CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203341Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Addendum to Cross—Discipline Team Leader Review
`
`
`Date
`August 7, 2012
`From
`Vir '
`'a Kwitkowski, MS, RN, ACNP-BC
`Sub'ect
`Addendum to Cross-Disci u line Team Leader Review
`
`NBA #
`
`Sun lement#
`
`A licant
`
`Date of Submission
`
`PDUFA Goal Date
`
`203341
`
`0
`
`W eth a Pfizer con an
`
`November 17, 2012
`
`Se tember 17, 2012
`
`Proprietary Name /
`Established
`S 1
`
`names
`
`Bosulif/
`Bosutinib
`
`thera
`
`100 mg tablet
`Dosage forms / Strength
`
`500 mg tablet
`
`Proposed Indication(s)
`
`For the treatment of chronic, accelerated, or blast
`
`phase Ph + chronic myelogenous leukemia (CML) in
`adult patients with resistance or intolerance to prior
`
`Recommended:
`
`Addendum to Section 2.0:
`
`The Division requested a patient representative for Chronic Myelogenous Leukemia for a
`Divisional Assignment. Ms. Paige Brown was recommended by the AC staff. Ms
`Brown was consulted by the Division. A briefing package was issued to her for review.
`
`The question posed to her was:
`
`From a patient’s perspective, is the benefit:risk ratio for Bosutinib acceptable for adult
`patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia
`(CML) who demonstrate resistance or intolerance to prior therapy? This includes
`patients with chronic phase (CP), accelerated phase (AP), and blast phase (BP) CML in
`second or later lines settings.
`
`Consultant Response:
`
`I’ve reviewed the package and the answer I would offer is that yes, the benefit : risk
`
`ratio is acceptable. My challenge, or my curiosity in these reviews, is always related
`to the refractory arms. I always suspect, though the data is not here, that
`intolerance is always subjective and that intolerance is often consistent in tki
`
`Reference ID: 31 83656
`
`

`

`therapy. I am, of course
`
`M6)
`
`Responses for refractory patients are an important measure to me, and there is
`
`evidence of positive response. I am always particularly excited when I see sustained
`responses in advanced or blast crisis CML, which this does show indication of. I
`
`struggle because I can’t compare the ae’s or responses to the other therapies with
`this data, and again there is a difference to me between intolerance and resistance,
`but when you have patients achieving and maintaining responses, it shows that the
`
`drug has value to some patients.
`
`If you need a more formal statement or if you think I’ve misinterpreted something,
`
`please let me know. The bottom line is that I would use this therapy if others failed.
`
`Reference ID: 31 83656
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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/
`----------------------------------------------------
`
`VIRGINIA E KWITKOWSKI
`08/31/2012
`
`Reference ID: 3183656
`
`

`

`Cross Discipline Team Leader Review
`
`Cross—Discipline Team Leader Review
`
`
`Date
`August 3, 2012
`From
`Vir inia E. Kwitkowski, MS, RN, ACNP-BC
`m_ Cross-Disci o line Team Leader Review
`NDA/BLA #
`NDA 203341/0
`
`Su n lement#
`
`Date of Submission
`
`November 17, 2011
`
`W W a Pfizer coman
`
`
`
`Se .tember 17, 2012
`PDUFA Goal Date
`——
`Proprietary Name /
`Bosulif/
`Established
`S ‘
`bosutinib
`
`names
`
`Dosage forms / Strength
`
`Proposed Indication(s)
`
`100 mg tablet
`500 mg tablets
`For the treatment of chronic, accelerated. or blast phase Ph +
`chronic myelogenous leukemia (CML) in adult patients with
`resistance or intolerance to rior thera.
`
`Re IlarA roval
`
`1. lntrod uction
`
`Bosutinib is a tyrosine kinase inhibitor that is a new molecular entity. Bosutinib is
`manufactured as immediate release oral tablets in 100 mg and 500 mg strengths.
`
`Patients with chronic myelogenous leukemia who are relapsed, refractory, or intolerant of the
`approved tyrosine kinase inhibitors (imatinib, dasatinib, and nilotinib) have limited treatment
`options and a poor prognosis. The only curative treatment available for CML is allogeneic
`hematopoietic stem cell transplantation (HSCT). However, not all patients have available
`donors and due to comorbidities, may not be able to tolerate HSCT.
`
`On November 17, 2011, Pfizer submitted a New Drug Application for Bosutinib. In this
`submission, they requested priority review designation because they believed that Bosutinib
`provides a major advance in the treatment of patients with Philadelphia Chromosome Positive
`Chronic Phase, Accelerated Phase, and Blast Phase CML. The Division concluded that this
`request was not justified because there are available therapies for patients who were
`relapsed/refractory/intolerant of imatinib. On January 26, 2012, the FDA issued a letter
`informing Wyeth that their application had been filed under a standard review classification
`and providing a user fee date of September 17, 2012.
`
`The application contained only one efficacy trial (200-WW). This was considered acceptable
`to the Division because all of the previous applications for the second-line CIVIL indication
`have contained a single trial. CML is a rare disease with approximately 5430 patients
`diagnosed in the US. per yearl.
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`Cross Discipline Team Leader Review
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`In support of the proposed indication, Pfizer submitted the results of Trial 200-WW, a Phase
`1/2 single-arm trial enrolling a total of 570 patients. The largest number of patients enrolled
`had relapsed/refractory Chronic Myelogenous Leukemia (CML) in any one of three stages:
`Chronic Phase (CP), Accelerated Phase (AP), or Blast Phase (BP). The trial also enrolled a
`small number of patients with Philadelphia Chromosome-positive Acute Lymphocytic
`Leukemia (ALL). All patients had been treated previously with imatinib; some of the subjects
`were resistant to imatinib and others were intolerant of imatinib.
`
`The trial consisted of two parts; a dose escalation part (Part 1) and an efficacy part (Part 2).
`The primary objectives of Part 1 were to determine the maximum tolerated dose (MTD), and
`to evaluate pharmacokinetics (PK) in patients with CP-CML. The primary objectives of Part 2
`were to determine the rate of major cytogenetic response in subjects with imatinib-resistant
`chronic phase CML who had no prior Src, Abl, or Src-Abl kinase inhibitor exposure other than
`imatinib, and to determine the population PK parameters of this population.
`
`Pfizer submitted data that included 24 months of follow-up.
`
`The primary endpoint of Part 2 of Trial 200 was the MCyR at week 24 for second-line
`treatment of patients with CP-CML who were resistant to imatinib. The results for the primary
`endpoint were 35.5% (95% CI = 28.6, 42.8). The median duration of response was not
`reached.
`
`The MCyR rate at 24 weeks for the overall evaluable Chronic Phase CML population was
`33.8% (90 of 266 patients) [90% CI: 29, 38.9].
`
`The MCyR rate at week 24 for second line treatment of patients with CP CML who were
`intolerant of imatinib was 30% (95% CI = 21.6, 39.5). This cohort did not reach the pre-
`specified MCyR rate of 53%. The median duration of response was not reached.
`
`For the complete results, the reader is referred to Section 7 of this memo.
`
`The Risk:Benefit assessment for Bosutinib is positive for patients with CML that have
`relapsed after or are intolerant to prior TKI therapy. Activity was demonstrated in patients
`who received prior imatinib with a toxicity profile that was similar (with few exceptions) to
`other approved TKIs for CML.
`
`Prior regular approvals of tyrosine kinase inhibitors for CP-CML (dasatinib2 and nilotinib3)
`were also based upon 24 months of follow-up data also using MCyR (Major Cytogenetic
`Response) as the primary endpoint.
`
` do not concur with the recommendation in Section 1.4 of Ms. McGinn’s review for a “post-
`marketing requirement 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.” The reason for my disagreement is that the Applicant has demonstrated clinical
`benefit based upon acceptable MCyR rates of an acceptable duration and 24 months of follow-
`up in patients who have received prior TKI therapy for their CML. The Agency will
`
` I
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`Cross Discipline Team Leader Review
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`recommend a post-marketing commitment to follow the patients in the 200 trial for 5 years, as
`was specified in the protocol. This was discussed with Ms. McGinn and agreement reached
`after her review was finalized.
`
` concur with Ms. McGinn’s recommendation for regular approval of Bosutinib for the
`treatment of chronic, accelerated, or blast phase Ph + chronic myelogenous leukemia (CML) in
`adult patients with resistance or intolerance to prior therapy.
`
`Labeling negotiations are ongoing at the time of finalization of this review.
`
`
` I
`
`2. Background
`
`
`Prior to 2001, CML was managed with agents like busulfan, hydroxyurea, interferon alpha,
`and allogeneic bone marrow or stem cell transplantation.
`
`Approval of Gleevec
`The 2001 U.S. approval of imatinib (Gleevec ®) revolutionized the treatment of CML in this
`country and provided the first tyrosine kinase inhibitor (TKI) for use in patients with newly
`diagnosed Chronic Phase (CP) CML based upon the results from the randomized phase 3 IRIS
`trial.
`
`Approval of Sprycel
`On June 28, 2006, the FDA granted accelerated approval to dasatinib (Sprycel) for the
`treatment of adults with chronic myeloid leukemia [CP-CML, AP-CML, and BP-CML] with
`resistance or intolerance to prior therapy including imatinib. This approval was based upon at
`least 12 months follow-up of all patients. As a condition of accelerated approval, the Applicant
`was required to submit 24 month follow-up data from the original Phase 2 trial. On May 21,
`2009 the FDA converted the accelerated approval to regular approval based upon 24 months of
`follow-up data submitted by the Applicant. On October 28, 2010, the FDA approved
`dasatinib, for the treatment of newly diagnosed adult patients with CML-CP, with a
`recommended dose of 100 mg/day.
`
`Approval of Tasigna
`On October 29, 2007, FDA granted accelerated approval for nilotinib (Tasigna) “for chronic
`phase (CP) and accelerated phase (AP) Philadelphia positive chronic myelogenous leukemia
`(CML) in adult patients resistant to or intolerant to prior therapy that included Gleevec ®
`(imatinib)”. This approval was based upon at least 12 months follow-up of all patients. As a
`condition accelerated approval, the Applicant was required to submit 24 month follow-up data
`from the original Phase 2 trial.
`
`On June 17, 2010, the accelerated approval was converted to regular approval based upon 24
`months of follow-up data submitted by the Applicant. At the same time, nilotinib was granted
`accelerated approval by the FDA for the treatment of adult patients with newly diagnosed CP-
`CML based upon a randomized trial comparing nilotinib to imatinib in patients with newly
`diagnosed chronic phase CML. The recommended nilotinib dose for the newly diagnosed
`
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`Cross Discipline Team Leader Review
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`patients is 300 mg by mouth twice daily. The recommended nilotinib dose for patients with
`CML that is resistant or intolerant to imatinib is 400 mg by mouth twice daily. Nilotinib also
`has regular approval for the treatment of accelerated phase CML in adult patients resistant to
`or intolerant to prior therapy that included imatinib.
`
`
`Summary of Evidence Needed for FDA Approval
`
`The last two drugs approved for CP-CML (dasatinib2 and nilotinib3), received accelerated
`approval based upon 12 months of data using MCyR (major cytogenetic response). Nilotinib
`was converted to regular approval based upon 24 months of data using the endpoint of MMR
`(major molecular response) at 1 year, with a supportive secondary endpoint of CCyR by 1 year
`(complete cytogenetic response). Dasatinib was converted to regular approval based upon 24
`months of data and the primary endpoint of CCyR (complete cytogenetic response) within 1
`year, with a supportive secondary endpoint of MMR (major molecular response).
`
`Among patients with CP-CML who receive nilotinib or dasatinib in a second line setting (after
`imatinib), 40-50% of them do not achieve a major cytogenetic response (MCyr). Among
`patients with AP-CML who receive dasatinib, 64% do not achieve a major hematologic
`response (MHR). Among patients with AP-CML who receive nilotinib, 35% do not achieve a
`MHR.
`
`In Blast Phase CML, the only second generation TKI approved is dasatinib and approximately
`50% of these patients do not experience a MHR.
`
`Today, the standard first treatment for CML in Chronic Phase is one of the three approved
`TKIs (imatinib, nilotinib, or dasatinib). If the disease does not respond to the first TKI, the
`patient may receive a second different TKI. At the present time, there are no approved TKI
`agents for patients with CP-CML in the third-line setting (those whose disease is refractory or
`intolerant to second-line TKI therapy). The National Comprehensive Cancer Network
`(NCCN) guidelines presently recommend investigational therapies or allogeneic HSCT after
`failure of 2 prior TKIs.
`
`Because this application was not being presented to an Advisory Committee, the Division
`requested clearance of two leukemia specialists and one patient representative for consultation
`during the review. The Advisors and Consultants staff were consulted to begin clearance of
`the two leukemia experts on 4/17/12. The two leukemia experts were not able to be cleared for
`participation prior to the due date for primary or CDTL reviews. However, the patient
`representative, Elizabeth Paige Brown Strong, was cleared in adequate time for consultation
`with the Division. Her review is pending as of finalization of this memo. An addendum will
`be drafted to capture her recommendation once it is received.
`
`
`3. CMC
`
`
`
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`

`Cross Discipline Team Leader Review
`
`The primary review was completed by Joyce Crich, PhD. The information in this section is
`from Dr. Crich ’s primary review. Dr. Crich was unable to provide a recommendationfor
`approvalfrom a CMC standpointprior tofinahation ofher review. Thefinal
`recommendation was pending the firms agreement to revise the Postapproval Stability
`Commitment [refer ICH QIA (R2) II(B)(8)] to monitor the stability ofmarketed drugproducts
`in the proposed commercial container closure system.
`
`In the Dir'lsion Director Memo authored bv Sarah Miksinski, PhD, it is stated that ONDQA
`recommends apprmal ofthis NDA and that there are no outstanding CMC deficzenczesfor this
`NDA.
`
`Dr. Miksinski recommends that thefollowing language be placed into the action letter:
`
`An expiration datingperiod of24 months is grantedfor the drugproduct, when stored at 25°C
`(77°F) acutsions permitted between 15°C to 30°C (59°F to 86°F).
`
`The rest of the text in this section is directlyfrom Dr. Crich ’s review.
`
`0 General product quality considerations
`
`Drug Substance
`The drug substance bosutinib is a new molecular entity. Detailed information regarding
`the drug substance is provided in the NDA. Bosutinib monohydrate is manufactured by a
`
`(mo
`
`Detailed information regarding designation of the M4) proposed
`starting materials, the commercial sources, acceptance criteria, and associated methods
`of analysis are provided.
`
`A Quality by Design (QbD) approach was employed for the manufacturing process
`based on the principles of ICH Q8, Q9 and Q11, including quality target product
`profile (QTPP), identification of the potential critical quality attributes (CQAs), the
`process parameters (CPP, KPP) that have a potential impact on these CQAs, and
`operating spaces for each step of the drug substance manufacturing process by
`statistically designed multivariate experimental (DoEs) approaches, leading to the
`overall operating space and control strategy for the manufacturing process. The
`quality attributes of bosutinib monohydrate are defined in the drug substance
`specification based on a traditional approach. The key and critical process
`parameters for each manufacturing step are provided, as well as the regulatory
`commitment for the operating range.
`
`Bosutinib monohydrate is a white to yellowish tan powder. It is classified as a BCS
`Class 4 compound (low soluble and low permeable material) with pH dependent
`solubility. It is non—hygroscopic. The selected polymorph form
`(m4) ofbosutinib
`monohydrate for development and commercialization is the
`(we)
`
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`

`Cross Discipline Team Leader Review
`
`two when
`The submitted stability data support the proposed retest period of
`packaged in the proposed container system and stored at controlled room temperature.
`
`Drug Product
`Bosulif® (bosutinib) tablets are available in 100 mg and 500 mg dosage strengths. The
`tablets contain bosutnib monohydrate as the active pharmaceutical ingredient
`equivalent to 100 mg and 500 mg of bosutinib anhydrous together with
`microcrystalline cellulose, croscarmellose sodium, poloxamer, povidone,
`magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc,
`and iron oxide yellow (for 100 mg tablet) and iron oxide red (for 500 mg tablet).
`(hm)
`
`Stabilifl and Shelf Life
`The applicant submitted the stability data from three primary batches for the 100 mg
`strength and 500 mg strength tablets up to 24 months at 25°C/60% RH and 30°C/75%
`RH, and up to 6 months at 40°C/75% RH in the primary stability container closure system.
`Those stability data support the proposed 24 months shelf-life for the drug
`product in both strengths packaged in HDPE bottles and stored at controlled room
`temperature. Additionally, the submitted photostability study results on the primary lots
`indicate that the drug product does not require protection fiom light.
`
`The NDA submission did not include any stability data for the proposed commercial
`container closure system which is different from the primary stability container closure
`system (e.g. configuration, fill volume, headspace, MVTR, and amount of desiccant).
`According to ONDQA’s Initial Quality Assessment and Filling Review for this NDA
`dated 21-Dec-2011 in DARRTS, the issue of lacking stability data for the proposed
`commercial container closure system was determined as a review issue. During this
`review cycle, instead of providing any stability data for the proposed commercial
`container closure system afler Agency’s information request for such data, the applicant
`provided the calculations for moisture absorption capacity of desiccant canister and
`total available moisture within the commercial container closure system to justify
`the proposed shelf life in the proposed commercial container closure system. The
`provided justification appears to be reasonable, but it does not completely exclude
`possible impact on quality attributes linked to water content due to the potential
`difference in moisture level control. Although the risk of changing container closure
`system for solid dosage form is relatively small, the provided theoretical
`calculation of moisture exposure (MVTR vs desiccant capacity) is only a supporting
`data for moisture-barrier equivalence, and is not a replacement for stability study
`result from the proposed container closure system. According to ICH Q1A(R2)
`Section lI(B)(4), Stability testing should be conducted on the dosage form packaged
`in the container closure system proposed for marketing. Therefore, it is
`recommended that the Postapproval Stability Commitment be revised to include
`accelerated studies for 6 months along with the long-term studies through the
`
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`Cross Discipline Team Leader Review
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`proposed shelf life for the first three production batches of bosutinib 100 mg and
`500 mg tablets, to monitor the stability trend and to confirm the shelf life, based on
`ICH Q1A(R2) Section II(B)(8) (refer to the Letter of Information Request dated 18-
`Jul-2012). The approvability of the drug product bosutinib 100 mg and 500 mg
`strength tablets packaged in the proposed commercial container closure system is
`pending the applicant’s response to this deficiency.
`
`Release Specifications
`All lots manufactured were successfully processed through to product and met the
`proposed release specification criteria. The manufacture experiences at the proposed
`manufacturing site and proposed manufacturing scale confirm the suitability of the proposed
`manufacturing process for bosutinib tablets (100 mg and 500 mg).
`
`
`
` Facilities review/inspection
`The Office of Compliance issued an overall “acceptable” recommendation dated 10-
`May-2012 for all facilities used for manufacturing and control of the drug substance
`and drug product.
`
` Product Quality Microbiology: The review was conducted by Robert J. Mello, Ph.D.
`His review concludes that the application is recommended for approval from
`microbiology product quality standpoint.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Other notable issues:
`The application cannot be recommended for approval from a chemistry, manufacturing,
`and controls (CMC) standpoint until the following deficiency is satisfactorily resolved:
`
`The post-approval stability commitment in Section P.8.2 is not adequate according to
`ICH Q1A(R2) Section II(B)(8).
`
`The approvability and the granted expiration dating period for the drug product is pending
`on the resolution of the deficiency.
`
` 
`
` The recommendation and conclusion on the approvability for this NDA were made by
`incorporating QBD principle, risk management, and scientific rationale based on the
`stability data from the primary stability study container closure system, provided that if
`the firm agrees to revise the Postapproval Stability Commitment [refer ICH
`Q1A(R2) II(B)(8)] to monitor the stability of marketed drug products in the
`proposed commercial container closure system.
`
`
`
`Note: The deficiency above noted by Dr. Crich was resolved and noted as such in Dr.
`Miksinski’s memo.
`
`4. Nonclinical Pharmacology/Toxicology
`
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`Cross Discipline Team Leader Review
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`The non-clinical pharmacology/toxicology review was conducted by Shwu-Luan Lee, Ph.D.
`(Team Leader, Haleh Saber, Ph.D.). Their review states that there are no
`pharmacology/toxicology issues which preclude approval of bosutinib
`(Bosulif®) for the proposed indication. Dr. Lee and Dr. Saber recommend approval of this
`NDA.
`The text in this section is taken directly from Dr. Lee’s review.
`
`Pharmacologic Class: Kinase inhibitor
`Mechanism of action: inhibitor of Src and Abl family of kinases
`
`Bosutinib (SKI-606) inhibits Bcr-Abl and Src tyrosine kinases. In in vitro and/or in vivo
`systems bosutinib inhibited the cellular activities of several imatinib-resistant Bcr-Abl
`mutants including E255K, G250E, D276G and Y253F mutations. These mutations are
`commonly identified in CML patients who relapsed after or were resistant to imatinib
`treatment. Bosutinib exhibited much less effect against T315I mutation than the wildtype
`Abl.
`
`Orally administered bosutinib was absorbed fairly rapidly (tmax of ~ 1.3-5.5 hr), with
`variable oral bioavailability (23% to 64%) in animal species. Bosutinib was highly
`bound to plasma proteins in all species tested (over 90%): mouse, rat, rabbit, dog, and
`human plasma. Metabolite M5 exhibited a similar protein binding. Following an oral
`dose of [14C]bosutinib in Sprague-Dawley rats, radioactivity was distributed in most
`tissues and organs, except for brain, indicating a limited ability of bosutinib and/or its
`metabolites to cross the blood-brain barrier in rats. Radioactivity was found in the
`placenta, fetus, as well as in the milk of lactating rats. The level of radioactivity in milk
`was up to 8-fold higher than that in maternal plasma, suggesting excretion of bosutinib
`and/or its metabolites into the milk of lactating rats. Radioactivity was present in the
`plasma of suckling pups 24 to 48 hours after lactating rats received a single oral dose of
`radioactive bosutinib. The level of radioactivity in pup plasma at 24 and 48 hr post-dose
`was at least 8-fold higher than that in the maternal plasma. In a separate distribution
`study, tissues rich in melanin, such as uveal tract, showed higher and longer
`radioactivity retention, indicating that the drug and/or its metabolites have affinity for binding
`to melanin. However, phototoxicity assessment was negative in pigmented
`Long Evans rats. After oral administration of [14C]bosutinib to mice, rats and dogs,
`bosutinib was the predominant radiolabeled component in plasma. The major circulating
`metabolites were M5 (11%) in mice, M9 (up to 17%-24%) in rats, and M5 (up to
`20%)/M6 (up to 10%) in dogs. Similarly, bosutinib was the major component in patients’
`plasma. Of note, the prominent circulating metabolites in humans are M2 and M5
`(~19% and 25% of the AUC of parent drug, respectively). The metabolite M2 is a
`human-specific metabolite. In human liver microsomes, bosutinib was predominantly
`metabolized by CYP3A4. Metabolite M2 was mainly metabolized via glucuronation by
`UGT enzymes. The primary route of elimination of bosutinib was via the feces in
`animals. Under the conditions tested, bosutinib did not inhibit or induce a panel of CYP
`enzymes. Based on studies conducted in caco-2 cells, P-glycoprotein transporter (P-gp)
`may be involved in bosutinib transport. There was a concentration dependent inhibition
`of P-gp mediated digoxin (a prototype P-gp substrate) efllux. While no gender effects
`were found in PK parameters in dogs, higher systemic exposures to bosutinib were
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`Cross Discipline Team Leader Review
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`found in female rats after oral administration of bosutinib.
`
`The safety pharmacology studies and general toxicology studies in rats and dogs identified
`GI tract, lymphoid tissues, adrenal, thyroid and mammary glands as the target
`organs/tissues. The major findings are as follows:
`
`
` Gastric-intestinal tract:
`The most prominent effect of bosutinib in rats and dogs was dose-dependent GI
`toxicities. The toxicities were observed following a single or multiple oral administration
`of the drug, and were considered the cause of mortalities. Rats were more susceptible
`to GI toxicities than dogs. GI clinical signs included: liquid and mucoid feces with red
`pigment/blood. GI histopathology findings of mucosal/ goblet cell hyperplasia,
`hemorrhage, erosion and hyperkeratosis were dose-dependent and with a steep dose response
`relationship. Similar GI-related effects were noted in rabbits in the
`embryofetal developmental study.
`
`
` Hematopoietic/lymphoid system:
`The hematology findings were primarily related to bosutinib-induced inflammation and
`bleeding. These findings included increased white counts (except for lymphocyte),
`increased platelet count, slight reduction in red cell mass, and increased fibrinogen.
`
`
` Liver:
`Hepatobiliary findings were reported in rats treated at 70 mg/kg of bosutinib (2-week
`and 4-week studies) but were of low incidence or of low severity. These findings
`included centrilobular hyperplasia. There were no changes in liver enzymes.
`
`
` Cardiovascular system:
`Bosutinib inhibited hERG channel currents at an IC50 value of 0.3 (cid:31)M and may be
`considered a moderate potency blocker. In a single-dose safety pharmacology in
`Beagle dogs, an oral bosutinib dose of 10 mg/kg did not induce cardiovascular toxicity.
`This dose resulted in an exposure in animals that was less than 2-fold the exposure in patients
`at the recommended dose of 500 mg. In a separate safety pharmacology study
`in dogs, transient increases in blood pressure and a secondary reduction in heart rate
`were observed for 2 minutes after IV infusion of bosutinib. QTc prolongation was
`reported in patients treated with bosutinib.
`
`Mutagenicity
`Bosutinib was not mutagenic in bacterial Ames test or clastogenic in a chromosome
`aberration test in human peripheral blood lymphocytes (HPBL). Bosutinib did not increase
`micronucleus formation in mice after oral doses up to 2000 mg/kg. Metabolite M2 was
`negative in two in vitro genotoxicity studies, the Ames test and the chromosome aberration
`assay in human peripheral blood lymphocytes (HPBL).
`
`Reproductive Toxicity
`Reproductive and developmental toxicities of bosutinib were investigated in rats and
`rabbits. Bosutinib was administered orally to pregnant rats during the period of
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`organogenesis at doses of 1, 3 and 10 mg/kg/day. There was no maternal toxicity or
`adverse embryo-fetal developmental effects in rats treated with bosutinib up to 10
`mg/kg/day (AUCs comparable to those reported in patients at the 500 mg/day dose). This
`study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes.
`In a fertility and early embryonic developmental study, decreased implantation and reduced
`number of viable embryos were observed at 30 mg/kg/day of bosutinib; approximately 1.4
`times the human exposure at the clinical dose of 500 mg/day.
`In a study conducted in rabbits, bosutinib was administered orally to pregnant animals
`during the period of organogenesis at doses of 3, 10 and 30 mg/kg/day. At the maternallytoxic
`dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and
`two fetuses had various visceral observations), and an approximate 6% decrease in fetal
`body weight. The exposure at 30 mg/kg/day resulted in exposures (total AUC)
`approximately 4 times those in humans at the 500 mg/day dose of bosutinib.
`In a rat fertility study, drug-treated males were mated with untreated females, or untreated
`males were mated with drug-treated females. The dose of 70 mg/kg/day of bosutinib
`resulted in reduced fertility in males as demonstrated by 16% reduction in the number of
`pregnancies. There were no lesions in the male reproductive organs at this dose. This dose
`of 70 mg/kg/day resulted in exposure (total AUC) in male rats approximately equal to that in
`humans at the 500 mg/day dose of bosutinib. Fertility (number of pregnancies) was not
`affected when female rats were treated with bosutinib; although, decreased implantation
`and embryonic toxicities were evident at the dose of 30 mg/kg/day (see above). There
`were no effects on reproductive organs in general toxicology studies.
`
`Carcinogenicity
`The result of a 2-year carcinogenicity study in rats is under review.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`The Clinical Pharmacology review was conducted by Elimika Pfuma, PharmD, PhD and her
`Team Leader was Bahru Habtemarium, PharmD. The Genomics review was also conducted by
`Elimika Pfuma, PharmD, PhD and her team leader was Rosane Charlab Orbach, PhD. The
`Pharmacometrics reviewer was Justin Earp, PhD, and his team leader was Christine Garnett,
`PharmD.
`
`The text in this section is taken directly from Dr. Pfuma’s review.
`
`During the review cycle, an OCP Briefing was held on June 18, 2012.
`
`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.
`
`Bosutinib is a tyrosine kinase inhibitor (TKI), specifically an inhibitor of Bcr-Abl and the Src-
`family kinases including Src, Lyn, and Hck. Bosutinib is proposed for the treatment of chronic
`phase (CP), accelerated phase (AP) or blast phase (BP) Ph+ chronic myelogenous leukemia
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`(CML) in adult patients with resistance or intolerance to prior therapy. The proposed oral
`dosing regimen is 500 mg once daily taken with food.
`
` A
`
` pivotal phase 1/2 trial and a supportive phase 3 trial were submitted to support the proposed
`indication and dosing regimen. Data from a total of 15 single and multiple dose trials were
`submitted to support the Clinical Pharmacology Section of the NDA. The single dose trials
`were performed in healthy volunteers and consisted of three bioequivalence trials, a dose
`escalation trial, a food effect trial, a mass balance trial, a thorough QT trial,