CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`203341Orig1s000
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`OFFICE DIRECTOR MEMO
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`1
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`Summary Review for Regulatory Action
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`(electronic stamp)
`Richard Pazdur, MD
`Office Director Decisional Memo
`203341
`
`Wyeth Pharmaceuticals, Inc.
`11/17/11
`09/17/12
`Bosulif/Bosutinib
`
`Office Director Decisional Memo
`203341_Bosulif (bosutinib)
`
`
`
`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)
`
`Action/Recommended Action for NME:
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Division Director
`Medical Officer Review
`
`Regulatory Project Manager
`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
`
`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
`
`Ann Farrell, MD
`Karen McGinn MSN, CRNP/ Virginia Kwitkowski MS, RN, ACNP-
`BC
`Diane Hanner
`Kallappa Koti Ph.D./Mark Rothmann, PhD
`Shwu Luan Lee PhD/Haleh Saber, PhD
`Joyce Crich, PhD/Janice Brown, MS/Akm Khairuzzaman,
`PhD/Angelica Dorantes, PhD
`Robert Mello, PhD/John Metcalfe, PhD
`Elimika Pfuma, PhD/Justin Earp, PhD/Bahru Habtemariam
`PhD/Rosane Charlab Orbach, PhD
`
`Anthony Orencia, MD/Janice K. Pohlman, MD/Susan D Thompson,
`MD
`Virginia Kwitkoswki CRNP
`
`
`
`Venkatesh Bhattaram/Nitin Mehrotra/Moh Jee Ng/Joanne Zhang/
`Monica L Fiszman/Norman Stockbridge
`
`
`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: 3183648
`
`

`

`Office Director Decisional Memo
`203341_Bosulif (bosutinib)
`
`
`2
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`Introduction & Background
`1.
`On November 17, 2011, Wyeth submitted this NDA 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. Bosutinib is not marketed in the United States or in any other country.
`
`There are multiple approved products to treat CML in the chronic, accelerated or blast phases of the disease. See
`table below for information on the recently approved indications for CML.
`
`
`Table 1. FDA Approved Tyrosine Kinase Inhibitor Drugs for Chronic Myelogenous Leukemia
`Drug
`Indication
`Imatinib
`• Adults with newly diagnosed Philadelphia positive (Ph+) chronic phase (CP) 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-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
`Reviewer’s Table
`
`Dasatinib
`
`Nilotinib
`
`
`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.
`
`2. CMC/Device
`CMC reviews 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.
`
`3. Nonclinical Pharmacology/Toxicology
`There are no outstanding nonclinical issues that preclude approval. Nonclinical reviewers indicate in their reviews
`that bosutinib is not genotoxic nor mutagenic nor is there any evidence that bosutinib is carcinogenic.
`
`Dr. Saber’s TL memo states:
`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.
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`Reference ID: 3183648
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`

`

`3
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`Office Director Decisional Memo
`203341_Bosulif (bosutinib)
`
`
`4. Clinical Pharmacology/Biopharmaceutics
`The primary review of the Clinical Pharmacology review states:
`
`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 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 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.
`
`5. Clinical Microbiology
`There are no outstanding microbiology issues that preclude approval.
`
`6. Clinical/Statistical-Efficacy
`The primary trial supporting this NDA is Trial 200, which was a single-arm, open-label, multi-center trial enrolling
`546 patients with either chronic phase (CP), accelerated phase (AP) or blast phase (BP) CML previously treated
`with at least one prior tyrosine kinase inhibitor (TKI). All patients received prior imatinib therapy. In the total
`patient population, 73% were imatinib resistant and 27% were imatinib intolerant. In this trial, 53% of patients were
`males, 65% were Caucasian, and 20% were 65 years old or older. The efficacy endpoints for patients with CP
`CML were the rate of major cytogenetic response (MCyR) at week 24 and the duration of MCyR. The efficacy
`endpoints for patients with AP or BP CML were the rate of confirmed complete hematologic response (CHR) and
`overall hematologic response by week 48.
`
`The following table outlines the trial design for the trials that were submitted within this NDA. 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.
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`Reference ID: 3183648
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`4
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`Endpoint
`MCyR @ week 24
` CHR by week 48
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`
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`CCyR @ 1 year
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`CCyR @ 1 year
`MTD
`MCyR and CHR
`
`Office Director Decisional Memo
`203341_Bosulif (bosutinib)
`
`Table 2. Tables of Clinical Trials (Reviewer Table)
`
`
`
`Trial Design
`Treatment Groups (N)
`• CP CML Second line (288) and Third line (118)
`Phase 1/2 open-label, 2-part trial in
`• AP CML (144); Ph+ ALL (24)
`subjects with Ph+ leukemia
`
`• CP CML treated with bosutinib (248)
`
` •
`
` CP CML treated with imatinib (251)
`• Phase 1 (17)
`• Phase 2 (35)
`
`Phase 3 RCT in subjects with newly
`diagnosed CP-CML to compare
`bosutinib to imatinib
`Phase 1/2 open-label trial in
`subjects with Ph+ leukemia
`
`
`
`Trial
`200
`
`3000
`
`2203
`
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`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.
`
`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%
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`Reference ID: 3183648
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`

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`5
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`Office Director Decisional Memo
`203341_Bosulif (bosutinib)
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`(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.
`
`Dr. Farrell disagrees with the interpretation that efficacy was not demonstrated in the “intolerant” population as
`conveyed in her Summary review. Dr. Farrell states:
`
`Patients with CML who were intolerant to other therapies had durable 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 Dr. Koti’s 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).
`
`The review team requests longer follow-up data (2 years) from the ongoing 200 trial.
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`7. 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.
`
`8. Advisory Committee Meeting
`This product was not taken to an Oncologic Drugs Advisory Committee Meeting since multiple other tyrosine
`kinase inhibitors using the same primary efficacy endpoint for use in the treatment of CML and with similar safety
`concerns have been approved.
`
`9. Pediatrics
`This application has Orphan drug designation and is therefore exempt from PREA requirements.
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`Reference ID: 3183648
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`

`

`Office Director Decisional Memo
`203341_Bosulif (bosutinib)
`
`
`10. Other Relevant Regulatory Issues
`DSI inspection of requested sites did not reveal any unreliable data or study misconduct.
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`6
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`11. Labeling
`There are no unresolved issues that preclude approval.
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`12. Decision/Action/Risk Benefit Assessment
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` Recommended regulatory action: Approval
`
` 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. The Risk
`benefit profile, which was also discussed by Dr. Farrell, Ms. Kwitkowski and McGinn, is acceptable. In
`addition, the review team recommends approval of this NDA, and I concur.
`
` 
`
` Recommendation for Post marketing Risk Management Activities
`A REMS is not Recommended. Routine post-marketing surveillance is recommended.
`
` 
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` Recommendation for other Post marketing Study Requirements (PMR)/ Commitments (PMC)
`See action letter.
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`Reference ID: 3183648
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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/
`----------------------------------------------------
`
`TAMY E KIM
`08/31/2012
`
`RICHARD PAZDUR
`08/31/2012
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`Reference ID: 3183648
`
`