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

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`CLINICAL REVIEW
`
`Application Type NDA
`Application Number 203341
`Priority or Standard Standard
`
`Submit Date November 17, 2011
`Received Date November 17, 2011
`PDUFA Goal Date September 17, 2012
`Division / Office Division of Hematology
`Products/Office of Hematology
`and Oncology Products
`
`Reviewer Name Karen McGinn, MSN, CRNP
`Review Completion Date July 20, 2012
`
`Established Name Bosutinib
` Trade Name Bosulif
`Therapeutic Class Tyrosine Kinase Inhibitors
`Applicant Wyeth Pharmaceuticals
`
`Formulation 100 mg and 500 mg tablets
`Dosing Regimen 500 mg orally once daily
`Indication Patients with Relapsed or
`Refractory Chronic,
`Accelerated or Blast Phase
`Chronic Myeloid Leukemia
`Intended Population Adults
`Template Version: March 6, 2009
`
`Reference ID: 3162984
`
`

`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ........................................ 10
`1.1 Recommendation on Regulatory Action ........................................................... 10
`1.2 Risk Benefit Assessment.................................................................................. 11
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 12
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 13
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 13
`2.1 Product Information .......................................................................................... 13
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 14
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 15
`2.4
`Important Safety Issues with Consideration to Related Drugs.......................... 15
`2.5 Summary of Presubmission Regulatory Activity Related to Submission........... 16
`2.6 Other Relevant Background Information .......................................................... 17
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 18
`3.1 Submission Quality and Integrity ...................................................................... 18
`3.2 Compliance with Good Clinical Practices ......................................................... 18
`3.3 Financial Disclosures........................................................................................ 20
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 21
`4.1
` Chemistry Manufacturing and Controls ........................................................... 21
`4.2
` Clinical Microbiology........................................................................................ 21
`4.3
` Preclinical Pharmacology/Toxicology .............................................................. 21
`4.4
` Clinical Pharmacology..................................................................................... 22
`4.4.1 Mechanism of Action.................................................................................. 22
`4.4.2 Pharmacodynamics.................................................................................... 22
`4.4.3 Pharmacokinetics....................................................................................... 23
`4 SOURCES OF CLINICAL DATA............................................................................ 24
`5.1 Tables of Studies/Clinical Trials........................................................................ 24
`5.2 Review Strategy ............................................................................................... 25
`5.3 Discussion of Individual Clinical Trials .............................................................. 25
`5.3.1. Eligibility Criteria for Trial 200..................................................................... 32
`5.3.2 Schedule of Assessments.......................................................................... 34
`5.3.3 Dosing Regimens....................................................................................... 35
`6 REVIEW OF EFFICACY......................................................................................... 36
`6.1 Indication .......................................................................................................... 36
`6.1.1 Methods ..................................................................................................... 36
`6.1.2 Demographics ............................................................................................ 39
`6.1.3 Subject Disposition..................................................................................... 40
`
`Reference ID: 3162984
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`

`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`
`6.1.4 Analysis of Primary Endpoints.................................................................... 41
`6.1.5 Analysis of Secondary Endpoints............................................................... 42
`6.1.7 Subpopulations .......................................................................................... 51
`6.1.8. Analysis of Clinical Information Relevant to Dosing Recommendations .... 51
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 52
`6.1.10 Additional Efficacy Issues/Analyses ........................................................... 52
`7 REVIEW OF SAFETY............................................................................................. 54
`7.1
` Methods.......................................................................................................... 54
`7.1.1 Clinical Trials Used to Evaluate Safety ...................................................... 54
`7.1.2 Categorization of Adverse Events.............................................................. 55
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 55
` Adequacy of Safety Assessments ................................................................... 56
`7.2
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 56
`7.2.2 Explorations for Dose Response................................................................ 57
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 57
`7.2.4 Routine Clinical Testing ............................................................................. 57
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 57
`7.3
` Major Safety Results ...................................................................................... 58
`7.3.1 Deaths........................................................................................................ 58
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 62
`7.3.2 Dropouts and/or Discontinuations .............................................................. 62
`7.3.4 Significant Adverse Events ........................................................................ 62
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 65
`7.4 Supportive Results .......................................................................................... 66
`7.4.1 Common Adverse Events .......................................................................... 66
`7.4.2 Laboratory Findings ................................................................................... 67
`7.4.3 Vital Signs .................................................................................................. 68
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 68
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 68
`7.4.6
`Immunogenicity.......................................................................................... 68
`7.5 Other Safety Explorations................................................................................. 68
`7.5.1 Dose Dependency for Adverse Events ...................................................... 68
`7.5.2 Time Dependency for Adverse Events....................................................... 68
`7.5.3 Drug-Demographic Interactions ................................................................. 68
`7.5.4 Drug-Disease Interactions.......................................................................... 69
`7.5.5 Drug-Drug Interactions............................................................................... 69
`7.6 Additional Safety Evaluations ........................................................................... 69
`7.6.1 Human Carcinogenicity.............................................................................. 69
`7.6.2 Human Reproduction and Pregnancy Data................................................ 70
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 70
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 70
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`Reference ID: 3162984
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`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`
`7.7 Additional Submissions / Safety Issues............................................................ 70
`8 POSTMARKET EXPERIENCE............................................................................... 70
`
`9 APPENDICES ........................................................................................................ 71
`9.1 Literature Review/References .......................................................................... 71
`9.2 Labeling Recommendations ............................................................................. 72
`9.2 Advisory Committee Meeting........................................................................... 74
`
`
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`Reference ID: 3162984
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`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`
`Table of Tables
`
`Table 1 Drug Product Composition (Applicant Table) ................................................. 14
`Table 2 Tables of Currently Available Treatments for CML (Reviewer Table)............. 15
`Table 3 Protocol Violations in Trial 200 (Reviewer Table)........................................... 19
`Table 4 Division of Scientific Integrity Findings Regarding Data Integrity.................... 20
`Table 5 Disclosable Financial Interests in Trials 200 and 3000 (Reviewer Table) ...... 21
`Table 6 Tables of Clinical Trials (Reviewer Table) ...................................................... 24
`Table 8 Protocol Amendments (Reviewer Table)........................................................ 29
`Table 9 Schedule of Assessments (Applicant Table) .................................................. 34
`Table 10 Definition of Disease Phases at Diagnosis (Applicant Table)......................... 37
`Table 11 Definition of Hematologic Responses to Treatment in CP CML (Applicant
`Table)............................................................................................................. 37
`Table 12 Definition of Hematologic Responses to Treatment in Advanced Phases of
`CML (Applicant Table) ................................................................................... 38
`Table 13 Definition of Cytogenetic Responses to Treatment (Applicant Table) ............ 38
`Table 14 Definition of Molecular Responses to Treatment (Applicant Table)................ 38
`Table 15 Demographics and Disease Parameters at Baseline in Trial 200 (Reviewer
`Table)............................................................................................................. 39
`Table 16 Countries Where Patients Were Enrolled and Number of Patients per Country
`(Reviewer Table)............................................................................................ 40
`Table 17 Disposition of Subjects in Trial 200 (Reviewer Table) .................................... 40
`Table 18 Efficacy of Bosutinib in Second-line Treatment of Patients with CP CML
`(Reviewer Table)............................................................................................ 41
`Table 19 Efficacy of Bosutinib in Third-line Treatment of Patients with CP CML
`(Reviewer Table)............................................................................................ 45
`Table 20 Efficacy of Bosutinib in Patients with Advanced Phases of CML and ALL
`(Reviewer Table)............................................................................................ 48
`Table 21 Major Molecular Response in Patients with CP CML Receiving Second Line
`Treatment with Bosutinib (Reviewer Table) ................................................... 50
`Table 22 Subpopulation Analysis of Response in Patients with CP CML Who Achieved
`MCyR and in Patients with AP and BP CML Who Achieved OHR................. 51
`Table 23 Transformation of CP CML to AP/BP CML in Patients Treated with Second
`Line Bosutinib (Reviewer Table) .................................................................... 52
`Table 24 Transformation of CP CML to AP/BP CML in Patients Treated with Third Line
`Bosutinib (Reviewer Table)............................................................................ 53
`Table 25 Emergence of New Mutations in Patients with CP CML in Second Line
`Treatment with Bosutinib (Applicant Table) ................................................... 54
`Table 26 Patient Exposure to Bosutinib in Trial 200 (Reviewer Table) ......................... 56
`Table 27 Safety Overview for Trial 200 ......................................................................... 58
`Table 28 Agreement and Differences in Attributions of Cause of Death within 30 Days of
`Treatment with Bosutinib between Applicant and Reviewer (Reviewer Table)
`....................................................................................................................... 59
`
`Reference ID: 3162984
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`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`Table 29 Discontinuations from Bosutinib Treatment Due to Adverse Events in Patients
`with CML........................................................................................................ 62
`Table 30 Review of Patients with CML Receiving Bosutinib Reported as Having Tumor
`Lysis Syndrome ............................................................................................. 65
`Table 31 Common Treatment Emergent Adverse Events in 10% or More Patients
`Taking Bosutinib for Ph+ CML ....................................................................... 66
`Table 32 Grade 3 and 4 TEAEs in Patients Taking Bosutinib for Ph+ CML .................. 67
`Table 33 Adverse Reactions that Occurred in > 20% of Patients in Phase 1/2 Safety
`Population...................................................................................................... 73
`
`Reference ID: 3162984
`
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`

`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`
`Table of Figures
`
`Figure 1 Chemical structure of bosutinib monohydrate (Applicant Figure).................. 13
`Figure 2 Kaplan-Meier Estimate of Time to MCyR in Patients with CP CML in Second-
`line Treatment with Bosutinib (Applicant Figure)............................................ 42
`Figure 3 Kaplan-Meier Estimate of Maintaining MCyR at Year 1 and at Year 2 in
`Patients with CP CML Treated with Bosutinib as Second-line Therapy
`(Applicant Figure)........................................................................................... 43
`Figure 4 Kaplan-Meier Estimates of PFS in Patients with CP CML in Second Line
`Treatment with Bosutinib ............................................................................... 44
`Figure 5 Kaplan-Meier Estimates of Overall Survival in Patients with CP CML in
`Second Line Treatment with Bosutinib........................................................... 44
`Figure 6 Kaplan-Meier Estimate of Duration of MCyR at Year 1 and at Year 2 in
`Patients with CP CML Treated with Bosutinib as Third Line Therapy (Applicant
`Figure) ........................................................................................................... 46
`Figure 7 Kaplan-Meier Estimate of Time to Major Cytogenetic Response in Patients in
`Third Line Treatment with Bosutinib for CP CML (Applicant Figure).............. 46
`
`
`
`Reference ID: 3162984
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`

`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`Abbreviation Definition
`Abl
`
`Abelson kinase
`AE
`
`adverse event
`ALL
`
`acute lymphoblastic leukemia
`ALT
`
`alanine aminotransferase
`ANC
`absolute neutrophil count
`AP
`
`accelerated phase
`ASCO
`American Society of Clinical Oncology
`AST
`aspartate aminotransferase
`AUC
`total area under the concentration-time curve
`Bcr
`
`breakpoint cluster region
`Bcr-Abl
`protein resulting from the transcription of the Philadelphia chromosome
`following 9:22 chromosomal translocation
`fusion gene transcript for Bcr-Abl protein
`BCR-ABL
`blast phase
`BP
`
`complete blood count
`CBC
`complete cytogenetic response
`CCyR
`congestive heart failure
`CHF
`complete hematologic response
`CHR
`confidence interval
`CI
`
`creatine kinase
`CK
`
`peak concentration
`Cmax
`chronic myelogenous leukemia
`CML
`complete molecular response
`CMR
`central nervous system
`CNS
`chronic phase
`CP
`
`case report form
`CRF
`Crk-like protein
`Crkl
`
`clinical study report
`CSR
`cytochrome P450
`CYP
`dose-limiting toxicity
`DLT
`
`electrocardiogram
`ECG
`echocardiogram
`ECHO
`Eastern Cooperative Oncology Group
`ECOG
`European Medicines Agency
`EMA
`fluorescence activated cell scanning
`FACS
`FACT-Leu Functional Assessment of Cancer Therapy-Leukemia
`FDA
`Food and Drug Administration
`FISH
`Fluorescence in situ hybridization
`GVHD
`graft versus host disease
`HIV
`
`human immunodeficiency virus
`HLA
`human leukocyte antigen
`HRQOL
`Health-related Quality-of-life
`ICF
`
`informed consent form
`
`Reference ID: 3162984
`
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`

`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`International Conference on Harmonization
`
`ICH
`Independent Ethics Committee
`
`IEC
`International Normalized Ratio
`
`INR
`Institutional Review Board
`
`IRB
`lactate dehydrogenase
`LDH
`lower limit of normal
`LLN
`
`left ventricular ejection fraction
`LVEF
`major cytogenetic response
`MCyR
`Medical Dictionary for Regulatory Activities
`MedDRA
`major hematologic response
`MHR
`myocardial infarction
`MI
`
`minor hematologic response
`MiHR
`major molecular response
`MMR
`maximum tolerated dose
`MTD
`
`multiple gated acquisition scan
`MUGA
`NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
`NEL
`no evidence of leukemia
`OHR
`overall hematologic response
`OS
`
`overall survival
`PCR
`polymerase chain reaction
`p-CrkL
`phospho-CrkL
`PCyR
`partial cytogenetic response
`PD
`
`progressive disease
`PDGFR
`platelet-derived growth factor receptor
`PFS
`progression free survival
`Ph+
`
`Philadelphia chromosome-positive
`PK
`
`pharmacokinetics
`PS
`
`performance status
`QTc
`
`corrected QT interval
`QTcF
`QT interval corrected using the Fredericia formula
`RCP
`
`return to chronic phase
`RT-PCR
`reverse transcriptase polymerase chain reaction
`SAE
`serious adverse event
`SAP
`statistical analysis plan
`SOC
`system organ class
`SRC
`proto-oncogene tyrosine-protein kinase
`t½
`
`terminal-phase elimination half-life
`TEAE
`treatment-emergent adverse event
`TKI
`
`tyrosine kinase inhibitor
`tmax
`time of peak concentration
`ULN
`upper limit of normal
`WHO
`World Health Organization
`
`Reference ID: 3162984
`
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`

`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`1 Recommendations/Risk Benefit Assessment
`
`
`1.1 Recommendation on Regulatory Action
`
`This reviewer recommends regular approval of Bosulif (bosutinib) for the treatment of chronic,
`accelerated, or blast phase Philadelphia chromosome positive (Ph+) chronic myelogenous
`leukemia (CML) in adult patients with resistance to, or intolerance of prior therapy. The
`Applicant has provided clinical evidence of activity for bosutinib in patients with CML in second
`and later lines of treatment and an acceptable risk profile. The pivotal trial was a Phase 2,
`single arm trial which required all subjects to have previously been treated with imatinib. The
`trial enrolled 288 patients with Chronic Phase (CP) CML in second line treatment with
`bosutinib. Of the 288 patients, 200 were resistant to imatinib, and 88 were intolerant of
`imatinib. The primary endpoint of the trial was major cytogenetic response (MCyR) at 24
`weeks in patients with CP CML who were resistant to imatinib. The trial also enrolled patients
`with CP CML who had been exposed to more than one tyrosine kinase inhibitor (TKI) and
`patients in advanced phases of CML which includes accelerated phase (AP) and blast phase
`(BP) and enrolled a small cohort of patients with Ph+ acute lymphoblastic leukemia (ALL). Key
`secondary endpoints were MCyR at 24 weeks in patients with CP CML who were intolerant of
`imatinib in second line treatment with bosutinib; MCyR by 24 weeks in patients with third line
`CP CML, and objective hematologic response (OHR) by 48 weeks in patients with AP CML,
`BP CML and Ph+ ALL.
`
`The MCyR rate for patients with CP CML who were imatinib resistant and were in second line
`treatment with bosutinib at 24 weeks was 35.5% (95% CI: 29, 42). The Kaplan-Meier estimate
`of maintaining MCyR at Year 1 and Year 2 was 68.4% (95% CI: 58, 77) for both years in the
`imatinib-resistant cohort.
`
`
`The MCyR rate for patients with CP CML who were imatinib intolerant and were in second line
`treatment with bosutiniib at 24 weeks was 30% (95% CI: 20, 40). The Kaplan-Meier estimate
`of maintaining MCyR at Year 1 and Year 2 was 88% (95% CI: 71, 95) for both years in the
`imatinib-intolerant cohort.
`
`The MCyR rate for patients with CP CML who were in third line treatment with bosutinib
`following prior treatment with imatinib and dasatinib or imatinib and nilotinib by week 24 was
`27% (95% CI: 19, 36). The Kaplan-Meier estimate of maintaining MCyR was 63.9% (95% CI:
`[44, 78) at Year 1 and 59% (95% CI: 39, 75) at Year 2.
`
`The confirmed OHR rate by week 48 in patients with AP CML and prior therapy with more than
`one TKI (AP multi TKI) was 43% (95%CI: 26, 63) with a median duration of 42 weeks.
`Confirmed CHR rate in the same cohort was 27% (95% CI: 11, 42) with a median duration of
`74 weeks. The confirmed OHR rate by week 48 in patients with AP CML and prior imatinib
`
`Reference ID: 3162984
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`

`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`only was 64% (95% CI: 47, 79) with a median duration of 53 weeks. The confirmed CHR rate
`by week 48 in the same cohort was 41% (95% CI: 26, 56) with a median duration of 69 weeks.
`
`The confirmed OHR rate by week 48 in patients with BP CML and prior therapy with more than
`one TKI (BP multi TKI) was 19% (95% CI: 6, 38) with a median duration of 31 weeks.
`Confirmed CHR in the same cohort was 4% (95% CI: 0, 20) with a duration of 28 weeks. The
`confirmed OHR rate by week 48 in patients with BP CML and prior imatinib only was 36%
`(95% CI: 20, 55) with a median duration of 29 weeks. Confirmed CHR rate in the same cohort
`was 24% (95% CI: 10, 39) with a median duration of 26 weeks.
`
`Only 2 of 24 patients with Ph+ ALL responded, and the Applicant discontinued enrollment of
`this cohort after the first interim analysis. Because the population of patients with Ph+ ALL
`was small in this trial, and because there were few responders in this cohort, the Sponsor did
`not seek an indication and the results will not be reflected in labeling.
`
`
`1.2 Risk Benefit Assessment
`
`This risk benefit assessment of bosutinib considers the following factors: patients with chronic
`myeloid leukemia (CML) who are refractory to or intolerant of approved TKIs have a poor
`prognosis and limited treatment options; the usual course of CML is response to initial therapy
`followed by eventual relapse and retreatment with another TKI and eventual progression of
`disease and death; the only curative treatment is stem cell transplant (SCT), but not all
`patients have donors and many have comorbidities that preclude SCT; the clinical activity of
`bosutinib must be weighed against the toxicities of therapy; and the limitations of a single arm
`trial must be considered.
`
`The Applicant has demonstrated clinical activity of bosutinib in the treatment of patients with
`relapsed and refractory chronic, accelerated and blast phases of chronic myeloid leukemia
`(CML). Responses in patients in all phases of CML were durable, and as expected, patients in
`chronic phase CML had higher response rates and more durable responses than patients in
`accelerated and blast phases. Also as expected, patients in second line treatment with
`bosutinib had better response rates than those in third line treatment. However the trial data is
`not yet mature; and median duration of response in most cohorts had not been reached.
`
`The toxicity profile of bosutinib is similar to the other approved tyrosine kinase inhibitors with a
`few exceptions. More than eighty per cent of patients treated with bosutinib experienced
`diarrhea, but this toxicity was manageable, was usually low grade, and did not account for
`many discontinuations. The incidence of diarrhea with bosutinib was worse than what has
`been seen in trials of other TKIs in patients with CML.
`
`Prolongation of the QT interval has been observed in patients treated with nilotinib, but this
`toxicity was not observed with patients taking bosutiniib. In addition, a thorough QT study was
`
`Reference ID: 3162984
`
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`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`conducted by the Applicant and reviewed by the Independent Review Team of the Office of
`New Drugs.
`
`Myelosuppresion was expected and manifested as thrombocytopenia, neutropenia, anemia,
`and neutropenia in rates similar to what were observed in the pivotal trials for the other TKIs.
`Fluid retention was expected by the Applicant to be less frequent than with the previously
`approved TKIs, because bosutinib did not inhibit the PDGF receptor in preclinical studies.
`Fluid retention did manifest in patients treated with bosutinib. Events of peripheral edema and
`pleural and pericardial effusions were reported. However, an additional serious toxicity,
`congestive heart failure, was not reported with bosutinib.
`
`Hepatotoxicity has been observed with imatinib, dasatinib and nilotinib, and all three agents
`have Warnings and Precautions for hepatotoxicity in their labels. Bosutinib also causes
`elevations of liver enzymes, but there have been no cases of drug induced liver injury in the
`CML trials. However, there was one patient with drug induced liver injury enrolled in Trial
`2207-WW, a trial that enrolled patients with metastatic breast cancer who received a
`combination of bosutinib and letrozole. The hepatotoxicity started within the first week of
`treatment and resolved after discontinuation of bosutinib.
`
`Tumor lysis syndrome has occurred in patients taking nilotinib, but has not been observed with
`bosutinib. Hemorrhage has occurred in patients taking imatinib and dasatinib and to a lesser
`degree in patients taking bosutinib. Because the pivotal trial is a single arm trial with a small
`number of subjects (570), the safety profile of bosutinib is limited. The Applicant submitted the
`safety database from a failed Phase 3 trial (Trial 3000-WW) as supportive evidence. The trial
`was a randomized, controlled trial which compared 248 patients randomized to receive
`bosutinib with 251 patients randomized to receive imatinib as first line treatment for CML. The
`safety profile in the Phase 3 trial was similar to that of the Phase 2 trial.
`
`In addition, the Applicant submitted data from a Phase 2 trial in Japan in 52 patients with CML
`(Trial 2203-JA). The total safety database for patients with CML receiving treatment with
`bosutinib is comprised of 870 patients. The safety profile in the Japanese trial was similar to
`that of the pivotal trial.
`
`In summary, bosutinib offers another treatment option for patients with CML who have limited
`options, and has an acceptable safety profile. Bosutinib has demonstrated activity in patients
`with CP, AP and BP CML that is resistant to or intolerant of previous TKI therapy.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`There are no recommended postmarket risk evaluation and mitigation strategies for bosutinib.
`
`Reference ID: 3162984
`
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`

`

`Clinical Review
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`Bosulif (bosutinib)
`
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`This reviewer recommends that the Applicant have postmarket requirements to continue long
`term follow up of patients enrolled in clinical trials 200 and 3000 for a minimum of eight years
`and to submit the final completed study reports to the NDA.
`
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`
`Bosutinib monohydrate is a new molecular entity with the chemical name 3-Quinoline-
`carbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)
`propoxy]-, hydrate (1:1). See Figure 1. Bosutinib is manufactured into 100 mg and 500 mg
`tablets. The 100 mg tablets are yellow, oval-shaped, immediate release film coated tablets with
`appropriate debossing; Bosutinib film coated tablets, 500 mg are red, oval-shaped, immediate
`release film coated tablets with appropriate debossing.
`
`
`Figure 1 Chemical structure of bosutinib monohydrate (Applicant Figure)
`
`
`
`
`
`The drug product composition is presented in Table 1.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3162984
`
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`

`

`Clinical Review
`
`Karen M. McGinn, M.S.N., C.R.N.P.
`NDA 203341
`
`Bosulif (bosutinib)
`
`Table 1 Drug Product Composition (Applicant Table)
`% w/w
`
`In redient
`
`‘
`
`Quality
`Standard
`
`(Unconted
`Tablet)
`
`Unit Dose
`(mg/table!)
`
`100 mg
`
`I
`
`-.I h
`
`Unit Dose
`(mg/tablet)
`
`500 mg
`
`Function
`
`.
`
`':°
`
`:
`
`'.
`
`—
`
`.u -.'=.
`
`Bosutinib monohydrate
`
`Pfizer'
`
`Microcrystalline cellulose
`
`NF/Ph. Eur.
`
`Croscarmellose sodium
`
`NF/Ph. Eur.
`
`Poloxamer
`
`Povidone
`
`NF/Ph. Eur.
`
`
`
`
`
`
`
`Total (Final Tablet)
`
`14 .35
`
`746.75
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`Currently there are three tyrosine kinase inhibitors approved for the fleahnent of patients with
`CML. All three have demonstrated efficacy in inducing remissions; however the only curative
`teatment for patients with CML is allogeneic hematopoietic stem cell transplantation. Many
`patients are ineligible for transplantation due to other co-morbidities or advanced age, and
`many pafients do not have a suitable donor. See Table 2.
`
`Other drugs that have been approved for patients with CML but do not have as favorable a
`benefit/risk profile as the TKIs are me following: Busulfan, cyclophosphamide, interferon
`alpha, cytarabine and mechorethamine.
`
`Reference ID: 3162984
`
`14
`
`

`

`Clinical Review
`
`Karen M. McGinn,
`NDA 203341
`
`Bosulif (bosutinib)
`
`M.S.N., C.R.N.P.
`
`Table 2 Tables of Currently Available Treatments for CML (Reviewer Table)
`
`-_—
`
`400 mglday
`
`34o mg/mzlday
`(NTE* 600 mg)
`600 mglday
`
`100 mglday
`140 mglday
`
`140 mglday
`
`
`
`Adults with newly diagnosed Philadelphia positive
`(Ph+) chronic phase (CP) chronic myeloid leukemia
`(CML)
`Adults with Ph+ CP CML after failure of interferon-
`
`alpha therapy
`Children with newly diagnosed Ph+ CP CML
`Patients with Ph+ CML in blast crisis, (BC)
`accelerated phase (AP), or in chronic phase after
`failure of interferon-al ha thera-
`
`Dasatinib
`
`N

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