. The monitor will collect a copy of the Serious Adverse Event Form and deliver it to Novartis. Follow-up information is sent to the same person who was sent the original Serious Adverse Event Form, re-stating the date of the original report. Either a new Serious Adverse Event Form is sent (stating that this is a follow-up), or the original one resent (with the new information highlighted and a new date provided). The follow-up should describe whether the event has resolved or continues, if and how it was treated and whether the patient continued or discontinued study participation. The form and fax confirmation sheet must be retained. Contact persons and numbers The telephone and fax numbers of the local Clinical Research (CR) contact person, the contact person at the Clinical Research Organization (CRO) and the contact person in the local Novartis CS&E Department, specific to the site, are all listed in the investigator folder provided for each individual site. Questions referring to a specific serious adverse event occurring in a study patient should be directed to the local Clinical Research (CR) contact person specified in the investigator folder provided for the site. Questions concerning the fax transmission of a Serious Adverse Event Form should be directed to the Contract Research Organization (CRO) monitoring the study OR the local Novartis CS&E Department. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 36 ® Zometa (Zoledronic Acid) / CZOL446G DE08 9.1.2. DELAY IN ZOMETA® (ZOLEDRONIC ACID) ADMINISTRATION AFTER INCREASED SERUM CREATININE VALUES Serum creatinine should be measured prior to each dose of study drug. A two weeks window for checking creatinine is allowed prior to the next dose. The local laboratory serum creatinine result must be available prior to administration of the dose of study drug. If the patient's baseline serum creatinine was < 1.4 mg/dl at the time of study entry, an increase of 0.5 mg/dL or more will require the delaying of the dose of study drug until the patient's serum creatinine returns to no higher than 10% above the baseline value. If the patient's baseline serum creatinine was > 1.4 mg/dL, then any increase in the serum creatinine of 1.0 mg/dL or more will require that the study drug be delayed until the patients serum creatinine returns to no higher than 10% above the baseline value. Any doubling of the baseline serum creatinine value will require that the study drug be delayed until the patient's serum creatinine returns to no higher than 10% above the baseline value. Should the study drug need to be delayed, the patient’s serum creatinine will continue to be followed at intervals according to the Investigator’s clinical judgement, but at least at the regularly scheduled study visits until full recovery (i.e., return to no higher than 10% above the baseline value). 9.1.3. INSTRUCTIONS FOR COMPLETING ADVERSE EVENT CASE REPORT FORMS Each adverse event is to be reported on an Adverse Event Case Report Form. As far as possible, each adverse event must also be described by: 1. its duration (start and end dates), 2. its severity grade (grade 1 - 4), 3. its relationship to the study drug (suspected / not suspected), 4. the action(s) taken. Examples of the severity grade, relationship to study treatment and actions taken, as presented in the case report form, are provided below. The severity grade of an adverse event provides a qualitative assessment of the extent or intensity of an adverse event, as determined by the investigator or as reported by the subject. The severity grade does not reflect the clinical seriousness of the event, only the degree or extent of the affliction or occurrence (e.g. severe nausea, mild seizure), and does not reflect the relationship to study drug. The severity grade of an adverse event should be evaluated with the following categories: Severity grade for adverse events 1 = Grade 1 2 = Grade 2 3 = Grade 3 4 = Grade 4 Mild Moderate Severe life-threatening The relationship between the administration of study drug and the occurrence of the adverse event is described as belonging to one of only 2 categories, either suspected by the investigator or not suspected by the investigator. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 37 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Relationship of adverse events to study drug 0 = Not suspected the temporal relationship of the clinical event to study drug administration makes a causal relationship unlikely, or other drugs, therapeutic interventions or underlying conditions provide a sufficient explanation for the observed event. The temporal relationship of the clinical event to study drug administration makes a causal relationship possible, and other drugs, therapeutic interventions or underlying conditions do not provide a sufficient explanation for the observed event. 1 = Suspected The actions taken in response to an adverse event are described on a numerical scale, from 0 to 5 that cover the various possibilities. One or more of these is to be selected. Actions taken in response to an adverse event 0 = No action taken 1 = Study drug dosage adjusted / temporarily interrupted 2 = Study drug permanently discontinued due to this adverse event 3 = Concomitant medication taken 4 = Non-drug therapy given 5 = Hospitalization / prolonged hospitalization 9.2. Administrative procedures 9.2.1. INTERNATIONAL INTER-GROUP STEERING COMMITTEE The following persons are members of the Steering Committee: Prof. Manfred Wirth / University Clinic Dresden, Study Chairman Prof. Georg Bartsch / University of Innsbruck Prof. Frans Debruyne /University Medical Center Nijmegen Prof. Peter Iversen / University of Copenhagen Prof. Kurt Miller / University Clinic Benjamin Franklin, Berlin Prof. Anup Patel / St. Mary’s Hospital, London Prof. Teuvo Tammela /Tampere University Hospital Prof. Andrea Tubaro / "La Sapienza" University of Rome Dr. Ulrike Haus / Novartis Pharma GmbH, Nürnberg The Study Chairman chairs the Steering Committee. The steering Committee is responsible for: coordination of the study across countries standardization/harmonization of study policies within the study and across countries guarantee the quality and completeness of the data approve protocol amendments based on accumulating evidence from the trial and the literature inform the members of the Scientific Committee and Novartis of study progress through periodic reports approve any single publication produced by each cooperative group or institutions decision about discontinuation of study when necessary AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 38 ® Zometa (Zoledronic Acid) / CZOL446G DE08 The Steering Committee Members will meet as driven by study needs. Electronic mail or a dedicated Web facility or teleconferences will be used for ordinary communications within the Steering Committee. All Investigators will be kept informed of the discussions within the Steering Committee and of study progress through periodic reports. The Steering Committee can always widen discussions to all Investigators, by using electronic mail or Web facilities as well as dedicated meetings. 9.2.2. SCIENTIFIC COMMITTEE The members of the Steering Committee, one leading investigator from each participating Country/Cooperative Group (Local Study Chairman), and the statistician responsible for the study methodology and data analysis, are members of the Scientific Committee. The Study Chairman chairs the Scientific Committee. The Scientific Committee is responsible for: coordination of the study within their countries standardization/harmonization of study policies within their countries across centers inform the Steering Committee of study progress in their countries through periodic reports and communicate the reports released by the Steering Committee to all investigators in their countries guarantee the quality and completeness of the data generated in their countries - The Scientific Committee Members will meet as driven by study needs. Electronic mail or a dedicated Web facility or teleconferences will be used for ordinary communications within the Scientific Committee. All Investigators will be kept informed of the discussions within the Scientific Committee and of study progress through periodic reports. The Scientific Committee can always widen discussions to all Investigators, by using electronic mail or Web facilities as well as dedicated meetings. 9.2.3. CHANGES TO THE PROTOCOL Any change or addition to the final protocol requires a written protocol amendment that must be approved by the Steering Committee and Scientific Committee before implementation. Amendments significantly affecting the safety of subjects, the scope of the investigation or the scientific quality of the study, require additional approval by the IRB/IEC/REB of all centers, and, in some countries, by the regulatory authority. A copy of the written approval of the IRB/IEC/REB, which becomes part of the protocol, must be given to the Data Center and the CRO in charge of monitoring. Amendments affecting only administrative aspects of the study do not require formal protocol amendments or IRB/IEC/REB approval but the IRB/IEC/REB of each center must be kept informed of such administrative changes. 9.2.4. MONITORING PROCEDURES Monitoring will be done by local CROs/Study Groups of the individual participating countries. Before study initiation, at a site initiation visit the monitor will review the protocol and case report forms (CRFs) with the investigators and their staff. During the study the monitor will visit the site regularly, to check the completeness of patient records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good Clinical Practice, the AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 39 ® Zometa (Zoledronic Acid) / CZOL446G DE08 progress of enrolment, and also to ensure that study medication is being stored, dispensed and accounted for according to specifications. The investigator and key trial personnel must be available to assist the monitor during these visits. The investigator must give the monitor access to relevant hospital or clinical records, to confirm their consistency with the CRF entries. No information in these records about the identity of the subjects will leave the study center. Monitoring standards require full verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs and the recording of primary efficacy and safety variables. Additional checks of the consistency of the source data with the CRFs are performed according to the study-specific monitoring plan. The investigator is responsible for completing the CRFs within 5 days of the patient’s visit and the monitor is responsible for reviewing them and clarifying and resolving any data queries. The completed and corrected CRFs for completed visits will be collected by the monitor initially, and may then be either collected or sent for data processing, as arranged by the monitor. A copy of the CRFs is retained by the investigator, who must ensure that it is stored with other study documents, such as the protocol, the investigators brochure and any protocol amendments, in a secure place. 9.2.5. RECORDING OF DATA AND RETENTION OF DOCUMENTS Data on subjects collected on CRFs during the trial will be documented in an anonymous fashion and the subject will only be identified by the subject number, and by his/her initials if also required. If, as an exception, it is necessary for safety or regulatory reasons to identify the subject, all parties are bound to keep this information confidential. All the information required by the protocol should be provided and any omissions require explanation. All CRFs must be completed and available for collection no more than 5 days after the patient’s visit, so that the monitor may check the entries for completeness, accuracy and legibility, ensure the CRF is signed by the investigator and transmit the data to the CRO responsible for data management. All entries to the CRFs must be made clearly in black ball-point pen, to ensure the legibility of self-copying or photocopied pages. Corrections are made by placing a single horizontal line through the incorrect entry, so that it can still be seen, and placing the revised entry beside it. The revised entry must be initialed and dated by a member of the investigator's research team authorized to make CRF entries. Correction fluid must not be used. The investigator must maintain source documents for each patient in the study. All information on CRFs must be traceable to these source documents, which are generally maintained in the patient's file. The source documents should contain all demographic and medical information, including laboratory data, electrocardiograms, etc., also a copy of the signed informed consent form, which should indicate the study number and title of the trial. Essential documents, as listed below, must be retained by the investigator for as long as needed to comply with national and international regulations. The investigator agrees to adhere to the document retention procedures by signing the protocol. Essential documents include: 1. IRB/IEC approvals for the study protocol and all amendments 2. all source documents and laboratory records 3. CRF copies 4. patients' informed consent forms 5. FDA form 1572 6. any other pertinent study document. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 40 ® Zometa (Zoledronic Acid) / CZOL446G DE08 If an investigator withdraws from the study (for any reason), the records must be transferred to another person whose designation has been mutually agreed. The written notification of this transfer must be sent to the Data Center. The Data Center will produce periodic (every 6 months) updates on the status of the study including: Number of active Centers Patient recruitment status (overall and by Center) Total number of patients who have discontinued the study Reasons for discontinuation Number of completed patients Number and details of SAEs The periodic report will be circulated to the Steering Committee Members for circulation to Members of the Scientific Committee. 9.2.6. HANDLING OF STUDY MEDICATION All study medication will be supplied by local Novartis to the centers. Drug supplies must be kept in an appropriate, secure area (e.g. locked cabinet) and stored in accordance with the conditions specified on the drug labels. The investigator must maintain an accurate record of the shipment and dispensing of the study drug in a drug accountability ledger. An accurate record of the date and amount of study drug dispensed to each subject must be available for inspection at any time. All drug supplies are to be used only for this protocol and not for any other purpose. The investigator must not destroy any drug labels or unused drug supply. At the conclusion of the study, and, as appropriate during the course of the study, the investigator will return all unused drug containers, drug labels and a copy of the completed drug disposition form to the monitor. 9.2.7. PUBLICATION OF RESULTS Any formal presentation or publication of data collected from this trial will be considered as a joint publication by the investigator(s). The principle investigator is author on presentations/publications. Every cooperative group should designate one member to be author on presentations/publications. Further authorship will be determined according to the number of eligible patients enrolled at each participating site. For multi-center studies, it is mandatory that the first publication is based on data from all centers, analyzed as stipulated in the protocol by statisticians, and not by the investigators themselves. Investigators participating in multi-center studies agree not to present data gathered from one center or a small group of centers before the full, initial publication, unless formally agreed to by the Steering Committee. The substudies on bone mineral density and parameters of bone turnover will be published separately. The first author of these publications will be the investigator leading the substudy. The Steering Committee must receive copies of any intended communication in advance of publication (at least 15 working days for an abstract or oral presentation and 45 working days for a journal submission). The Steering Committee will review the communications for accuracy (thus avoiding potential discrepancies with submissions to health authorities), verify that confidential information is not being inadvertently divulged and to provide any relevant supplementary information. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 41 ® Zometa (Zoledronic Acid) / CZOL446G DE08 9.2.8. DISCLOSURE AND CONFIDENTIALITY The investigator will guarantee that all persons involved will respect the confidentiality of any information concerning the trial subjects. All parties involved in a clinical trial will maintain the strict confidentiality to assure that neither the person not the family privacy of a patient participating in the trial is violated. Likewise, the appropriate measures shall be taken to avoid the access of non-authorized persons to the trial data. The processing of the personal data on the patients taking part in this trial, and in particular regarding data concerning consent, shall comply with the local law on the privacy and with the European Directive on the Privacy of data (95/46/EC). 9.2.9 DISCONTINUATION OF STUDY It is agreed that, for reasonable cause, the Steering Committee may terminate this study provided a written notice is submitted at a reasonable time in advance of intended termination. 9.3 Ethics and Good Clinical Practice This study must be carried out in compliance with the protocol, in accordance with current local legislation and in accordance with: 1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 2. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European Community. 3. Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996 and Edinburgh). The investigator agrees, when signing the protocol, to adhere to the instructions and procedures described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms to. 9.3.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE Before implementing this study, the protocol, the proposed informed consent form and other information to subjects, must be reviewed by a properly constituted Institutional Review Board/Independent Ethics Committee (IRB/IEC/REB). A signed and dated statement that the protocol and informed consent have been approved by the IRB/IEC/REB must be archive with the other documents of the study. Any amendments to this protocol, other than administrative ones, must be approved by this Committee. 9.3.2 INFORMED CONSENT The investigator must explain to each patient (or legally authorized representative) the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits involved and any discomfort it may entail. Each patient must be informed that participation in the study is voluntary and that she may withdraw from the study at any time and that withdrawal of consent will not affect her subsequent medical treatment or relationship with the treating physician. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 42 ® Zometa (Zoledronic Acid) / CZOL446G DE08 This informed consent should be given by means of a standard written statement, written in non-technical language. The patient should read and consider the statement before signing and dating it, and should be given a copy of the signed document. If the subject cannot read or sign the documents, oral presentation may be made or signature given by the subject’s legally appointed representative, if witnessed by a person not involved in the study, mentioning that the patient could not read or sign the documents. No patient can enter the study before her informed consent has been obtained. The informed consent form has to be considered part of the protocol, and must be submitted by the investigator with it for IRB/IEC/REB approval. 9.3.3. INSURANCE POLICY Local law requires that subject participating in clinical trials be covered by a civil liability policy. The Local Study Groups or Local Principal Investigators as the sponsors of the study agree to take out adequate clinical trial insurance or make alternative arrangements as necessary and required by applicable l ocal and regulatory requirements to cover its obligations as sponsors of the study, including but not limited to provide compensation to participants in the study suffering injury or death or loss caused by the administration of drugs or any clinical intervention or procedure in accordance with the relevant protocol and all legal requirements laid down by local regulations. 9.3.4. DECLARATION OF HELSINKI WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles for Medical Research Involving Human Subjects Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002 A. INTRODUCTION 1. The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects includes research on identifiable human material or identifiable data. It is the duty of the physician to promote and safeguard the health of the people. The physician's knowledge and conscience are dedicated to the fulfillment of this duty. The Declaration of Geneva of the World Medical Association binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient." Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens. 2. 3. 4. 5. 6. 7. AUO/EAU/SPCG Protocol Version 02.10.03 8. Confidential Page 43 ® Zometa (Zoledronic Acid) / CZOL446G DE08 9. Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care. Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration. B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 10. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject. 11. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation. 12. Appropriate caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected. 13. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol. This protocol should be submitted for consideration, comment, guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be independent of the investigator, the sponsor or any other kind of undue influence. This independent committee should be in conformity with the laws and regulations of the country in which the research experiment is performed. The committee has the right to monitor ongoing trials. The researcher has the obligation to provide monitoring information to the committee, especially any serious adverse events. The researcher should also submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects. 14. The research protocol should always contain a statement of the ethical considerations involved and should indicate that there is compliance with the principles enunciated in this Declaration. 15. Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given consent. 16. Every medical research project involving human subjects should be preceded by careful assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This does not preclude the participation of healthy volunteers in medical research. The design of all studies should be publicly available. 17. Physicians should abstain from engaging in research projects involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results. 18. Medical research involving human subjects should only be conducted if the importance of the objective outweighs the inherent risks and burdens to the subject. This is especially important when the human subjects are healthy volunteers. 19. Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research. 20. The subjects must be volunteers and informed participants in the research project. 21. The right of research subjects to safeguard their integrity must always be respected. Every precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's information and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject. 22. In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician should then obtain the subject's freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed. 23. When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship with the physician or may consent under duress. In that case the AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 44 ® Zometa (Zoledronic Acid) / CZOL446G DE08 24. 25. 26. 27. informed consent should be obtained by a well-informed physician who is not engaged in the investigation and who is completely independent of this relationship. For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a legally incompetent minor, the investigator must obtain informed consent from the legally authorized representative in accordance with applicable law. These groups should not be included in research unless the research is necessary to promote the health of the population represented and this research cannot instead be performed on legally competent persons. When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorized representative. Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent, should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population. The specific reasons for involving research subjects with a condition that renders them unable to give informed consent should be stated in the experimental protocol for consideration and approval of the review committee. The protocol should state that consent to remain in the research should be obtained as soon as possible from the individual or a legally authorized surrogate. Both authors and publishers have ethical obligations. In publication of the results of research, the investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be published or otherwise publicly available. Sources of funding, institutional affiliations and any possible conflicts of interest should be declared in the publication. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication. C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 28. The physician may combine medical research with medical care, only to the extent that the research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with medical care, additional standards apply to protect the patients who are research subjects. 29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists. See footnote. 30. At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study. 31. The physician should fully inform the patient which aspects of the care are related to the research. The refusal of a patient to participate in a study must never interfere with the patient-physician relationship. 32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. Where possible, these measures should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded and, where appropriate, published. The other relevant guidelines of this Declaration should be followed. FOOTNOTE: NOTE OF CLARIFICATION ON PARAGRAPH 29 of the WMA DECLARATION OF HELSINKI The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances: - Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or - Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm. All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and scientific review. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 45 ® Zometa (Zoledronic Acid) / CZOL446G DE08 10. Appendices Appendix 1: Performance status - ECOG Criteria for Estimation of Performance Status: GRADE 0 SCALE Fully active, able to carry out all pre-disease performance without restriction, (Karnofsky 90-100) Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work. (Karnofsky 70-80) Ambulatory and capable of all self-care but unable to carry out work activities. Up and about more than 50% of waking hours. (Karnofsky 50-60) Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. (Karnofsky 30-40) Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. (Karnofsky 10-20) 1 2 3 4 AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 46 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Appendix 2: New York State Heart Association functional classification CLASS I No Limitation. Ordinary physical activity does not cause undue fatigue, dyspnea, palpitation, or anginal pain. Slight limitation of physical activity. Such patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation dyspnea, or anginal pain . Marked limitation of physical activity. Although patients are comfortable at rest, less than ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome are present even at rest. With any physical activity increased discomfort is experienced. CLASS II CLASS III CLASS IV New York Heart Association, Inc: Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for Diagnosis. 6th Ed. Boston, Little, Brown and Co., 1964. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 47 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Appendix 3: Staging of Prostate Cancer TNM Staging Primary Tumor, Clinical (T) TX T0 T1 Primary tumor cannot be assessed No evidence of primary tumor Clinically inapparent tumor not palpable nor visible by imaging T1a T1b T1c T2 T2a T2b T3 T3a T3b T4 Tumor incidental histologic finding in 5% or less of tissue resected Tumor incidental histologic finding in more than 5% of tissue resected Tumor identified by needle biopsy (e.g., because of elevated PSA) Tumor involves one lobe Tumor involves both lobes Extracapsular extension (unilateral or bilateral) Tumor invades seminal vesicles(s) Tumor confined within prostate* Tumor extends through the prostate capsule** Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall *Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified at T1c. **Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2. Primary Tumor, Pathologic (pT) pT2∗∗∗ pT2a pT2b pT3 pT3a pT3b pT4 Organ confined Unilateral Bilateral Extraprostatic extension Extraprostatic extension Seminal vesicle invasion Invasion of bladder, rectum ∗∗∗Note: There is no pathologic T1 classification. Regional Lymph Nodes (N) NX N0 Regional lymph nodes cannot be assessed No regional lymph node metastasis AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 48 ® Zometa (Zoledronic Acid) / CZOL446G DE08 N1 Metastasis in regional lymph node or nodes (M) Distant Metastasis MX M0 M1 Distant metastasis cannot be assessed No distant metastasis Distant metastasis M1a M1b M1c Nonregional lymph node(s) Bone(s) Other site(s) ∗∗∗∗Note: When more than one site of metastasis is present, the most advanced category is used. pM1c is most advanced. AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 49 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Appendix 4: NCIC Common Toxicity Criteria GRADES 0 BLOOD/BONE-MARROW Hemorrhage (clinical) none mild, no transfusion gross, 1 - 2 units transfusion per episode moderate intake significantly decreased but can eat 2 - 5 episodes in 24 hours gross, 3 - 4 units transfusion per episode severe no significant intake massive, >4 units transfusion per episode life-threatening 1 2 3 4 Infection GASTROINTESTINAL Nausea none none mild able to eat reasonable intake 1 episode in 24 hours Vomiting none 6 - 10 episodes in 24 hours >10 episodes in 24 hrs or requiring parenteral support Increase of >10 stools/day, or grossly bloody diarrhea, or need for parenteral support requires parenteral or enteral support Diarrhea none increase of 2 3 stools/day over pre-Rx increase of 4 - 6 stools/ day, or nocturnal stools, or moderate cramping painful erythema, edema, or ulcers, but can eat --- increase of 7 9 stools/day or incontinence or severe cramping Stomatitis none painless ulcers, erythema, or mild soreness painful erythema, edema or ulcers, and cannot eat precoma LIVER Liver (clinical) no change from baseline neg no loss none or no change --hepatic coma KIDNEY/BLADDER Hematuria ALOPECIA PULMONARY micro only mild hair loss asymptomatic, with abnormal PFT's gross, no clots pronounced or total hair loss dyspnea on significant exertion gross + clots --dyspnea at normal level of activity requires transfusion --dyspnea at rest AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 50 ® Zometa (Zoledronic Acid) / CZOL446G DE08 NCI common toxicity criteria (continued) GRADES 0 HEART Cardiac dysrhythmias none asymptomatic, transient, requiring no therapy recurrent or persistent, no therapy required requires treatment requires monitoring; or hypotension or ventricular tachy-cardia, or fibrillation severe or refractory CHF 1 2 3 4 Cardiac function none asymptomatic, decline of resting ejection fraction by less than 20% of baseline value asymptomatic, decline of resting ejection fraction by more than 20% of baseline value asymptomatic, ST and T wave changes suggesting ischemia pericarditis (rub, chest pain, ECG changes) recurrent or persistent increase by greater than 20 mm Hg (D) or to >150/100 if previously WNL. No treatment required requires fluid replacement or other therapy but not hospitalization mild CHF, responsive to therapy Cardiac ischemia none non-specific T-wave flattening angina without evidence for infarction acute myocardial infarction Cardiac pericardial none asymptomatic, effusion, no intervention required asymptomatic, transient increase by greater than 20 mm Hg (D) or to >150/100 if previously WNL. No treatment required changes requiring no therapy (including transient orthostatic hypotension) symptomatic effusion, drainage required requires therapy tamponade: drainage urgently required hypertensive crisis BLOOD PRESSURE Hypertension none or no change Hypotension none or no change requires therapy and hospitalization; resolves within 48 hours of stopping the agent requires therapy and hospitalization for >48 hrs after stopping the agent AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 51 ® Zometa (Zoledronic Acid) / CZOL446G DE08 NCI common toxicity criteria (continued) GRADES 0 NEUROTOXICITY Neuro-sensory none or no change mild paresthesia, loss of deep tendon reflexes mild or moderate objective sensory loss: moderate paresthesias mild objective weakness without significant impairment of function moderate somnolence or agitation severe objective sensory loss or paresthesias that interfere with function objective weakness with impairment of function --1 2 3 4 Neuro-motor none or no change subjective weakness: no objective findings paralysis Neuro-cortical none mild somnolence or agitation severe somnolence, agitation, confusion, disorientation or hallucinations locomotor ataxia coma, seizures, toxic psychosis Neuro-cerebellar none slight incoordination, dysdiadokinesia intention tremor, dysmetria, slurred speech, nystagmus moderate anxiety or depression moderate or severe but transient moderate cerebellar necrosis Neuro-mood no change none mild anxiety or depression mild severe anxiety or depression unrelenting and severe severe suicidal ideation Neuro-headache --- Neuro-constipation none or no change none or no change mild ileus > 96 hours Neuro-hearing asymptomatic, hearing loss on audiometry only tinnitus hearing loss interfering with function but correctable with hearing aid symptomatic subtotal loss of vision deafness not correctable Neuro-vision none or no change --- --- blindness AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 52 ® Zometa (Zoledronic Acid) / CZOL446G DE08 NCI common toxicity criteria (continued) GRADES 0 SKIN none or no change 1 scattered macular or papular eruption or erythema that is asymptomatic 2 scattered macular or papular eruption or erythema with pruritus or other associated symptoms urticaria, drug fever = 38°C, 100.4°F mild bronchospasm 38.1°- 40.0°C 100.5° 104.0°F 3 generalised symptomatic macular papular or vesicular eruption 4 exfoliative dermatitis or ulcerating dermatitis ALLERGY none transient rash, drug fever < 38°C 100.4°F 37.1°- 38.0°C 98.7° - 100.4°F serum sickness, bronchospasm, requires parenteral meds >40.0°C (>104.0°F) for less than 24 hours anaphylaxis FEVER IN THE ABSENCE OF INFECTION none >40.0°C (104.0°F) for more than 24 hours or fever accompanied by hypotension plastic surgery indicated LOCAL none pain pain and swelling, with inflammation, or phlebitis 10.0 - 19.9% ulceration WEIGHT GAIN/LOSS <5.0% 5.0 - 9.9% >20.0% --- AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 53 ® Zometa (Zoledronic Acid) / CZOL446G DE08 NCI common toxicity criteria (continued) GRADES UNITS BLOOD/BONE-MARROW WBC PLT Hb Granulocytes / Bands Lymphocytes LIVER Bilirubin Transaminases (SGOT, SGPT) Alkaline phosphatase or 5'Nucleotidase KIDNEY/BLADDER Creatinine Proteinuria WNL no change < 1.5 x N 1+ or < 0.3 g% or < 3g/L 116 - 160 1.5 - 3.0 x N 2 - 3+ or 0.3 - 1.0 g% or 3 - 10 g/L 161 - 250 3.1 - 6.0 x N 4+ or > 1.0 g% or > 10 g/L 251 - 500 > 6.0 x N nephrotic syndrome WNL WNL WNL < 1.5 x N 2.6 - 5.0 x N 2.6 - 5.0 x N 1.5 - 3.0 x N 5.1 - 20.0 x N 5.1 - 20.0 x N > 3.0 x N > 20.0 x N > 20.0 x N 109/L 109/L g/dL 109/L 109/L 0 1 3.0 - 3.9 75.0 - normal 10.0 - normal 1.5 - 1.9 1.5 - 1.9 2 2.0 - 2.9 50.0 - 74.9 8.0 - 9.9 1.0 - 1.4 1.0 - 1.4 3 1.0 - 1.9 25.0 - 49.9 6.5 - 7.9 0.5 - 0.9 0.5 - 0.9 4 < 1.0 < 25.0 < 6.5 < 0.5 < 0.5 ≥ 4.0 WNL WNL ≥ 2.0 ≥ 2.0 ≤ 2.5 x N ≤ 2.5 x N METABOLIC Hyperglycemia mg/dL < 116 > 500 or ketoacidos is < 30 > 5.1 x N >13.5 Hypoglycemia Amylase Hypercalcemia Hypocalcemia Hypomagnesemia COAGULATION Fibrinogen* Prothrombin time Partial thromboplastin time mg/dL mg/dL mg/dL mEq/L > 64 WNL < 10.6 > 8.4 > 1.4 WNL WNL WNL 55 - 64 < 1.5 x N 10.6 - 11.5 8.4 - 7.8 1.4 - 1.2 0.99-0.75 x M 1.01-1.25 x N 1.01-1.66 x N 40 - 54 1.5 - 2.0 x N 11.6 - 12.5 7.7 - 7.0 1.1 - 0.9 0.74 - 0.50 x M 1.26 - 1.50 x N 1.67 - 2.33 x N 30 - 39 2.1 - 5.0 x N 12.6 - 13.5 6.9 - 6.1 0.8 - 0.6 0.49-0.25 x M 1.51-2.00 x N 2.34-3.00 x N ≤ 6.0 <0.5 ≤ 0.24 x M > 2.00 x N > 3.00 x N N = upper limit of normal value; WNL = within normal limits; * M = lower limit of normal value AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 54 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Appendix 5: Gleason Grading Grade 1 2 3A 3B 3C 4A 4B 5A 5B Description Simple rounded glands, close-packed in rounded masses with well-defined edges Simple rounded glands, loosely packed in vague, rounded masses with loosely defined edges Medium sized single glands of irregular shape and irregular spacing with ill-defined infiltrating edges Very similar to 3A, but small to very small glands, which must not form significant chains or cords Papillary and cribriform epithelium in smooth, rounded cylinders and masses; no necrosis Small, medium, or large glands, fused into cords, chains or ragged, infiltrating masses Very similar to 4A, but with many large clear cells, sometimes resembling “hypernephroma” Papillary and cribriform epithelium in smooth, rounded masses, more solid than 3C and with central necrosis Anaplastic adenocarcinoma in ragged sheets vDonald F. Gleason: Histologic Grading of Prostate Cancer. Human Pathology, Vol. 23, No. 3 (March 1992) AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 55 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Appendix 5: Novartis Contact Person for SAE reporting Each serious adverse event must be reported by the investigator to Novartis within 24 hours of learning of its occurrence, even if it is not felt to be treatment-related. Follow-up information about a previously reported serious adverse event must also be reported to Novartis within 24 hours of receiving it. SAE reporting must be sent to: Germany Novartis Pharma GmbH Abteilung Arzneimittelsicherheit Roonstraße 25 90429 Nürnberg Fax-Nr.: 0911 - 273 12 985 or Fax-Nr.: 0911 - 273 12 703 Belgium Italy Novartis Farma S.p.A. Largo Umberto Boccioni, 1 21040 Origgio (VA) ITALY Fax: +39 02 9670 30 51 Denmark Novartis Healthcare A/S Lyngbyvej 172 DK-2100 Kopenhagen Fax: +45 39 16 84 01 or +45 39 16 84 02 Finland United Kingdom Novartis Pharmaceuticals UK Ltd. Frimley Business Park Frimley, Camb; Surrey GU16 7SR United Kingdom Fax: +44 1276 69 83 19 Novartis Pharma N.V. Medialaan 40 bus 1 B-1800 Vilvoorde Fax: +32 2 246 17 00 Novartis Finland Oy Metsänneidonkuja 10 FIN-02130 Espoo Fax: +358 9 6133 22 04 France Novaratis Pharma S.A.S. 2 & 4, rue Lionel Terray Boîte Postale 308 F-92506 Rueil-Malmaison Cedex Phone: +33 1 554 763 84 The Netherlands Novartis Pharma B.V. Postbus 241 NL-6800 LZ Arnhem Norway Novartis Norge AS Medical Department Brynsalleén 4 N-0510 Oslo Fax: +31 26 378 24 14 Fax: +47 23 05 20 87 Austria Novartis Pharma GmbH Brunner Strasse 59 A-1235 Wien Turkey Novartis Ürünleri Pharma Sector Barbaros Bulvar_No: 83 TR-80690 Besiktas - Istanbul +90 212 227 52 80 Sweden Novartis Sverige AB Novartis Läkermedel Kemistvägen 1 or P.O.Box 1150 SE-183 11 Täby Fax: +46 8 732 32 01 Fax: +43 1 8665 77 94 AUO/EAU/SPCG Protocol Version 02.10.03 Confidential Page 56 ® Zometa (Zoledronic Acid) / CZOL446G DE08 Spain Novartis Farmacéutica S.A. Gran Via de Les Corts Catalanes, 764 E-08013 Barcelona Fax: +34 93 306 44 12 Greece Novartis (Hellas) S.A.C.I. 12th klm. National Road Athens - Lamia No. 1 P.O. Box 52001 Metamorphosis, 14451 Fax: +30 944 27 57 93 This document was created with Win2PDF available at http://www.daneprairie.com. The unregistered version of Win2PDF is for evaluation or non-commercial use only.