`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203341Orig1s000
`
`STATISTICAL REVIEW(S)
`
`
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`

`

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`
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`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`
`S TAT I S T I C A L T E A M L E A D E R R E V I E W
`M E M O
`
`
`NDA/Serial Number:
`Drug Name:
`Indication(s):
`
`Applicant:
`Submitted date:
`PDuFA date:
`Review Priority:
`
`203341/0000
`Bosulif® (Bosutinib) Tablets
`Adult Patients with Relapsed or Refractory Chronic, Accelerated
`or Blast Phase Chronic Myeloid Leukemia (CML)
`Wyeth Pharmaceuticals, Inc.
`November 17, 2011
`September 17, 2012
`Standard
`
`Division of Biometrics V
`Dr. Mark Rothmann, Lead Mathematical Statistician
`
`Concurring Reviewers: Dr. Rajeshwari Sridhara, Director, Division of Biometrics V
`
`
`Medical Division:
`Division of Hematology Products
`Clinical Team:
`Dr. Karen McGinn, clinical reviewer
`Dr. Virginia Kwitkowski, clinical team leader
`Project Manager:
`CDR Diane Hanner
`
`
`Keywords: Single arm study
`
`
`
`
`Biometrics Division:
`Statistical Reviewer:
`
`
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`Reference ID: 3165869
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`1
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`Table of Contents
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`EXECUTIVE SUMMARY................................................................................................................. 3
`1.
`1.1 CONCLUSIONS AND RECOMMENDATIONS ......................................................................................... 3
`1.2 BRIEF OVERVIEW OF STUDY 3160A4-200-WW ............................................................................... 4
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`Reference ID: 3165869
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`EXECUTIVE SUMMARY
`
`1.
`
`The purpose of this review is to present and comment on rationales on what populations
`should be included in the possible approval of Bosulif and provide recommendations and
`conclusions.
`
`This NDA submission consists of results from study 3160A4-200-WW, an open-label, 2-
`part, safety and efficacy study of bosutinib once daily orally in subjects with Ph+
`leukemia. This study consists of two parts. Part 1 was a dose-escalation study in subjects
`with chronic phase (CP) chronic myelogenous leukemia (CML) who were resistant to
`imatinib for the purpose of establishing the maximum tolerated dose and determining a
`dose for part 2. Eighteen (18) subjects total were enrolled, at dose levels of 400 mg, 500
`mg and 600 mg. Based on part 1 data, and the starting dose for part 2 was selected to be
`500 mg. Part 2 studied the efficacy of bosutinib 500 mg daily in subjects with chronic,
`accelerated, or blast phase Philadelphia-positive (Ph+) CML in adult patients with
`resistance, or intolerance to prior therapy. The study also enrolled a small number of
`patients with Ph+ acute lymphoblastic leukemia (ALL).
`
`The primary objective of study 3160A4-200-WW was to rule out a major cytogentic
`response (MCyR) rate of 23% or less for the imatinib-resistant cohort. There was a
`variety of cohorts entered into the study (see Section 1.2 for further details).
`
`The results of study 3160A4-3000-WW in subjects with newly diagnosed Ph+ leukemia
`were also submitted as a supportive study. Study 3160A4-3000-WW was a randomized,
`open-label study of bosutinib versus imatinib in subjects with newly diagnosed chronic
`phase Philadelphia chromosome positive CML. The primary objective was the
`demonstration of a greater complete cytogenetic response (CCyR) rate at 1 year for the
`bosutinib arm relative to the imatinib arm. Study 3160A4-3000-WW failed to
`demonstrate a superior CCyR rate at 1 year for bosutinib compared to imatinib.
`
`
`1.1 Conclusions and Recommendations
`
`
`The primary objective on MCyR at week 24 for the imatinib-resistant CP CML cohort
`was met. In the sponsor’s final clinical study report, they write that the endpoint of
`MCyR at week 24 in patients with imatinib-intolerant CP CML was not met.
`Additionally, a Simon 2-stage design appears to have been used in the evaluation of
`MCyR at week 24 in patients with imatinib-intolerant disease. A Simon 2-stage design is
`traditionally a design to address a “go no-go” question, not for drawing conclusion on
`efficacy. Other than the imatinib-resistant and imatinib-intolerant cohorts, the analyses
`were expressed as exploratory for the other cohorts in the protocol dated November 21,
`2008 and in the final study report. From just these facts, it clear how a conclusion or
`recommendation can be made that approval and labeling claims be made for only patients
`with imatinib-resistant CP CML.
`
`Based on the statistical analysis plan dated March 28, 2011 (which was also the data
`cutoff date), the cohorts had separate designs and decision rules. The specified
`uninterested response rates in the designs are arbitrary. The evaluations of the endpoints
`for these smaller cohorts were pre-specified as secondary endpoints in the protocol dated
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`November 21, 2008. These are single arm evaluations on response rates in a second-line
`or later setting. The benefit in such setting is generally based on the magnitude of the
`response rate and the durability of the responses. In this application the responses were
`fairly durable. For example, from the statistical review of Dr. Kallappa Koti
`
`
`“Thirty-nine imatinib-intolerant CP CML subjects achieved MCyR. Eighteen
`major cytogenetic imatinib-intolerant CP CML responders were censored by
`104.3 weeks (by 2 years) and four responders lost response by 104.3 weeks. The
`remaining 17 (43.6%) imatinib-intolerant responders maintained MCyR at Year
`2.”
`
`
`Based on the size of the response rates and the durability of the responses across CML
`cohorts, it clear how a conclusion or recommendation can be made for approval and
`labeling claims for all cohorts except the Ph+ ALL cohort (which had a 0% MCyR rate at
`24 weeks).
`
` I
`
` recognize that for the CML cohorts the size of the response rates are not small and the
`responses appear to be durable and may be appropriately so for approval in the CML
`cohorts.
`
`1.2 Brief Overview of Study 3160A4-200-WW
`
` A
`
` total of 571 patients were enrolled in study 3160A-200-WW. Among these patients,
`288 patients with CP CML were previously treated with imatinib only, 118 patients with
`CP CML were previously treated with both imatinib and at least one additional tyrosine
`kinase inhibitor, 76 patients with accelerated phase CML were previously treated with at
`least imatinib, and 64 patients with blast phase CML were previously treated with at least
`imatinib. The study enrolled its first patient w on January 18, 2006 and its last patient on
`April 20, 2010. The data cutoff date was March 28, 2011. Among these 571 patients, 503
`with CML were in the evaluable (analysis) population (defined as all enrolled patients
`who received at least one dose of bosutinib and had an adequate baseline efficacy
`assessment).
`
`The primary objective was the determination of efficacy in patients with CP CML
`resistant to imatinib who have had no prior exposure to other tyrosine kinase inhibitors.
`The determination of efficacy was based on MCyR rate at 24 weeks. The hypotheses on
`the MCyR rate at 24 weeks (p) were H0: p ≤ 0.23 against the 1-sided alternative H1: p >
`0.23. Testing was based on a one-sided type 1 error rate of 0.05 and 80% power at p =
`0.33. The design of the primary cohort incorporated a 4-stage group sequential design,
`with interim analyses at 25%, 50%, and 75% information fraction based on a maximum
`sample size of 167 evaluable subjects for the imatinib-resistant cohort.
`
` A
`
` secondary objective involved the MCyR rate in the imatinib-intolerant cohort. The
`hypotheses on the MCyR rate at 24 weeks (p) were H0: p ≤ 0.56 and H1: p > 0.73. Testing
`and the intended sizing of the cohort was based a Simon 2-stage design. For alpha = 0.05,
`beta = 0.2, a maximum of 55 patients are required with 16 patients evaluated for response
`in the first stage.
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`The sponsor’s conclusion in the final clinical study report are:
`
`
`“The primary objective of MCyR rate at Week 24 in imatinib-reistant second-line
`CP CML subjects was met; 35.5% (95% Cl: [29.7, 41.7]) of subjects attained
`MCyR at Week24.”
`
`“The secondary objective of the protocol, MCyR at Week 24, was not met for
`second-line imatinib-intolerant CP CML subjects; 30% (90% CI: [21.6, 39.5]) of
`subjects attained MCyR at Week 24. When cumulative MCyR was assessed
`including subjects who maintained or achieved MCyR as responders, 61.3% of
`imatinib-intolerant subjects had MCyR.”
`
`
`There were separate designs (sample size and analysis) for the various cohorts. Some of
`these are provided below via the statistical analysis plan dated March 28, 2011.
`
`
`1. CP CML patients who have failed imatinib and are resistant to dasatinib (cohort
`7): The design was based on a Simon 2-stage design with interesting and
`uninteresting 24 week MCyR rates of 30% and 10%, respectively, a one-sided
`alpha=0.05 and power =80%. The first stage would be based on a sample size of
`ten and the second stage would be based on a sample size of 29.
`
`2. CP CML patients who have failed imatinib and are intolerant of dasatinib (cohort
`8): The design was based on a Simon 2-stage design with interesting and
`uninteresting 24 week MCyR rates of 37% and 17%, respectively, a one-sided
`alpha=0.05 and power =80%. The first stage would be based on a sample size of
`12 and the second stage would be based on a sample size of 35.
`
`3. CP CML cohort of patients who have failed imatinib and are resistant to nilotinib
`(cohort 9): The design was based on a Simon 2-stage design with interesting and
`uninteresting 24 week MCyR rates of 30% and 10%, respectively, a one-sided
`alpha=0.05 and power =80%. The first stage would be based on a sample size of
`ten and the second stage would be based on a sample size of 29.
`
`4. “Patients in cohort 2 (failed imatinib and either nilotinib intolerant or treated with
`both nilotinib and dasatinib) will be described. No testing is planned for this
`group.”
`
`5. Advanced disease (AP, BP and ALL cohorts combined) with failure on imatinib
`and unexposed to other kinase inhibitors (cohort 3): The design was based on a
`Simon 2-stage design with interesting and uninteresting 24 week complete
`hematological response (CHR) rates of 29% and 9%, respectively, a one-sided
`alpha=0.05 and power =80%. The first stage would be based on a sample size of
`11 and the second stage would be based on a sample size of 24.
`
`6. Advanced disease (AP, BP and ALL cohorts combined) with failure on imatinib
`and on other TKI treatment (cohort 4): The design was based on a Simon 2-stage
`design with interesting and uninteresting 24 week complete hematological
`response CHR rates of 26% and 6%, respectively, a one-sided alpha=0.05 and
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`power =80%. The first stage would be based on a sample size of 6 and the second
`stage would be based on a sample size of 26.
`
`The statistical analysis plan also states the following “amendment” during the study
`to perform separate analyses for BP and AP patients in cohort 3 on the endpoint of
`overall hematological response (OHR):
`
`
`“Preliminary analysis of the cohort of advanced Ph+ leukemia patients who had failed
`imatinib and were unexposed to other tyrosine kinase inhibitors in addition to
`emerging data from studies of other agents suggested that efficacy should be assessed
`in AP and BP cohorts of imatinib-resistant patients unexposed to other tyrosine kinase
`inhibitors, using the endpoint of 48 week OHR. The revised analysis strategy is as
`follows.”
`
`7. Imatinib-resistant/intolerant CML patients in AP, unexposed to other tyrosine
`kinase inhibitors (cohort 31): The design was based on a Simon 1-stage design
`with interesting and uninteresting 48 week OHR rates of 61% and 43%,
`respectively, an alpha=0.05 and power =80%. The maximum sample size is 49
`with an interim look based on the response rates from 42 patients.
`
`8. Imatinib-resistant/intolerant CML patients in BP, unexposed to other tyrosine
`kinase inhibitors (cohort 32) The design was based on a Simon 1-stage design
`with interesting and uninteresting 48 week OHR rates of 48% and 30%,
`respectively, an alpha=0.05 and power =80%. The maximum sample size is 45
`with an interim look based on the response rates from 41 patients.
`
`9. Imatinib-resistant/intolerant CML patients in AP exposed to other tyrosine kinase
`inhibitors (cohort 41) and Imatinib-resistant/intolerant CML patients in BP
`exposed to other tyrosine kinase inhibitors (cohort 42) will be analyzed
`descriptively.
`
`• Estimate MCyR rate in CP CML patients who have failed imatinib and are
`resistant to other tyrosine kinase inhibitors (dasatinib or nilotinib)
`
` Estimate MCyR rate in CP CML patients who have failed imatinib and are
`intolerant to dasatinib
`
` •
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`The protocol dated November 21, 2008 included the following in a list of secondary
`endpoints:
`
`
`• Estimate CHR rate in advanced leukemia patients and
`
`• Estimate OHR rate in imatinib-resistant accelerated phase and blast phase CML
`patients
`
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`The protocol listed the following efficacy endpoint as exploratory
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`Reference ID: 3165869
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`MCyR at Week 24
`(95% CI)
`CCyR at Week 24
`(95% CI)
`
`Table 2. Efficacy Results in Ph+ CP CML PatientsPreviously Treated with Imatinib
`and Dasatinib and/or Nilotinib
`IM + (NI + D)
`
`or IM + NI
`IM + D
`Intolerant
`Resistant
`(n=4)
`(n=35)
`50.0%
`25.7%
`(6.8%, 93.2%)
`(12.5%, 43.3%)
`25.0%
`8.6%
`(0.6%, 80.6%)
`(1.8%, 23.1%)
`
`
`
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`IM + D
`Intolerant
`(n=43)
`25.6%
`(13.5%, 41.2%)
`18.6%
`(8.4%, 33.4%)
`
`
`IM + NI
`Resistant
`(n=26)
`26.9%
`(11.6%, 47.8%)
`11.5%
`(2.5%, 30.2%)
`
`• Estimate the rate of molecular responses in those whose best prior response was
`CCyR and cytogenetic responses in those previously attaining only CHR.
`
`
`The efficacy results are summarized in Tables 1-3.
`
`Table 1. Efficacy Results in Ph+ CP CML Patients Previously Treated with Imatinib
`
`IM Resistant
`IM Intolerant
`(n=186)
`(n=80)
`35.5%
`30.0%
`(28.6%, 42.8%)
` (20.3%, 41.3%)
`24.2%
`25.0%
`(18.2%, 31.0%)
`(16.0%, 35.9%)
`
`MCyR by Week 24
`(95% CI)
`CCyR by Week 24
`(95% CI)
`
`
`
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`OHR by Week 48
`(95% CI)
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`Table 3. Efficacy Results in Accelerated-Phase and Blast Phase Patients Previously
`Treated with at Least Imatinib
`AP
`Total
`(N=69)
`55.1%
`(42.6%, 67.1%)
`
`BP
`Total
`(N= 60)
`28.3%
`(17.5%, 41.4%)
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARK D ROTHMANN
`07/27/2012
`
`RAJESHWARI SRIDHARA
`07/27/2012
`
`Reference ID: 3165869
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`

`

`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`
`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
`
`NDA Serial Number:
`Drug Name:
`Indication(s):
`
`Applicant:
`Submitted date:
`PDuFA date:
`Review Priority:
`
`
`
`
`Medical Division:
`Clinical Team:
`
`203341 / 0000
`Bosulif® (Bosutinib) Tablets
`Chronic, accelerated, or blast phase Ph+ chronic myelogenous
`leukemia (CML)
`Wyeth Pharmaceuticals, Inc.
`17-NOV-2011
`17-SEPT-2012
`Standard
`
`Biometrics Division:
`DB V / CDER
`Statistical Reviewer:
`Dr. Kallappa M. Koti
`Concurring Reviewers: Dr. Mark Rothmann, Lead Mathematical Statistician
`Dr. Rajeshwari Sridhara, Director
`Division of Biometrics V
`
`DHP
`Dr. Karen McGinn
`Dr. Virginia Kwitkowski, Team Leader
`Project Manager:
`Ms. Diane Hanner
`
`
`Keywords: Proportion, confidence interval, Kaplan-Meier estimate
`
`
`
`
`Table of Contents
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`Reference ID: 3162444
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`

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` S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N B O S U L I F T A B L E T S
`
`
`
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES ...........................................................................1
`FOOD AND DRUG ADMINISTRATION ................................................................................................................1
`STATISTICAL REVIEW AND EVALUATION .....................................................................................................1
`LIST OF TABLES.......................................................................................................................................................3
`LIST OF FIGURES.....................................................................................................................................................3
`1. EXECUTIVE SUMMARY .................................................................................................................................4
`2.
`INTRODUCTION ...............................................................................................................................................5
`2.1
`OVERVIEW......................................................................................................................................................5
`2.1.1
`Study 3160A4-200-WW........................................................................................................................6
`2.1.2
`Study 3160A4-3000-WW......................................................................................................................6
`2.2
`DATA SOURCES ..............................................................................................................................................7
`3. STATISTICAL EVALUATION ........................................................................................................................7
`3.1
`DATA AND ANALYSIS QUALITY .....................................................................................................................7
`3.2
`EVALUATION OF EFFICACY ............................................................................................................................8
`3.2.1
`Sponsor’s sample size rationale...........................................................................................................10
`3.2.2
`Statistical Methodologies.....................................................................................................................11
`3.2.3
`Patient Disposition, Demographic and Baseline Characteristics .........................................................11
`3.2.4
`Sponsor’s results and conclusions from Study 200-WW.....................................................................12
`3.2.5
`Reviewer’s analyses and results from Study 200-WW........................................................................13
`3.3 EVALUATION OF SAFETY ....................................................................................................................................21
`4.
` FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................................................21
`4.1
`GENDER, RACE, AGE, AND GEOGRAPHIC REGION ........................................................................................21
`4.1.1
`Imatinib Resistant CP CML subjects...................................................................................................21
`4.1.2
`Imatinib Intolerant CP CML subjects..................................................................................................22
`4.2
`OTHER SPECIAL/SUBGROUP POPULATIONS ..................................................................................................22
`5. SUMMARY AND CONCLUSIONS ................................................................................................................22
`5.1
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE .......................................................................................22
`5.2
`CONCLUSIONS AND RECOMMENDATIONS .....................................................................................................23
`APPENDICES............................................................................................................................................................24
`SIGNATURES/DISTRIBUTION LIST...................................................................................................................27
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`Reference ID: 3162444
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` S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N B O S U L I F T A B L E T S
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`
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`LIST OF TABLES
`
`
`
`Table 2.1.1: List of studies reviewed.............................................................................................. 5
`
`
`Table 3.2.1: Study 200-WW Flowchart.......................................................................................... 9
`Table 3.2.2: Reasons for treatment discontinuation in Study 200-WW ....................................... 11
`Table 3.2.3: Primary endpoint MCyR at Week 24- all enrolled subjects..................................... 13
`Table 3.2.4: Primary endpoint MCyR at Week 24 in Evaluable subjects .................................... 14
`Table 3.2.5: MCyR by 24 weeks in chronic phase third line patients .......................................... 15
`Table 3.2.6: Confirmed OHR by Week 48 in advanced leukemia subjects ................................. 15
`
`
`
`
`LIST OF FIGURES
`
`
`Figure 3.2.1: Time to MCyR for imatinib-resistant and imatinib intolerant cohorts combined... 15
`Figure 3.2.2: Kaplan-Meier curve for MCyR duration in the 103 IM-resistant patients.............. 16
`Figure 3.2.3: Kaplan-Meier curve for MCyR duration in the 39 IM-intolerant patients.............. 17
`Figure 3.2.4: Kaplan-Meier curve for PFS in IM-Resistant patients............................................ 18
`Figure 3.2.5: Kaplan-Meier curve for OHR duration in the AP Total patients ............................ 19
`Figure 3.2.6: Kaplan-Meier curve for OHR duration in the AP Total patients ............................ 21
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` S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N B O S U L I F T A B L E T S
`
`
`
`
`
` o
`
` o
`
`
`
`BOSULIF® (bosutinib monohydrate) is indicated for the treatment of chronic, accelerated, or
`blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in
`adult patients with resistance or intolerance to prior therapy. Evidence of the efficacy of
`Bosulif® (bosutinib) in the proposed indication derives primarily from the ongoing Phase 1/2
`Study 3160A4-200-WW (Study 200-WW) of bosutinib
`in subjects with Philadelphia
`chromosome positive (Ph+) leukemia whose disease is resistent or intolerant to prior tyrosine
`inhibitor (TKI) therapy, based on a database snapshot date of 28 March 2011. The maximum
`tolerance dose (MTD) of bosutinib, which was used in Study 200-WW was 500 mg. Bosutinib
`capsules or tablets (100 mg dosage strength) were supplied in bottles. The primary efficacy
`endpoint in Study 200-WW was the major cytogenetic response (MCyR) rate at Week 24.
`
`This NDA also includes the efficacy conclusions of the supportive Phase 3 Study 3000-WW in
`subjects with newly diagnosed Ph+ leukemia. Study 3160A4-3000-WW (Study 3000-WW) was
`a Phase 3 randomized, open-label study of bosutinib versus imatinib in subjects with newly
`diagnosed chronic phase Philadelphia chromosome positive CML. The complete cytogenetic
`response (CCyR) rate at 1 year was the primary endpoint.
`
`
`Key results from Study 3160A4-200-WW:
`
`1.
`
`EXECUTIVE SUMMARY
`
` The primary objective of MCyR rate at Week 24 in imatinib-resistant second-line chronic
`phase (CP) CML subjects was met. MCyR rate at Week 24 was significantly greater than
`23% (p-value < 0.0001). The MCyR rate at Week 24 in imatinib-resistant second-line CP
`CML subjects was 35.5% (66/186 subjects; 95% CI: 28.6%, 42.4%).
`
` The median duration of MCyR was not reached for the second-line CP CML imatinib-
`resistant cohort. Only 34.9% [95% CI: (25.7%, 44.6%)] of the responders in the imatinib-
`resistant cohort maintained MCyR at Year 2.
`
` o
`
` o
`
`
`
` o
`
`
`
` The MCyR rate at Week 24 in imatinib-intolerant second-line CP CML evaluable subjects
`was 30% (24/80 subjects; 95% CI: 20%, 40%). MCyR rate at Week 24 in imatinib-intolerant
`subjects was significantly lower than the expected rate of 56% (see Sponsor’s sample size
`rationale in Section 3.2 of this review).
`
` CCyR at Week 24 in imatinib-resistant second-line CP CML evaluable subjects was 26.3%
`[49/186; 95% CI: (20%, 32.7%)].
`
` CCyR at Week 24 in imatinib-intolerant second-line CP CML evaluable subjects was 35%
`[28/80; 95% CI: (24.5%, 45.5%)].
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`Reference ID: 3162444
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` S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N B O S U L I F T A B L E T S
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`
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`
` o
`
` o
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` Overall hematologic response (OHR) rate in AP Total patients who were treated with at least
`imatinib was 50% [38/76; 95% CI: (38.8%, 61.2%)]. A 28.9% [95% CI: (14.5%, 43.4%)] of
`the responders in the AP Total cohort maintained OHR at Year 2.
`
` OHR rate in BP Total patients who were treated with at least imatinib was 26.6% [17/64;
`95% CI: (15.7%, 37.4%)]. The median duration of OHR was 31.5 weeks [95% CI: (24.3,
`48)]. Only 11.8% [95% CI: (1.5%, 36.4%)] of the responders in the BP Total cohort
`maintained OHR at Year 2.
`
`
`Key results from Phase 3 Study 3000-WW:
`
` o
`
` There was no significant difference in the primary endpoint 1-year CCyR rates between the
`bosutinib and imatinib arms. The CCyR rate at 1 year was numerically higher on the
`bosutinib arm (70%, 175/250 subjects; 95% CI: 64.3%, 75.7%) compared to the imatinib arm
`(67.9%, 171/252 subjects; CI: 62.1, 73.6), although this did not reach statistical significance
`(p-value = 0.6).
`
`
`
`Overall conclusion and recommendation:
`
` o
`
` Except the imatinib-resistant cohort analysis in Study 3160A4-200-WW, all other cohorts’
`analyses were either exploratory or indicated inefficacy or were based on small samples.
`Efficacy results from cohorts other than imatinib-resistant cohort should not be used to
`support labeling claims.
`
`
`
`
`2.
`
`
`
`INTRODUCTION
`
`2.1 Overview
`
`
`Two clinical trials are reviewed in this review. Basic details are provided in Table 2.1.1 below,
`followed by an overview of each study.
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`Table 2.1.1: List of studies reviewed
`
`Study
`
`Phase and
`Design
`1/2
`3
`
`Treatment
`Period
`Until PD
`Until PD
`
`Follow-up
`Period
`≥ 2 years
`8 years
`
`Study
` # of Subjects
`Population
`per Arm
`Total of 571 CP CML
`250 per arm
`Ph+ CML
`
`5
`
`200-WW
`3000-WW
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`
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`Reference ID: 3162444
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` S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N B O S U L I F T A B L E T S
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`2.1.1 Study 3160A4-200-WW
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`Study 3160A4-200-WW was a Phase 1/2, open-label, 2-part, multicenter, safety and efficacy
`study of SKI-606 once daily orally in subjects with Philadelphia chromosome positive
`leukemias. It was conducted during the period of 18 January 2006 to 28 March 2011. Part 1 was
`a dose escalating study in CP CML subjects who were resistant or refractory to imatinib to
`establish the MTD in this subject population and determine a dose for part 2. Part 2 studied the
`efficacy of Bosutinib 500 mg daily in subjects with CP, imatinib-resistant/refractory CML, who
`had no prior Src, Abl, or Src-Abl inhibitor exposure other than imatinib.
`
`Subjects 18 years of age or older with a cytogenetic or polymerase chain reaction (PCR) based
`diagnosis of any phase of Ph+ CML or Ph+ ALL whose disease was resistant to full-dose
`imatinib (≥600 mg), or was intolerant of any dose of imatinib were included. Subjects who had
`received prior treatment with dasatinib or nilotinib in addition to imatinib were also eligible to be
`included in the study.
`
` A
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` total of 686 subjects were screened for Part 2 and 571 were enrolled in 80 study sites. The five
`countries enrolling the most subjects were the United States (147), Russia (66), Italy (53), China
`(43), and Germany (39). The remaining 223 subjects came from other countries. Part 2 also
`included exploratory cohorts of the subjects: (i) CP CML Second-line imatinib intolerant, (ii) CP
`CML Third-line, and (iii) Advanced Leukemias (AP CML, BP CML, Ph+ ALL). In part 2,
`efficacy was determined based on physical examination and peripheral blood and bone marrow
`analyses. MCyR at week 24 was the primary endpoint.
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`2.1.2 Study 3160A4-3000-WW
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`Study 3160A4-3000-WW was a Phase 3 randomized, open-label study of Bosutinib versus
`imatinib in subjects with newly diagnosed chronic phase Philadelphia chromosome positive
`Chronic Myelogenous Leukemia. It was conducted during the period 05 February 2008 to 15
`November 2010. A total of 173 sites enrolled subjects including 21 sites in the United States and
`2 sites in Canada. A total of 581 subjects were assessed for eligibility and 502 were randomized
`1:1 to receive either bosutinib 500 mg per day or imatinib 400 mg per day. Enrollment has been
`completed, and follow-up of patients in the study is ongoing.
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`Randomization of subjects into each arm was stratified based on site-entered Sokal score (low,
`intermediate, high) and geographical region (United States, Canada, and Western Europe vs.
`Eastern Europe vs. South America).
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`Reference ID: 3162444
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`6
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` S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N B O S U L I F T A B L E T S
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`Complete cytogenetic response (CCyR) rate at 1 year was the primary endpoint in Study 3000-
`WW. Key pre-specified secondary and long-term endpoints included: MMR at 1 year, duration
`of CCyR, duration of MMR, duration of CHR, time to transformation from CP to AP or BP, and
`event-free survival (EFS). The efficacy results were analyzed in the intent-to-treat (ITT) and
`evaluable populations.
`
` A
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` sample size of 370 was aimed to detect a difference in CCyR rates at one year of 0.15
`(improvement from 0.65 in the imatinib arm to 0.8 in the bosutinib arm), with 90% power and
`one interim analysis at 40% information, using a 1-sided test of the rate difference at the 2.5%
`significance level. Assuming that 10% of the subjects enrolled are not evaluable, approximately
`412 subjects were needed to have 370 evaluable subjects.
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`The primary endpoint of CCyR rate at 1 year in the ITT population showed no statistically
`significant difference between study arms.
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`Sponsor’s results
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`In the ITT population of Study 3000-WWW, the CCyR rate at 1 year was numerically higher on
`the bosutinib arm (70%, 175/250 subjects; 95% CI: 64.3%, 75.7%) compared to the imatinib arm
`(67.9%, 171/252 subjects; CI: 62.1, 73.6), although this did not reach statistical significance. The
`2-sided p-value was 0.6 [Cochran-Mantel-Haenszel (CMH) test, adjusted for Sokal score and
`geographic region]. This reviewer verified the sponsor’s analysis.
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`2.2 Data Sources
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`The path to the CDER Electronics Document Room (EDR) is:
`\\CDSESUB1\EVSPROD\NDA203341\0000
`The SAS dataset used in this review: CYTO.XPT, CONCLU.XPT, CYTRES.XPT,
`ENDPT.XPT, and ENDEFS.XPT.
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`3.
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`STATISTICAL EVALUATION
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`3.1 Data and Analysis Quality
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`The SAS dataset cyto.xpt was the efficacy dataset for Study 200-WW. It was possible to easily
`reproduce the primary analysis results. It did not contain baseline demographic variables, which
`were needed in the subgroup analyses in this review. Considerable effort was needed to process
`and analyze the data. The SAS dataset endpt.xpt was the efficacy dataset for Study 3000-WW. It
`was possible to easily reproduce the primary analysis results.
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`7
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`Reference ID: 3162444
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` S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N B O S U L I F T A B L E T S
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`3.2 Evaluation of Efficacy
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`This section focuses on results from Study 200-WW. The results from Study 3000-WW are
`provided in section 2.1.2.
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`Study Design and Endpoints
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`Study 200-WW was an open-label, multicenter, 2-part, safety and efficacy study of bosutinib
`once daily orally in subjects with Ph+ leukemia. Part 1 was a dose-escalation study in subjects
`with CP CML who were resistant/refractory to imatinib to establish the MTD in this subject
`population and determine a dose for part 2. After completion of part 1, the