PCO Research Summary

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					IRB 00020566

MC0983: Phase II Trial of Pentostatin, Cyclophosphamide, and Ofatumumab for
Previously Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Purpose of the Study
Primary objective: To assess the rate of complete and overall response using pentostatin,
cyclophosphamide, and ofatumumab in patients with previously untreated CLL or SLL requiring
therapy and to determine the proportion of patients who achieve a minimal residual disease
(MRD) negative state as assessed by flow cytometry.

Secondary objectives:
   • To monitor and assess toxicity of pentostatin, cyclophosphamide, and ofatumumab in
      patients with previously untreated CLL or SLL.
   • To determine the progression-free survival in CLL patients treated with pentostatin,
      cyclophosphamide, and ofatumumab.
   • To assess the complete and overall response as well as progression free survival of CLL
      patients treated with pentostatin, cyclophosphamide, and ofatumumab as compared to a
      historic control of patients treated with pentostatin, cyclophosphamide, and rituximab in
      an exploratory manner.
   • To determine if molecular prognostic parameters (ZAP-70, CD38, cytogenetic
      abnormalities identified by FISH, IgVH mutation status, etc) relate to response to PCO
   • Assess the mechanisms of ofatumumab induced cell death and explore methods to
      enhance ofatumumab cytotoxicity.

Background & Significance
The prevalence of CLL increases with age and the median age at the time of diagnosis is 65 to
70. Because most patients are observed for several years prior to treatment, more than half of the
patients requiring therapy are over the age of 70. Accordingly, identification of effective
treatment regimens that can be safely administered to older patients is a critical need in CLL

Although recent studies suggest that combining the anti-CD20 monoclonal anti-body rituximab
with chemotherapy improves response rates and progression free survival, the toxicity of some
chemoimmunotherapy regimens precludes their administration to many older patients.

Ofatumumab represents a novel anti-CD20 monoclonal antibody, since it recognizes CD20
epitopes localized in both extracellular loops distinct from the site of the epitope recognized by
rituximab. In vitro studies show that ofatumumab induced complement-mediated lysis of primary
tumor B cells and performed superior to rituximab. In addition, ofatumumab was able to induce
complement-mediated lysis of rituximab-resistant cells expressing low levels of CD20 and high
levels of CD55/CD59. In Trial 402 in CLL patients, ofatumumab treatment in subjects with
relapsed or refractory CLL led to a 50% objective response rate in the highest dose group C (1st
dose: 500 mg; 2nd, 3rd and 4th dose: 2000 mg) and included 12 PRs and one nPR.

The proposed clinical trial will study the effect of 6 cycles of pentostatin, cyclophosphamide, and
ofatumumab (PCO). Pentostatin is selected over fludarabine as the purine nucleoside analogue in
this combination in an effort to improve tolerability. Patients will receive up to 6 cycles of PCO.

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Design & Procedures
Subjects will receive up to 6 cycles of pentostatin, cyclophosphamide, and ofatumamab given
every 21 days (+/- 4 days).

Cycles 1-6 every 3 weeks (21 days)
Pentostatin 2 mg/m2 IV over 30 minutes on Day 1
Cyclophosphamide 600 mg/m2 IV over 30 minutes on Day 1
Pegfilgrastim 6 mg SQ on Day 2

  Cycle 1:
      300 mg IV on Day 1
      1000 mg IV on Day 2
  Cycles 2-6: 1000 mg IV on Day 1

Two months after the last dose of chemotherapy is administered subjects will undergo complete
restaging including bone marrow biopsy to evaluate their response to induction therapy and
assessment of minimal residual disease (MRD) using highly sensitive flow cytometry assays. In
addition to assessing the response rate and tolerability of this regimen, we will compare outcome
of subjects treated with PCO to a well characterized historic cohort of patients treated with PCR.
Subjects not progressing on active treatment will have a bone marrow biopsy 56 days after day 1
of cycle 6 or after the last cycle of treatment for those who stop prior to cycle 6 (± 2 week).

After completion of chemotherapy, subjects will enter follow-up “Observation” for 12 months.
During observation subjects will be seen every 90 days (+/- 2 weeks) for 12 months or until
progression. At progression or after 12 months of Observation follow-up, subjects will enter
“event monitoring” follow up every 6 months for up to 5 years from time of registration.

Ancillary Studies:
The ancillary studies associated with this protocol are primarily intended to evaluate the
following aspects:
1. Test CLL cell sensitivity to ofatumumab complement dependent cytotoxicity.
2. Measure complement activation in CLL cells not killed by ofatumumab in vitro and in vivo.
3. Develop new methods to enhance ofatumumab cytotoxicity.

With the exception of ZAP-70 and IgVH, which will be done for clinical purposes, all other
ancillary studies (such as VEGF, bFGF, thrombospondin, TGF-beta, Peripheral blood
mononuclear cells and plasma used to assess the effects of therapy on immune function, etc) are
for research and will not be charged to the subject. Specimens (blood, bone marrow) will be sent
to Mayo Clinic for specified studies. Subjects will be asked for permission for Mayo to keep any
remaining material remaining for use for future research.

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Selection of Subjects
A maximum of 33 evaluable subjects will be enrolled. An estimated 10 subjects will be enrolled
at Duke. This study will be open to all demographic groups who meet the eligibility criteria.
Inclusion Criteria
1. Diagnosis of CLL according to the NCI criteria or SLL according to the WHO criteria
    This includes previous documentation of:
    • Biopsy-proven small lymphocytic lymphoma
    • Diagnosis of CLL according to NCI working group criteria as evidenced by all of the
            o Peripheral blood lymphocyte count of >5,000/mm3 consisting of small to
                moderate size lymphocytes, with <55% prolymphocytes
            o Immunophenotyping consistent with CLL defined as:
                    The predominant population of lymphocytes share both B-cell antigens
                       (CD19, CD20, or CD23) as well as CD5 in the absence of other pan-T-cell
                       markers (CD3, CD2, etc.)
                    Dim surface immunoglobulin expression
                    Restricted surface κ or λ light chain expression
  NOTE: Splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis
  of CLL. Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by
  demonstrating a negative FISH analysis for t(11;14)(IgH/CCND1) on peripheral blood or
  tissue biopsy or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy.
2. Patients must be previously untreated (see note below) and meet at least one of the following
indications for chemotherapy:
    • Evidence of progressive marrow failure as manifested by the development of or
        worsening anemia (<11 g/dl) and/or thrombocytopenia (<100,000/mm3) not due to
        autoimmune disease
    • Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly.
    • One or more of the following disease-related symptoms:
            o Weight loss >10% within the previous 6 months
            o Extreme fatigue attributed to CLL
            o Fevers >100.5oF for 2 weeks without evidence of infection
            o Drenching night sweats without evidence of infection
    • Progressive lymphocytosis due to CLL with an increase of >50% over a two–month
        period or an anticipated doubling time of less than six months.
       1. Prior chemotherapy or monoclonal antibody based therapy for treatment of CLL will
       be considered prior therapy. Neutraceutical treatments with no established benefit in CLL
       (such as epigallocatechin gallate or EGCG, found in green tea or other herbal treatments)
       will not be considered “prior treatment”.
       2. Marked hypogammaglobulinemia or the development of a monoclonal protein in the
       absence of any of the above criteria for active disease are not sufficient for protocol
3. The following laboratory values obtained ≤14 days prior to registration:
   • Serum creatinine ≤1.5 x UNL

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     •  Total bilirubin ≤1.5 x UNL unless due to Gilbert’s disease. If total bilirubin is >1.5 x
        ULN, a direct bilirubin should be performed and must be <1.5 mg/dL for Gilbert’s to be
     • AST ≤3.0 x UNL and ALT ≤3.0 x UNL (unless due to hemolysis or CLL)
4.   ≥18 years.
5.   ECOG performance status (PS): 0, 1, or 2
6.   Willingness to provide blood samples as required.
7.   Able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria
1. Any of the following comorbid conditions:
   • New York Heart Association Class III or IV heart disease
   • Recent myocardial infarction (<1 month)
   • Uncontrolled infection
   • Infection with the human immunodeficiency virus (HIV/AIDS) as further severe
       immunosuppression with this regimen may occur.
   • Infection with known chronic, active Hepatitis B or C or Hepatitis B carriers
2. Any of the following because this study involves an investigational agent whose genotoxic,
   mutagenic and teratogenic effects on the developing fetus and newborn are unknown.
   • Pregnant women
   • Nursing women
   • Men or women of childbearing potential who are unwilling to employ adequate
3. Other active primary malignancy requiring treatment or limiting survival to ≤2 years.
4. Any radiation therapy ≤4 weeks prior to registration.
5. Any major surgery ≤ 4 weeks prior to registration.
6. Current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone
   or equivalent dose of other steroid) used for treatment of non-hematologic medical
   conditions. NOTE: Previous use of corticosteroids is allowed.
7. Active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic
   treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT
   excluded from participation.

Subject Recruitment and Compensation
Subjects will be identified from the patient populations of Duke University Medical Center
Hematologic Malignancies Program. A waiver for review of potential subjects’ medical records
prior to consent was included with the initial submission. Subjects will not receive
compensation for participating in this study.

Subject’s Capacity to Give Legally Effective Consent
Only subjects competent to give informed consent will be enrolled in this study.

Risk/Benefit Assessment
In order to minimize risks the following will be done.

Risk of infection/febrile neutropenia: Pegfilgrastim will be given at each cycle.

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Ofatumumab infusion-related symptoms:
The incidence of ofatumumab infusion-related symptoms was highest during the first infusion
and decreased substantially with subsequent infusions. Implementation of premedication before
infusions has reduced the number as well as the severity of infusion related adverse events. In
order to minimize the risk of infusion reactions, the initial dose of ofatumumab will be given
over 2 days. The infusion rate will be gradually increased during the cycle 1 day 1 infusion.
Vital signs are recommended to be measured every 15 minutes for the first 2 hours with the first
dose of ofatumumab, with each dose escalation and then as clinically indicated.
All subjects will receive the following medications 30 to 60 minutes prior to all ofatumumab
    • 1000mg Acetaminophen (po) or equivalent,
    • 50 mg Antihistamine (iv or po) diphenhydramine or equivalent
    • Glucocorticoid (iv) hydrocortisoneor equivalent

Per DUHS IRB requirements for category D drugs, 2 forms of contraception will be required to
be used at the same time.

Emesis: Antiemetic medications will be given prior to ofatumumab infusions. Patients will be
encouraged to drink fluids the night before treatment and will receive approximately 500 to 1000
mL of IV hydration over 1 hour prior to chemotherapy on days they receive pentostatin and

Tumor lysis: All patients must receive daily allopurinol (300 mg/day PO) for tumor lysis for
days 1-14 of Cycle 1 of PCO unless they have experienced hypersensitivity to allopurinol in the
past. The need for allopurinol with subsequent induction cycles is left to the discretion
of the treating physician.

Bactrim DS 1 tablet PO daily (or alternative Pneumocystis pneumonia prophylaxis) on
Monday/Wednesday/Friday AND acyclovir 400 mg PO twice daily (or equivalent) during
treatment with PCO and for 6 months after completion of induction therapy.

Dose modifications to ofatumumab, pentostatin and cyclophosphamide will be implemented for
a variety of adverse events and are specified in detail in the research protocol. Subjects will
receive full supportive care, including transfusions of blood and blood products, antibiotics, and
antiemetics when appropriate.

Available alternatives include other chemotherapy or chemoimmunotherapy regimens such as
pentostatin, cyclophosphamide and rituximab, and other research studies. Subjects may opt for
no treatment and supportive care only. Possible benefit from taking part in this study is disease

Costs to the Subject
Research tests done by Mayo Clinic on blood and bone marrow specimens will be not charged to
the subject. Ofatumumab will be provided free of charge. All other costs, including infusion
costs and pentostatin and cyclophosphamide,will be charged to the subject.

Data Analysis & Statistical Considerations

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Primary Endpoint: The primary endpoint of this trial is the proportion of complete responses.
Throughout this section, complete response will be considered synonymous with “success”,
unless specified otherwise. A complete response is defined to be a CR noted as the objective
status. Response will be evaluated 2 months after the completion of treatment (56 days after day
1 of or last cycle treatment for those discontinuing treatment before cycle). All subjects meeting
the eligibility criteria who have signed a consent form and have begun treatment will be
evaluable for response.

Sample Size: A maximum of 30 evaluable subjects will be accrued onto this phase II study
unless undue toxicity is encountered. We anticipate accruing an additional 3 subjects to account
for ineligibility, cancellation, major treatment violation, or other reasons. Therefore, the
maximum total sample size will be 33 subjects.

Statistical Design:
Decision Rule: In 3 out of 4 large randomized studies of purine nucleoside analogs in
combination with cyclophosphamide in patients with previously untreated CLL, the CR rate was
approximately 25%. It is expected that the addition of ofatumumab to the combination of a
purine nucleoside analog and cyclophosphamide will increase the CR rate. A 50% response rate
to PCO will be considered adequate evidence of promising activity and may lead to a
recommendation that this regimen be tested further in subsequent studies.

Therefore, the largest success proportion where the proposed treatment regimen would be
considered ineffective in this population is 25%, and the smallest success proportion that would
warrant subsequent studies with the proposed regimen in this patient population is 50%. The
following one-stage design uses 30 evaluable patients to test the null hypothesis that the true
success proportion in a given population is at most 25%.

Final Decision Rule: If 11 or fewer successes are observed in all 30 evaluable subjects accrued,
we will consider this regimen ineffective in this population. If 12 or more successes are
observed, this will be considered sufficient evidence that this treatment may be recommended for
further testing in subsequent studies.

Power and Significance Level: Assuming that the number of successes is binomially distributed,
the significance level is 0.05. The probability of declaring that this regimen warrants further
studies (i.e. statistical power) under various success proportions can be tabulated as a function of
the true success proportion as shown in the following table:

 If the true success proportion is...         0.25       0.3      0.35        0.4      0.45       0.5
 Then the probability of declaring that the
 regimen warrants further study is…           0.05      0.16      0.35      0.57       0.77       0.9

Data & Safety Monitoring
Subject research charts will be kept in locked offices of Hematologic Malignancies group.
Research records will be archived upon completion of the study. Subject study number and
initials will be used to identify subjects in the eCRFs/CRFs and on any samples sent to central

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The study chair(s) and the study statistician will review the study at least twice a year to identify
accrual, adverse event, and any endpoint problems that might be developing. The Mayo Clinic
Cancer Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible for reviewing
safety data for this trial at least twice a year, based on reports provided by the MCCC Statistical

Accrual will be temporarily suspended to this study if at any time we observe events considered
at least possibly related to study treatment (i.e. an adverse event with attribute specified as
“possible”, “probable”, or “definite”) that satisfy either of the following:
     • if 4 or more subjects in the first 15 treated subjects experience a grade 4 or higher non-
         hematologic adverse event at least possibly related to treatment.
     • if after the first 15 subjects have been treated, 30% of all subjects experience a grade 4 or
         higher non-hematologic adverse event at least possibly related to treatment.

Mayo will review grade 4 and 5 adverse events deemed “unrelated” or “unlikely to be related”,
to verify their attribution and to monitor the emergence of a previously unrecognized treatment-
related adverse event.

Version 12/30/2009                                                                                      7

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