CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203341Orig1s000
`
`SUMMARY REVIEW
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`

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`Summary Review for Regulatory Action
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`1
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`Date
`From
`Subject
`NDA/BLA #
`Supplement #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`Proposed Indication(s)
`
`(electronic stamp)
`Ann. T. Farrell, M.D., Acting Division Director
`Division Director Summary Review
`203341
`
`Wyeth Pharmaceuticals, Inc.
`11/17/11
`09/17/12
`Bosulif/Bosutinib
`
`Oral tablets/100 mg and 500 mg
`For the treatment of patients with chronic myelogenous
`leukemia (chronic phase, accelerated phase and blast
`phase) with resistance or intolerance to prior therapy
`Approval
`
`Ms. Karen McGinn MSN, CRNP/Ms. Virginia Kwitkowski MS,
`RN, ACNP-BC
`Kallappa Koti Ph.D./Mark Rothmann, Ph.D.
`Shwu Luan Lee PhD./Haleh Saber, Ph.D.
`Joyce Crich, Ph.D./Janice Brown, M.S. /Akm Khairuzzaman,
`Ph.D./Angelica Dorantes, Ph.D.
`Robert Mello, Ph.D./John Metcalfe, Ph.D.
`Elimika Pfuma, Ph.D./Justin Earp, Ph.D./Bahru Habtemariam
`Ph.D./Rosane Charlab Orbach, Ph.D.
`
`Anthony Orencia, M.D./Janice K. Pohlman, M.D./Susan D.
`Thompson, M.D.
`Ms. Virginia Kwitkoswki CRNP
`
`
`
`Venkatesh Bhattaram/Nitin Mehrotra/Moh Jee Ng/Joanne Zhang/
`Monica L Fiszman/Norman Stockbridge
`
`
`Action/Recommended Action for
`NME:
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`
`Statistical Review
`Pharmacology Toxicology Review
`CMC Review/OBP
`Review/Biopharmaceutics
`Microbiology Review
`Clinical Pharmacology Review
`
`DDMAC
`DSI
`
`CDTL Reviews
`OSE/DMEPA
`OSE/Epidemiology
`OSE/DRISK
`Other - IRT
`
`Other – Pediatrics
`
` Maternal Health Team
`
` Other- Pharmacometrics
`
`
`OND=Office of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`
`Reference ID: 3183658
`
`

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`Signatory Authority Review Template
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`2
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`1. Introduction
`Wyeth submitted this application for bosutinib, an oral tyrosine kinase inhibitor, for the
`treatment of chronic, accelerated, or blast phase Ph + chronic myelogenous leukemia
`(CML) in adult patients with resistance or intolerance to prior therapy.
`
`The PDUFA goal date is September 17, 2012.
`
`Bosutinib is not marketed in the United States or in any other country.
`2. Background
`There are multiple approved products to treat chronic myelogenous leukemia in the
`chronic, accelerated or blast phases of the disease. For details on the recent
`approved indications for CML see table below.
`
`
`Table 1. FDA Approved Tyrosine Kinase Inhibitor Drugs for Chronic
`Myelogenous Leukemia
`Drug
`Imatinib
`
`Indication
`• Adults with newly diagnosed Philadelphia
`positive
`(Ph+) chronic phase (CP) chronic myeloid
`leukemia
`(CML)
`• Adults with Ph+ CP CML after failure of
`interferonalpha
`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-alpha therapy
`• Newly diagnosed adults with Ph+ CML in CP
`• Adults with CP, AP, myeloid blast phase,
`lymphoid
`blast phase, Ph+ CML with resistance or
`intolerance
`to prior therapy including imatinib
`• Adults with Ph+ acute lymphoblastic leukemia
`(ALL)
`with resistance or intolerance to prior therapy
`• Newly diagnosed adult patients with Ph+ CML
`in CP
`• CP and AP CML in adult patients resistant to
`or
`intolerant to prior therapy that included imatinib
`
`Dasatinib
`
`Nilotinib
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`Reviewer’s Table
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`Reference ID: 3183658
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`3
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`Prior to the approval of the oral tyrosine kinase inihibitors, drug and biologic product
`treatment for CML included interferon, ara-c, hydroxyurea, busulfan, and other
`chemotherapy regimens.
`
`Prior to the development of tyrosine kinase inhibitors, stem cell transplant was the
`only hope for long term disease control. With the emergence of the tyrosine kinase
`inhibitor therapies, long term disease control can be achieved without stem cell
`transplant.
`3. CMC/Device
`Dr. Crich and Ms. Brown reviewed this application. In their reviews they state the
`following:
`
`From the chemistry, manufacturing and controls standpoint, this NDA is
`recommended for approval. There are no outstanding CMC issues that impact
`approvability of this NDA…
`
`Based on the provided stability data, a 24-month expiration dating period is granted
`for the drug product bosutinib tablets (100 mg and 500 mg) when stored at USP
`controlled room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-
`86ºF).
`
`The Office of Compliance has issued an overall “acceptable” recommendation on May
`10, 2012 for all facilities.
`
` I
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` concur with the conclusions reached by the CMC review team regarding the
`acceptability of the manufacturing of the drug product and drug substance. There
`are no outstanding issues which would preclude approval.
`
`
`4. Nonclinical Pharmacology/Toxicology
`Per Dr. Weis’ review, bosutinib is not genotoxic nor mutagenic nor is there any
`evidence that bosutinib is carcinogenic.
`
`From Dr. Saber’s TL memo
`I concur with Dr. Lee that from a nonclinical perspective, BOSULIF
`may be approved for the proposed indication. No additional nonclinical studies are
`needed to support approval of BOSULIF for the proposed indication.
`
` I
`
` concur with the conclusions reached by the pharmacology/toxicology reviewer that
`there are no outstanding pharm/tox issues that preclude approval.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`From Dr. Pfuma’s primary review:
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`Reference ID: 3183658
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`4
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`Bosutinib exhibits approximately linear PK in the dose range of 200 – 800 mg. No
`exposure response relationships for effectiveness or safety were observed at the
`dose of 500 mg. In a food-effect trial, a high-fat meal increased bosutinib exposure 2-
`fold. Bosutinib showed better tolerability when co-administered with food; as a result
`bosutinib was co-administered with food in patient trials. Bosutinib is primarily
`metabolized by CYP3A4. Clinical trials showed that the strong CYP3A4 inhibitor
`ketoconazole increased bosutinib AUC 9-fold while the strong CYP3A4 inducer
`rifampin decreased bosutinib AUC by 94%. A 2-fold increase in exposures
`was observed in patients with hepatic impairment. In a thorough QT trial, bosutinib did
`not cause significant changes in placebo adjusted, baseline-corrected QTc….
`
`The Office of Clinical Pharmacology Divisions of Clinical Pharmacology 5,
`Pharmacometrics and Pharmacogenomics have reviewed the information contained
`in NDA 203-341. This NDA is considered acceptable from a clinical pharmacology
`perspective.
`
`The IRT review stated that administration of BOSULIF at a recommended dose of 500
`mg with food does not prolong the QT interval and co-administration with
`ketaconazole also did not prolong the QT interval.
`
`The biopharmaceutics review found the proposed dissolution method and acceptance
`criteria acceptable.
`
` I
`
` concur with the conclusions reached by the clinical pharmacology/biopharmaceutics
`reviewer that there are no outstanding clinical pharmacology issues that preclude
`approval.
`
`The clinical pharmacology review team recommends the following post-marketing
`requirement:
`
`Requirement
`1) Conduct a drug-drug interaction trial to evaluate the effect of a moderate CYP3A4
`inhibitor (e.g. erythromycin) on the pharmacokinetics of bosutinib. The proposed
`protocol must be submitted for review prior to trial initiation.
`
`
`
`6. Clinical Microbiology
`The Product Quality Microbiology review by Drs. Mello and Metcalfe recommends
`approval.
`
`
`7. Clinical/Statistical-Efficacy
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`
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`Reference ID: 3183658
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`5
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`Endpoint
`MCyR @ week 24
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`CHR by week 48
`CCyR @ 1 year
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`CCyR @ 1 year
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`MTD
`MCyR and CHR
`
`The following table from the primary clinical review shows the efficacy and safety
`database. The major study for review is Trial 200. Trial 3000 was a failed trial that did
`not demonstrate the superiority of bosutinib over imatinib in the newly diagnosed
`setting. Dasatinib and nilotinib have suggested superiority over imatinb in the newly
`diagnosed setting and have received accelerated approval on that basis.
`
`Table 6 Tables of Clinical Trials (Reviewer Table)
`Trial
`Trial Design
`Treatment Groups (N)
`200
`Phase 1/2 open-label, 2-
`• CP CML Second line (288)
`part trial in subjects with
`and Third line (118)
`Ph+ leukemia
`• AP CML (144); Ph+ ALL (24)
`3000 Phase 3 RCT in subjects
`• CP CML treated with bosutinib
`with newly diagnosed
`(248)
`CP-CML to compare
`• CP CML treated with imatinib
`bosutinib to imatinib
`(251)
`2203 Phase 1/2 open-label
`• Phase 1 (17)
`trial in subjects with Ph+
`• Phase 2 (35)
`leukemia
`
`
`
`The following text is from the primary clinical reviewer’s Executive Summary:
`
`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.
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`Reference ID: 3183658
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`6
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`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 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.
`
`The statistical team confirmed the applicant’s findings. Here is language from Dr.
`Koti’s review:
`
`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...
`
`In this reviewer’s opinion, the collective evidence does not support the approval of this
`application as a whole.
`
` disagree with his interpretation that efficacy was not demonstrated in the “intolerant”
`population. Patients with CML who were intolerant to other therapies had durable
`
` I
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`Reference ID: 3183658
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`7
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`responses with bosutinib. In the absence of treatment, patients with CML who were
`intolerant to other therapies would be expected to have a 0% response rate.
`
`Drs. Rothmann and Sridhara did not concur with his recommendation. In their memo
`they concluded:
`
`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).
`
` concur with the clinical review team and the statistical team leader and statistical
`division director regarding approval for all but the acute leukemia cohort (Philadelphia
`positive ALL).
`
`The review team requests longer follow-up data (2 years) from the ongoing 200 trial.
`
`
` I
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`8. Safety
`The safety database was adequate for analysis.
`
`Similar safety findings for other approved TKIs were observed with bosutinib. These
`findings were myelosupression, gastrointestinal, fluid retention (peripheral edema,
`pleural and cardiac effusions), constitutional (fatigue) and hepatoxicity. The major
`serious safety findings associated with bosutinib use were: NCI CTCAE grade 3 and 4
`hematologic and diarrhea, pneumonia and rash. Myelosuppression, gastrotinestinal,
`hepatic toxicity, and fluid retention are in the warnings section of the labeling.
`
`Anaphylaxis
`Two cases of anaphylactic shock were observed in clinical trials. Prior episodes of
`hypersensitivity are mentioned as a contraindication to continued use.
`
`I concur with the conclusions of the clinical review teams regarding safety findings
`and the recommendation for additional follow-up data collection from the major trial for
`the indication.
`
`
`9. Advisory Committee Meeting
`This product was not taken to an Oncologic Drugs Advisory Committee Meeting. The
`Office of Hematology and Oncology Drug Products has approved multiple other
`tyrosine kinase inhibitors (see background) using the same primary efficacy endpoint
`for use in the treatment of CML and with similar safety concerns.
`
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`Reference ID: 3183658
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`8
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`Pediatrics
`10.
`Orphan designation
`11.
`Other Relevant Regulatory Issues
`The application complied with financial disclosure requirements and trials were
`conducted with good clinical practice.
`
`Office of Surveillance and Epidemiology was consulted including DMEPA who
`provided labeling input.
`
`Office of Scientific Investigation (DSI)
`Inspection of requested sites did not reveal any unreliable data or study misconduct.
`
`There are no other unresolved relevant regulatory issues.
`
`
`
`Labeling
`12.
`The labeling was reviewed by all disciplines and consultant staff.
`13.
`Decision/Action/Risk Benefit Assessment
`
`
`
`
`
` Recommended regulatory action
`Approval for the treatment of adult patients with chronic, accelerated, or blast
`phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia
`(CML) with resistance or intolerance to prior therapy
` Risk Benefit Assessment
`The risk benefit assessment suggests that bosutinib is effective for the
`treatment as stated in the indication. The treatment was tolerated with the side
`effect profile observed similar to other TKIs. The most common side effects
`were hematologic, gastrointestinal, dermatologic, and fatigue.
` Recommendation for Post marketing Risk Management Activities
`Routine post-marketing surveillance
` Recommendation for other Post marketing Study Requirements (PMR)/
`Commitments (PMC)
`We have asked the applicant for the following post-marketing reguirement and
`commitment:
`Conduct a drug-drug interaction trial to evaluate the effect
`PMR 1
`of a moderate CYP3A4 inhibitor (e.g. erythromycin) on the
`pharmacokinetics of bosutinib. The proposed protocol must be
`submitted for review and concurrence prior to trial initiation.
`PMR2
`Continue follow-up of patients (on treatment and in
`protocol defined post-treatment follow-up) enrolled in Study 200-WW at
`least an additional 2 years past the March 28, 2011 cut-off date. Submit
`
`
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`Reference ID: 3183658
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`

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`the Final Report, which will consist of an updated report containing, at a
`minimum, data through March 28, 2013.
`
`
`For final PMR and PMC see text of approval letter.
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`9
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`Reference ID: 3183658
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`

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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/
`----------------------------------------------------
`
`ANN T FARRELL
`08/31/2012
`
`Reference ID: 3183658
`
`