FDA Briefing Document NDA 21-673 Clolar® (clofarabine) Injection by omq25257

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									                                         NDA 21673
ODAC Briefing Document                   Clolar (Clofarabine)




                FDA Briefing Document
                      NDA 21-673
             Clolar® (clofarabine) Injection
                   September 1, 2009

        APPLICANT: Genzyme Corporation




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ODAC Briefing Document                                                                             Clolar (Clofarabine)


                                                      Contents
PROPOSED INDICATION............................................................................................. 4
EXECUTIVE SUMMARY .............................................................................................. 4
DESCRIPTION................................................................................................................. 5
BACKGROUND ............................................................................................................... 6
  Study Design .................................................................................................................. 7
  Study Objectives............................................................................................................ 7
    Primary Objective..................................................................................................... 7
    Secondary Objectives ............................................................................................... 7
  Inclusion Criteria .......................................................................................................... 7
  Exclusion Criteria ......................................................................................................... 8
  Treatment ...................................................................................................................... 9
  Study Results ............................................................................................................... 10
    Patient Enrollment by Site ..................................................................................... 10
    Baseline Prognostic Factors ................................................................................... 12
    Efficacy Results ....................................................................................................... 13
          Suitability for Standard Induction Chemotherapy or Other Intensive
    Chemotherapy Based on Protocol Specified AML Prognostic Factors ............. 15
          Suitability for Standard Induction Chemotherapy or Other Intensive
    Chemotherapy Based on Subsequent Therapy After Clolar .............................. 16
    Safety Results .......................................................................................................... 16
SUPPORTIVE STUDY (BIOV-121 .............................................................................. 19
FDA REVIEWER COMMENTS .................................................................................. 19
  Study Design ................................................................................................................ 19
  Study Objectives.......................................................................................................... 19
  Inclusion/Exclusion Criteria ...................................................................................... 20
  Treatment .................................................................................................................... 20
  Study Results ............................................................................................................... 21
    Patient Enrollment by Site ..................................................................................... 21
    Baseline Characteristics ......................................................................................... 22
    Response Criteria.................................................................................................... 23
    Efficacy Results ....................................................................................................... 23
    Safety Results .......................................................................................................... 24
ISSUES FOR ODAC CONSIDERATION…………………………………………...27
REFERENCES................................................................................................................ 27




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                                                     Table of Tables
Table 1 Patient Enrollment by Site ............................................................................ 10
Table 2 Patient Disposition ............................................................................................ 11
Table 3 Baseline Prognostic Factors ............................................................................ 12
Table 4 Response............................................................................................................ 13
Table 5 Response by Cycle ............................................................................................ 13
Table 6 Response Duration ........................................................................................... 14
Table 7 Survival Time ................................................................................................... 14
Table 8 Probability of Survival..................................................................................... 14
Table 9 Patients with Intermediate Karyotype Risk .................................................. 15
Table 10 Subsequent therapy after Clolar................................................................... 16
Table 11 Extent of Clolar Exposure ............................................................................. 16
Table 12 Overall Summary of Adverse Events ........................................................... 17
Table 13 Cause of Death Within 30 Days of First Dose.............................................. 18
Table 14 Selected Grade 3 or 4 Adverse Events Regardless of Relationship to Clolar
........................................................................................................................................... 18
Table 15 Patient Enrollment by Site ............................................................................ 21
Table 16 Baseline Characteristics................................................................................. 22
Table 17 Efficacy............................................................................................................ 23
Table 18 Best Response by Cycle.................................................................................. 24
Table 19 Survival Probability ....................................................................................... 24
Table 20 Number of Cycles of Clofarabine Received ................................................. 25
Table 21 AEs Grade 3 or Greater Occurring in at least 5% of Patients N=66 ....... 26




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PROPOSED INDICATION
Clolar is indicated for the treatment of previously untreated adults aged 60 years or older
with acute myeloid leukemia with at least one unfavorable baseline prognostic factor.

EXECUTIVE SUMMARY

The main study is a Phase 2 single arm study (CLO24300606) of 116 patients titled “A
Phase II Study of Single Agent Clofarabine in Previously Untreated Older Adult Patients
with Acute Myelogenous Leukemia (AML) for Whom Standard Induction Chemotherapy
is Unlikely to be of Benefit”.

Two other supportive Phase 2 single arm studies were submitted. Study BIOV-121 was
conducted by a predecessor Company in the UK, Ireland and Italy. Genzyme conducted
retrospective monitoring of case report form data for all patients where possible. Sixty-
six patients age 65 years or older with newly diagnosed AML considered not suitable for
intensive chemotherapy were studied. The critical inclusion criteria in the main study
(CLO24300606) (at least 1 of the following adverse AML prognostic factors: Age ≥70
years; or AHD; or ECOG performance status of 2; or intermediate or unfavorable
karyotype) were not part of this study protocol. Investigators decided which patients were
not suitable for intensive chemotherapy. Most patients in this study had intermediate
karyotype (65-73% depending on the classification used). Other differences from the
main study were a different Clolar treatment regimen and lack of an independent review
board to confirm the diagnosis of AML, the response rates and the response duration.
Study UWCM-0001 was conducted at 10 sites in the UK. Forty patients age 60 years or
older with untreated AML considered not suitable for intensive chemotherapy were
studied. Individual patient data are not submitted for this study without which the
required FDA independent and in depth review can not be done. This study is not
included in this Briefing Document.

In the main study (CLO24300606) 112 patients were included in the analysis. The CR +
CRp rate was 45.5% (95% CI 36.1-55.2), median duration of response for CR + CRp was
51.6 weeks (95% CI 33.1-68.7), median overall survival was 40.7 weeks (95% CI 28.3-
52.0) and median survival for patients with CR + CRp was 60.8 weeks (95% CI 49.9-
76.6). It is important to understand that this was not a study of elderly AML patients who
were not fit for standard induction chemotherapy because of poor general health. Patients
were eligible for the study because they had one or more of four adverse AML prognostic
factors specified in the protocol eligibility criteria. On this basis they were deemed
unsuitable (unlikely to benefit from) standard induction or other intensive chemotherapy.

Focusing on the main study (CLO24300606), the first issue is that a substantial number
of study patients (25% and possibly as many as 41%) may have been suitable




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candidates for standard induction chemotherapy or other intensive chemotherapy, based
on the four protocol specified adverse AML prognostic factors. This is supported by the
fact that post Clolar, 23 (21%) study patients did receive such therapy with a 48% CR or
Cri/CRp rate. In addition another 12 (11%) study patients had hematopoietic stem cell
transplantation post Clolar. The second issue is that the lack of a randomized study
combined with the heterogeneous patient population regarding AML prognostic factors
makes interpretation of the study results difficult.

There was no Special Protocol Assessment for any of the Clolar studies presented in this
ODAC Briefing Document. Minutes of a Pre-SNDA meeting on 12/4/07 state the
following regarding whether the results of study CLO243 would be sufficient to achieve
approval of the proposed new indication. “Determination of a clinically meaningful
complete response rate and response duration along with an acceptable safety profile will
be a review issue. Generally, approval of new drugs for initial treatment
of AML is based on results of randomized controlled trials. It will be difficult to interpret
the results of this trial without a control; we recommend that you conduct a randomized
controlled study.” The FDA believes that cross study comparison is generally not an
appropriate scientific basis for drug marketing approval and is especially not appropriate
for single arm studies.

The only previous Application for initial treatment of elderly patients with AML was
Zarnestra (tipifarnib), presented to the ODAC in May 2005. This application had
similarities to this Clolar application in that there was no randomized controlled study
and many of the patients could have been treated with standard induction chemotherapy.
The ODAC cited lack of a randomized study and the fact that many of the patients were
suitable candidates for standard induction chemotherapy in voting against approval
(7 No and 4 Yes).


DESCRIPTION

Clofarabine is a halogenated purine nucleoside analog with the following molecular
structure:




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BACKGROUND

Elderly patients with AML get poorer treatment results than younger patients. According
to Medicare records, only 30% of a cohort of 2657 patients older than 65 years was
provided chemotherapy treatment 1 . In comparison data from the Swedish Leukemia
Registry shows that 45% of 1842 patients 65 years or older were treated with standard
induction chemotherapy 2 . Some individual elderly patients get excellent results with
standard induction chemotherapy or other intensive chemotherapy.

There was no Special Protocol Assessment for any of the Clolar studies presented in this
ODAC Briefing Document. Minutes of a Pre-SNDA meeting on 12/4/07 state the
following regarding whether the results of study CLO243 would be sufficient to achieve
approval for the proposed new indication. “Determination of a clinically meaningful
complete response rate and response duration along with an acceptable safety profile will
be a review issue. Generally, approval of new drugs for initial treatment of AML is based
on results of randomized controlled trials. It will be difficult to interpret the results of this
trial without a control; we recommend that you conduct a randomized controlled study.”
The FDA believes that cross study comparison is generally not an appropriate scientific
basis for drug marketing approval and is especially not appropriate for single arm studies.

The only previous Application for initial treatment of elderly patients with AML was
Zarnestra (Tipifarnib), presented to the ODAC in May 2005. This Application had
similarities to the Clolar Application in that there was no randomized controlled study
and many of the patients could have been treated with standard induction chemotherapy.
The ODAC cited lack of a randomized study and the fact that many of the patients were
suitable candidates for standard induction chemotherapy in voting against approval
(7 No and 4 Yes).




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MAIN CLOLAR STUDY (CLO24300606)

Study Design

This is a Phase 2 single arm study of 116 elderly patients with previously untreated acute
myeloid leukemia conducted at 20 sites in the United States and Canada.

Study Objectives

Primary Objective
• To assess the efficacy of clofarabine in previously untreated adult
  Patients ≥60 years old with AML for whom standard induction
  chemotherapy is unlikely to be of benefit. The primary efficacy endpoint
  is ORR, where ORR is defined as a patient achieving either CR or CRp.
Secondary Objectives
• To assess the duration of remission.
• To evaluate disease-free survival (DFS).
• To evaluate OS.
• To assess the 30-day mortality rate (i.e., rate of deaths occurring between
  Day 1 and Day 30 of the Induction Cycle).
• To evaluate the safety and tolerability of clofarabine and the duration, severity (graded
using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events
[CTCAE] version 3.0) and relationship of adverse events (AEs) that occur during the
treatment and follow-up periods.

Inclusion Criteria
1. Diagnosis of AML (de novo, secondary, or with an AHD) according to the WHO
criteria.
2. Age ≥60 years.
3. ECOG performance status 0-2.
4. At least 1 of the following adverse prognostic factors:
         • Age ≥70 years; or
         • AHD; or
         • ECOG performance status of 2; or
         • Intermediate or unfavorable (i.e., adverse) karyotype defined as any cytogenetic
           profile except the presence of any of the following (Appelbaum Blood 2006;
           Grimwade Blood 1998):
                  o t (8;21) (q22;q22).
                  o inv(16)(p13q22) or t(16;16)(p13;q22).
                  o t(15;17)(q22;q12) and variants.
5. Provide signed written informed consent.
6. Be able to comply with study procedures and follow-up examinations.
7. Be non-fertile or agree to use birth control during the study through the end of last
treatment visit.



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8. Adequate renal and hepatic function as indicated by all of the following:
       • Total bilirubin ≤1.5 × institutional Upper Limit of Normal (ULN); and
       • AST and ALT ≤2.5 × ULN; and
       • Serum creatinine ≤1.0 mg/dL; if serum creatinine >1.0 mg/dL, then the
         estimated glomerular filtration rate (GFR) must be >60 mL/min/1.73 m2 as
         calculated by the Modification of Diet in Renal Disease (MDRD) equation.
9. Adequate cardiac function as measured by at least 1 of the following:
       • Left ventricular ejection fraction (LVEF) ≥40% on multigated acquisition
         (MUGA) scan or similar radionuclide angiographic scan; or
       • Left ventricular fractional shortening ≥22% on echocardiography exam; or
       • LVEF ≥40% on echocardiography exam.

Exclusion Criteria
1. Diagnosis of acute promyelocytic leukemia (APL, French-American-British [FAB]
classification M3 or WHO classification of APL with t(15;17)(q22;q12), (PML/RARα
and variants)
2. Prior treatment with clofarabine.
3. Prior treatment for AML or an AHD (excluding supportive care, hydroxyurea,
hematopoietic cytokines, or lenalidomide [the latter specifically for an AHD only]).
hematopoietic cytokines and lenalidomide must not have been received within 14 days
prior to first dose of study drug; hydroxyurea must not have been received within 24
hours prior to first dose of study drug. If any of the above treatments had been received
for AML or an AHD within the permissible time periods, drug-related toxicities had to
have recovered to Grade 1 or less prior to first dose of study drug.
4. Prior hematopoietic stem cell transplant (HSCT).
5. Prior external beam radiation therapy to the pelvis.
6. Investigational agent received within 30 days prior to the first dose of study drug. If
received any investigational agent prior to this time point, drug-related toxicities had to
have recovered to Grade 1 or less prior to first dose of study drug.
7. Psychiatric disorders that would interfere with consent, study participation, or follow-
up.
8. Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting
ongoing signs/symptoms related to the infection and without improvement, despite
appropriate antibiotics or other treatment).
9. Any other severe concurrent disease, or have a history of serious organ dysfunction or
disease involving the heart, kidney, liver or other organ system that could place the
patient at undue risk to undergo therapy with clofarabine.
10. Diagnosis of another malignancy, unless the patient had been disease-free for at least
5 years following the completion of curative intent therapy with the following exceptions:
        • Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical
           Intraepithelial neoplasia, regardless of the disease-free duration, were to be
           eligible for this study if definitive treatment for the condition had been
          completed.
        • Patients with organ-confined prostate cancer with no evidence of recurrent or



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        progressive disease based on prostate-specific antigen (PSA) values were also to
         be eligible for this study if hormonal therapy had been initiated or a radical
         prostatectomy had been performed.
11. Clinical evidence suggestive of central nervous system (CNS) involvement with
leukemia unless a lumbar puncture were to confirm the absence of leukemic blasts in the
cerebrospinal fluid (CSF).
12. Prior positive test for the human immunodeficiency virus (HIV).

Treatment

Induction (Cycle 1)
Patients were to receive an induction cycle of clofarabine 30 mg/m2/day as a 1-hour IV
infusion for 5 consecutive days (Treatment Cycle Days 1-5). Patients could then receive
up to 5 additional cycles, repeated minimally every 28 days, of clofarabine 20 mg/m2/day
as a 1-hour IV infusion for 5 consecutive days (Treatment Cycle Days 1-5).
Re-Induction (Cycle 2)
For patients who had not achieved a CR or CRp, the planned clofarabine dose and
schedule to be administered for re-induction was to be 20 mg/m2/day as a 1-hour IV
infusion for 5 consecutive days (Days 1-5). Prior to and during each treatment cycle, a
complete toxicity assessment was to be undertaken, incorporating dose modifications, as
detailed in the protocol.
Cycle 2: Consolidation and Cycles 3-6: Consolidation
Only patients who had attained a documented remission (i.e., CR or CRp after not more
than two treatment cycles) were to be allowed to continue with consolidation. The
planned clofarabine dose and schedule to be administered for consolidation was 20
mg/m2/day as a 1-hour IV infusion for 5 consecutive days (Days 1-5). Prior to and during
each treatment cycle, a complete toxicity assessment was to be undertaken, incorporating
dose modifications as required.




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Study Results

Patient Enrollment by Site

                              Table 1      Patient Enrollment by Site

                                                                                     Number of
                                                                                      Patients
Site                                                                                  Enrolled
Number      Institution Name                              Principal Investigator    Number (%)
            University of Texas MD Anderson Cancer
001         Center                                        Hagop Kantarjian, MD        26 (22.4)
003         Arizona Cancer Center                          Andrew Yeager, MD           4 (3.4)
004         USC Norris Comprehensive Cancer Center           Dan Douer, MD             4 (3.4)
006         Cancer Center of Central Connecticut             Peter Byeff, MD           1 (0.9)
007         Penn State Hershey Medical Center               David Claxton, MD         13 (11.2)
            Oregon Health and Science University
009         Center for Hematological Malignancies         Tibor Kovacsovics, MD        6 (5.2)
            Emory University School of Medicine,
010         Winship Cancer Institute                       Martha Arellano, MD         11 (9.5)
            University of Michigan Comprehensive
012         Cancer Center                                  Harry Erba, MD, PhD        14 (12.1)
013         Mayo Clinic Hospital, Phoenix                    James Slack, MD           1 (0.9)
            University of Utah, Huntsman Cancer
014         Institute                                        Paul Shami, MD            4 (3.4)
017         West Virginia University Hospital               Michael Craig, MD          4 (3.4)
021         Mount Sinai Medical Center                     Janice Gabrilove, MD        5 (4.3)
022         Vanderbilt University Medical Center           Madan Jagasia, MD           1 (0.9)
023         Scripps Cancer Center (San Diego)               James Mason, MD            2 (1.7)
024         Seattle Cancer Care Alliance                  Stephen Petersdorf, MD       4 (3.4)
026         Medical College of Georgia                      Anand Jillella, MD         2 (1.7)
                                                         Parameswaran Venugopal,
028
            Rush University Medical Center                        MD                   1 (0.9)
            Beth Israel Deaconess Medical Center and
030         Massachusetts General Hospital                  David Avigan, MD           2 (1.7)
031         Rocky Mountain Cancer Centers - Denver         Michael Maris, MD           4 (3.4)
034         Cancer Care Centers of South Texas              Roger Lyons, MD            7 (6.0)
Applicant Table




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Patient Disposition

Table 2 shows patient disposition in the study. A total of 112 patients are included in
analyses of the study.


                               Table 2 Patient Disposition




    Applicant Table




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Baseline Prognostic Factors


                       Table 3 Baseline Prognostic Factors




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1
  Antecedent hematologic disorder.
2
  Scale: 0 (fully active), 1 (capable of light work), 2 (no work but all self-care), 3 (limited
   self-care), 4 (completely disabled), 5 (dead).
3
  Defined as any cytogenetic profile except the presence of any of the following:
   t(8;21)(q22;q22); inv(16)(p13q22) or t(16;16)(p13;q22); t(l5;17)(q22;qI2) and variants.
4
  The diagnosis of secondary AML is based upon investigator judgment. -
5
  FLT status was not required by the protocol and was therefore not collected for all
   patients. Applicant Table

Efficacy Results

Each patient’s diagnosis was confirmed by central pathology review. Response and
response duration were determined by an Independent Response Review Panel.
Responses to Clolar are shown in Table 4.

                                             Table 4 Response
        N=112                  Response N (%)                           95% CI
        ORR                      51 (45.5%)                             36.1-55.2
         CR                      42 (37.5%)                             28.5-47.1
         CRp                      9 (8.0%)                                 ND
         PR                       4 (3.6%)                                 ND
         TF                      57 (50.9%)                                ND
ORR=Cr = CRp, CR=Complete Remission, CRp=Complete Remission with incomplete platelet
recovery, PR=Partial Remission, TF=Treatment Failure.
Response definitions for CR, CRp, partial remission (PR), treatment failure, and disease
recurrence for this study were derived from the revised recommendations of the International Working Group for
Response Criteria (Cheson J Clin Oncol 2003).
ND=Not Done


Thirty eight of the 51 patients with CR or CRp responded after one cycle of Clolar as
shown in Table 5.
                                       Table 5 Response by Cycle

Entered Cycle 1                                                                     112
Achieved CR or CRp in Cycle 1                                                   38 (33.9%)
Cycle 1 Non-Responders Who Discontinued                                        39/74 (52.7%)
Before Cycle 2
Cycle 1 Non-Responders Who Entered Cycle                                       35/74 (47.3%)
2
Achieved CR or CRp in Cycle 2                                                     13 (11.6%)




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Clolar response durations are shown in Table 6. Median follow-up for response duration
was 17.1 weeks (95% CI 0.1-91.7).

                                       Table 6 Response Duration
                               Median Response                     95% CI                       Censored
                                  Duration
         ORR                     51.6 weeks                       33.1-68.7                       54.9%
          CR                     60.7 weeks                       33.1-82.9                       57.1%
         CRp                         ND                              ND                            ND


Median survival times after Clolar treatment are shown in Table 7. Median follow-up for
overall survival was 46.7 weeks (95% CI 0.9-119.7).

                                          Table 7 Survival Time
       N=112                   Median Survival                     95% CI                       Censored
     All Patients                40.7 weeks                       28.3-52.0                      25.9%
        ORR                      60.8 weeks                       49.9-76.6                      35.3%
         CR                      65.3 weeks                       52.0-102.6                     38.1%
         CRp                         ND                              ND                           ND

ORR=CR+CRp, CR=Complete Remission, CRp=Complete Remission with incomplete platelet
recovery, PR=Partial Remission, TF=Treatment Failure, ND=Not Done

Response definitions for CR, CRp, partial remission (PR), treatment failure, and disease
recurrence for this study were derived from the revised recommendations of the International Working Group for
Response Criteria (Cheson J Clin Oncol 2003).


Kaplan Meir estimates of survival at 6, 12, 18 and 24 months are shown in Table 8.
                                    Table 8 Probability of Survival

Time Interval                6 months               12 months               18 months               24 months
Probability of                60.5%                  40.5%%                   24.3%                   15.2%
Survival




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Suitability for Standard Induction Chemotherapy or Other Intensive
Chemotherapy Based on Protocol Specified AML Prognostic Factors

The protocol indicates that intermediate karyotype risk alone regardless of other
prognostic factors makes patients unsuitable for (unlikely to benefit from) standard
induction chemotherapy or other intensive chemotherapy. The FDA disagrees with this.
Thus the FDA analyzed the 46 patients in the study with intermediate karyotype risk to
see if they had any of the other protocol specified adverse AML prognostic factors
that would make them unsuitable for standard induction chemotherapy or other intensive
chemotherapy. Acknowledging that AML experts may disagree among themselves, the
FDA believes based on protocol specified AML prognostic factors that 28 (25%) and
possibly 46 (41%) of the 112 patients in this study may have been suitable for standard
induction chemotherapy or other intensive chemotherapy (See Table 9).

                  Table 9 Patients with Intermediate Karyotype Risk
                                         N=46

 AHD*        AGE YRS.          ECOG     NUMBER             Suitable for Standard
                                           OF            Induction Chemo or Other
                                        PATIENTS             Intensive Chemo
   No            < 70            0-1        7                       Yes
   No            < 70             2         4                       Yes
   No            ≥ 70            0-1       15                       Yes
   Unk           < 70            0-1        1                       Yes
   Unk           ≥ 70            0-1        1                       Yes
   No            ≥ 70             2         6                       No ?
   Yes           < 70            0-1        3                       No ?
   Yes           ≥ 70            0-1        8                       No ?
   Yes           ≥ 70             2         1                       No ?
* AHD=antecedent hematologic disorder




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Suitability for Standard Induction Chemotherapy or Other Intensive
Chemotherapy Based on Subsequent Therapy After Clolar

The FDA position that a substantial number of elderly AML patients in this study were
suitable for standard induction chemotherapy or other intensive chemotherapy and would
have benefited from such therapy is also supported by the fact that 12 patients were
subsequently transplanted after Clolar. In addition another 23 patients received intensive
chemotherapy after Clolar with a CR+Cri/CRp rate of 48%. In all 59 (53%) of the 112
study patients received some additional therapy after Clolar (See Table 10).


                          Table 10 Subsequent therapy after Clolar
Total Patients with Subsequent Rx                   59 of 112 (53%)
    HSCT                                            12 of 112 (11%)
    *Intensive Chemotherapy                         23 of 112 (21%)
            CR+CRi/CRp                                                   11 of 23 (48%)
            CR                                                            8 of 23 (35%)
            CRi/CRp                                                       3 of 23 (13%)
*Intensive chemotherapy regimens included Ara-c + anthracycline (14), Ara-c + Topotecan (2),
 Ara—c + mitoxantrone + etoposide (2), Ara-c + mitoxantrone + etoposide + lestaurtinib (1),
 mitoxantrone + etoposide (1), Ara-c + Fludara (2), high dose Ara-C (1)



Safety Results

The extent of Clolar exposure over 6 cycles is shown in Table 11.

                             Table 11 Extent of Clolar Exposure




  Applicant Table




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Table 12 shows an overall summary of adverse events in the study.

                       Table 12 Overall Summary of Adverse Events
                                                                                                   Total
Category                                                                                         (N=112)
                                                                                                    112
Patients with any treatment-emergent AE regardless of relationship to study drug
                                                                                                 (100.0%)
Patients with any treatment-emergent AE related to study drug                                  108 (96.4%)
Patients with any treatment-emergent serious AE regardless of relationship to study drug        76 (67.9%)
Patients with any treatment-emergent serious AE related to study drug                           41 (36.6%)
Patients who discontinued due to any adverse event                                               7 (6.3%)
Patients who died during the study or within 45 days of the last dose                          22 (19.6%)
Patients who died due to drug-related AEs                                                        4 (3.6%)
Patients who died within 30 days of clofarabine dose (30-day mortality)                         11 (9.8%)
Patients who died within 30 days of first clofarabine dose due to drug-related AEs               3 (2.7%)
Patients with any treatment-emergent AE with a maximum (worst)
NCI Common Terminology Criteria of:
Grade 1                                                                                          2 (1.8%)
Grade 2                                                                                          6 (5.4%)
Grade 3                                                                                         46 (41.1%)
Grade 4                                                                                         34 (30.4%)
Grade 5                                                                                         24 (21.4%)
-Applicant Table




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Table 13 shows the causes of death within 30 days of the first Clolar dose.

                  Table 13 Cause of Death Within 30 Days of First Dose




    Applicant Table



Table 14 shows selected NCI CTC grade 3 or 4 adverse events regardless of investigator
assessment of relation to Clolar.
Table 14 Selected Grade 3 or 4 Adverse Events Regardless of Relationship to Clolar
                                         N=112
Adverse Event                         Grade 3 (%)                    Grade 4 (%)
Febrile Neutropenia                    68 (60.7%)                      3 (2.7%)
Pneumonia                              19 (16.9%)                      7 (6.3%)
Staph Bacteremia                       12 (10.7%)                      0 (0.0%)
Thrombocytopenia                        1 (0.9%)                      16 (14.3%)
Renal Failure Acute &*                  9 (8.0%)                       1 (0.8%)
Other
Dyspnea                                  7 (6.3%)                       4 (3.6%)
Atrial Fibrillation                      4 (3.6%)                       3 (2.7%)
ALT                                     11 (9.8%)                       0 (0.0%)
AST                                     13 (11.6%)                      2 (1.8%)
Hypokalemia                            17 (15.2 %(                      2 (1.8%)
Hypertension                           13 (11.6%)                       0 (0.0%)
*3 patients with grade 5 (deaths)


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SUPPORTIVE STUDY (BIOV-121

FDA REVIEWER COMMENTS

Study BIOV-121 was conducted by a predecessor Company in the UK, Ireland and Italy.
Genzyme conducted retrospective monitoring of case report form data for all patients
where possible. Sixty-six patients age 65 years or older with newly diagnosed AML
considered not suitable for intensive chemotherapy were studied. The investigators
decided which patients were not candidates for standard induction chemotherapy or other
intensive chemotherapy without the specific protocol guidance in the main study
(CLO24300606). Namely the critical inclusion criteria in the main study
(CLO24300606) (at least 1 of the following adverse prognostic factors: Age ≥70 years;
or AHD; or ECOG performance status of 2; or intermediate or unfavorable karyotype)
were not part of this study protocol. Other differences from the main study were a
different Clolar treatment regimen and lack of an independent review board to confirm
the diagnosis of AML, the response rates and response duration. Most patients in this
study had intermediate karyotype (65-73% depending on the classification used).

Study Design

This is a Phase 2 single arm study in 66 patients 65 years or older with previously
untreated AML for whom intensive chemotherapy was not considered suitable.

Study Objectives

Primary Objective:
To determine the overall response (OR) rate of older patients with untreated acute
myeloid leukemia (AML), for whom intensive chemotherapy is not considered suitable,
when given clofarabine at the study dose and schedule.
Secondary Objective:
1. To document the rate of complete remission(s) (CR) in the study population
2. To document the rate of complete remission(s) with incomplete blood count recovery
(CRi) in the study population
3. To document the rate of partial remission(s) (PR) in the study population
4. To document time to event parameters including:
a) duration of CR, b) overall survival (OS), c) time to CR, d) duration of OR
5. To document the safety profile and tolerability of clofarabine for this population and
dosing regimen
6. To determine the pharmacokinetic profile and intracellular triphosphate levels of
clofarabine in the study population.




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ODAC Briefing Document                                          Clolar (Clofarabine)

Inclusion/Exclusion Criteria
• Male and post-menopausal female patients with untreated AML as defined by the
   world health organization classification
• ≥ 65 years of age and were considered unsuitable for intensive chemotherapy.
• Patients had to have adequate organ function (alanine aminotransferase [ALT] and
   aspirate aminotransferase [AST] of <2x uln, serum bilirubin of <1.5x uln, serum
   creatinine of <1.7g/dl [or <1.5x uln], and prothrombin time of <1.5x control).

Treatment

The dose and number of scheduled cycles of clofarabine treatment was amended during
the study. Thus depending on when a patient was enrolled, they received one of the
following regimens:
• 30 mg/m2/day for 5 days, for a maximum of six cycles* (according to Protocol
Amendment 2)
• 30 mg/m2/day for 5 days for one cycle, followed by 20 mg/m2/day for subsequent
cycles, up to a maximum of three cycles according to Protocol Amendment 3
Study drug was administered daily over 1 hour, for five consecutive days and repeated
every 28 to 42 days (one cycle) for a maximum of six cycles. This was changed in
Protocol Amendment 3 to every 29 to 43 days for the second and subsequent cycles, and
up to a maximum of 3 cycles.




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ODAC Briefing Document                                                                Clolar (Clofarabine)

Study Results

Patient Enrollment by Site

                                 Table 15 Patient Enrollment by Site
Site       Investigator              Institution                                         No. of     % of
                                                                                        Patients    Total
                                                                                                   (N = 66)
United Kingdom
1          Prof. Alan Burnett        University of Wales College of Medicine,              6          9
                                     Cardiff
2          Prof. Nigel Russell       Nottingham City Hospital, Nottingham                  9         14
5          Dr. Dominic Culligan      Aberdeen Royal Infirmary, Aberdeen                    3          5
7          Prof. John Yin            Manchester Royal Infirmary, Manchester                6          9
9          Dr. Don Milligan                                                                4          6
                                     Birmingham Heartlands Hospital, Birmingham
10         Dr. Richard Clark                                                               3          5
                                     Royal Liverpool University Hospital, Liverpool

12         Dr. Steve Johnson         Taunton and Somerset Hospital, Somerset               2          3
13         Dr. Mary McMullin         Belfast City Hospital, Belfast                        5          8
15         Dr. Ann Hunter            Leicester Royal Infirmary, Leicester                  3          5
17         Dr. Peter Johnson         Western General Hospital, Edinburgh                   7         11
19         Dr. Robert Carr           Guy’s and St Thomas’ Hospital, London                 3          5
25         Prof. Ghulam Mufti        Kings College Hospital, London                        0
29         Dr. Michael Dennis        Christie Hospital NHS Trust, Manchester               4          6
Italy
26         Prof. Sergio Amadori      Cattedra di Ematologia, Rome                          0
27                                   Institute of Haematology and Medical                  8         12
           Prof. Michele Baccarani
                                     Oncology, Bologna
Ireland
24         Dr. Paul Browne           St. James’s Hospital Dublin                           0
30         Dr Philip Murphy          Beaumont Hospital, Dublin                             3          5
Applicant Table




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                                                               NDA 21673
ODAC Briefing Document                                         Clolar (Clofarabine)

Baseline Characteristics

                           Table 16 Baseline Characteristics




  Applicant Table




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ODAC Briefing Document                                                            Clolar (Clofarabine)


Response Criteria

Response to treatment was measured by assessment of morphology and blast count from
bone marrow aspirates and peripheral blood performed prior to the first dose and after
each cycle of clofarabine treatment (Day 24 to 28, but changed to Day 28 ± 7 days for
patients treated according to Protocol Amendment 3).

Responses were defined as CR, CRi, partial remission (PR) and treatment failure (TF,
include patients who were not evaluable [NE]).

Complete Remission (CR)
To qualify for CR, patients had to meet the following criteria:
   • Leukemic blasts absent from the peripheral blood,
   • <5% blasts in the bone marrow with no detectable Auer rods, as measured by
       morphology studies,
   • no evidence of extramedullary disease (e.g., central nervous system [CNS] or soft
       tissue involvement) and
   • platelets ≥100 × 109/L
   • and absolute neutrophil count (ANC) ≥1.0 × 109/L.

Complete Remission with incomplete blood count recovery (CRi)
To qualify for CRi, patients had to satisfy the definition of CR with the exception of
residual neutropenia (ANC <1.0 x 109/L) or thrombocytopenia (platelets <100 x 109/L).

Efficacy Results
                                          Table 17 Efficacy
                                Response %                Median Response            Median Overall
                                 (95% CI)                 Duration (95% CI)         Survival (95% CI)
 All Patients N=66                                                                    173 d (90-295
       ORR                         44%                     168 d (63-294)*           315 d (227-413)
        CR                      21% (12-33)                168 d (63-294)*           333 d (285-520)
       CRp                      23% (13-35)                                          255 d (122-769)
        PR                       5% (1-13)                        ND                       ND
ORR=Cr+Cri, CR=complete Response, Cri=CR with residual neutropenia or thrombocytopenia, ND=Not
Done

*The definition of response duration was changed in an addendum to the protocol. In the new definition of
response duration patients whose best response is CR are considered to still be in remission if their
response for subsequent visits is either CR or CRi. In comparison, using the definition used for the original
BIOV-121 CSR (dated 15 December 2006), a patient with CR whose response in a subsequent cycle is Cri
was considered to have relapsed. Using the new definition of response duration the median duration of
response Cr+Cri was 168 days (95% CI 63-294)




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                                                                     NDA 21673
ODAC Briefing Document                                               Clolar (Clofarabine)


                            Table 18 Best Response by Cycle
                                       Clolar N= 66
                                          Cycle 1                        Cycle 2
                 CR                     10 (71.4%)                      4 (29.6%)
                 CRi                    14 (93.3%)                       1 (6.7%)


                              Table 19 Survival Probability
Time Interval           6 months          12 months         18 months          24 months
Probability of            48%                26%               21%                18%
Survival

Median duration of follow-up for overall survival was 173 days (95% CI 90-295)



Safety Results

                                         Exposure

    •    66 patients received at least one dose.
    •    Number of cycles received: Mean±SD: 1.5±0.8 cycles; Median: 1 cycle (range:
         0.2 to 4).
    •    Number of days’ treatment received: Mean±SD: 7.5±4.03 days; Median: 5 days
         (range 1 -20).
    •    Fifteen patients (23%) were reported to have had a dose reduction, or a delay or
         interruption to the infusion of study drug at some point during the study.




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                                                                    NDA 21673
ODAC Briefing Document                                              Clolar (Clofarabine)

Table 20 Number of Cycles of Clofarabine Received

Patient Received                                              N          %
<1 cycle at 30 mg/m2                                          5*         7.6
1 cycle at 30 mg/m2                                           36        54.5
2 cycles                                                      15†       22.7
Both at 30 mg/m2                                               7        10.6
1 cycle at 30 mg/m2 + 1 cycle at 20 mg/m2 to 29 mg/m2          6         9.1
1 cycle at 30 mg/m2 + 1 cycle at 15 mg/m2                      2         3.0
3 cycles                                                      9#        13.6
All at 30 mg/m2                                                4         6.1
2 cycles at 30 mg/m2 + 1 cycle at 20 mg/m2                     2         3.0
1 cycle at 30 mg/m2 + 2 cycles at 20 mg/m2                     3         4.5
4 cycles at 30 mg/m2                                           1         1.5
Total                                                         66        100
Applicant Table




                                                    Deaths

Early Death: Fourteen patients died (of any cause) within 30 days of the first clofarabine
administration to give an early death rate of 21% (14/66). Of these 14 patients, seven
(11% of all patients) were assessed as having died of AEs possibly-related to clofarabine
within the first 30 days. The most common AEs leading to death in these patients were
neutropenic sepsis/sepsis and/or ARF/renal insufficiency which occurred in six out of the
seven patients. One patient had a fall reported as an SAE leading to death and considered
possibly-related to clofarabine.

Death in Remission: Five out of the 29 responders (17.2%) died without documented
relapse, with the most common reason for death being neutropenic sepsis and renal
failure (against a background of coexistent infection/sepsis).

Peripheral Blood Count Recovery: The median time to ANC recovery to >1.0 x 109/L
and platelet recovery to >100 x 109/L following Cycle 1 of clofarabine was 24 and 38
days, respectively.




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               Treatment Emergent Adverse Events Regardless of Relation to Clolar
           Table 21 AEs Grade 3 or Greater Occurring in at least 5% of Patients N=66




 Applicant Table




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ODAC Briefing Document                                                        Clolar (Clofarabine)



ISSUES FOR ODAC CONSIDERATION

    1. Is a randomized, controlled trial needed to establish the efficacy and safety of
       Clolar for the indication of treatment of previously untreated adults aged 60 years or
       older with acute myeloid leukemia with at least one unfavorable baseline prognostic
       factor?
    2. If not, has the applicant identified and studied a patient population that is not
       appropriate for treatment with a standard 3+7 induction chemotherapy regimen?
    3. If the identified patient population is not appropriate for standard induction
       chemotherapy, is the benefit:risk ratio for treatment with Clolar in this population
       favorable?


REFERENCES
1
  Menzin J, Lang K, Earle CC, et al. The outcome and costs of acute myeloid leukemia
among the elderly. Arch Intern Med 2002;162:1597-1603.
2
  Juliusson G, Antunovic P, Derolf A, et al., Age and Acute Myeloid Leukemia. Real world data on
decision to treat and outcomes from the Swedish acute leukemia registry. Blood 2009,113(18) 4179-87




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