CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203341Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
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`
`
`Indication:
`
`
`
`NDA
`Submission Date:
`Brand Name:
`Generic Name:
`Formulation:
`OCP and Genomics Reviewer:
`OCP Team Leader:
`Genomics Team Leader
`Pharmacometrics Reviewer:
`Pharmacometrics Team Leader:
`OCP Division:
`
`ORM Division:
`Applicant:
`Submission Type; Code:
`Dosing regimen:
`
`
`
`203341Clinical Pharmacology Review
`203-341
`17 November, 2011
`BosulifTM
`Bosutinib
`100 and 500 mg film coated tablets
`Elimika Pfuma, PharmD, PhD
`Bahru Habtemarium, PharmD
`Rosane Charlab Orbach, PhD
`Justin Earp, PhD
`Christine Garnett, PharmD
`Division of Clinical Pharmacology V
`Division of Hematology Products
`Pfizer/ Wyeth
`0000/1
`A single oral daily dose of 500 mg once daily with
`food
`The treatment of chronic, accelerated or blast phase
`Ph + chronic myelogenous leukemia (CML) in adult
`patients with resistance or intolerance to prior therapy
`
`
`
`
`The OCP Briefing was held on 18th June, 2012.
`
`Table of Contents
`
`Executive Summary ....................................................................................................5
`1.1
`Recommendations ...........................................................................................5
`1.2
`Phase IV Requirement.....................................................................................5
`1.3
`Summary of Clinical Pharmacology Findings ................................................6
`Question Based Review ..............................................................................................8
`2.1
`General Attributes ...........................................................................................8
`2.2
`General Clinical Pharmacology ......................................................................9
`2.3
`Intrinsic Factors.............................................................................................25
`
`
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` 1
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`2
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`3
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`Extrinsic Factors............................................................................................31
`2.4
`General Biopharmaceutics ............................................................................36
`2.5
`Analytical Section .........................................................................................39
`2.6
`Appendices................................................................................................................41
`3.1
`Pharmacometrics Review..............................................................................41
`
`
`List of Tables
`
`Table 1. Summary of the Pivotal and the Supportive Efficacy Trials ......................................9
`Table 2. Overview of Clinical Pharmacology Related Trials Submitted in the NDA............10
`Table 3. Pharmacokinetic Parameters of Single Dose Bosutinib in Healthy Volunteers.......19
`Table 4. Pharmacokinetic Parameters of Single Dose Bosutinib in Cancer Patients .............19
`Table 5. Pharmacokinetic Parameters of Multiple Dose Bosutinib in Cancer Patients..........20
`Table 6. Statistical Analysis of Dose-Normalized Pharmacokinetic Parameters Estimated
`for Single Doses of Bosutinib Ranging from 200 – 800 mg Taken with a High Fat
`Meal in Healthy Volunteers in Trial 3160A1-103-EU .............................................24
`Table 7. Statistical Analysis of Dose-Normalized Pharmacokinetic Parameters Estimated
`for Single Doses of Bosutinib Ranging from 100 – 600 mg Taken with a High Fat
`Meal and Ketoconazole in Healthy Volunteers in Trial 3160A4-1114-EU..............24
`Table 8. Summary of Bosutinib Pharmacokinetic Parameters Following a Single Oral Dose
`of Bosutinib 200 mg in Child-Pugh Class A, B and C and in Healthy Volunteers...28
`Table 9. Response in Patients With and Without Bcr-Abl Mutations at Baseline .................29
`Table 10. Summary of Bosutinib Trials Evaluating the Effect of a Strong CYP3A4 Inhibitor
`and a Strong CYP3A4 Inducer..................................................................................32
`Table 11. Summary of Bosutinib Pharmacokinetic Parameters Following a Single 100 mg
`Dose of Bosutinib Alone or in Combination with Ketoconazole in Healthy
`Volunteers in Trial 3160A4-104-US.........................................................................33
`Table 12. Summary of Bosutinib Pharmacokinetic Parameters Following Single Ascending
`Oral Doses of Bosutinib in Combination with Ketoconazole in Healthy Volunteers
`in Trial 3160A4-1114-EU. ........................................................................................34
`Table 13. Summary of Mean PK Parameters of Bosutinib after a Single Oral Dose of
`Bosutinib 500 mg Alone and in Combination With Multiple Oral Doses of
`Ketoconazole 400 mg in Healthy Volunteers Under Fed Conditions in Trial
`3160A4-105-US. .......................................................................................................34
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`Table 14. Simcyp Simulations of the Effect of CYP3A inhibitors on Bosutinib PK... ............34
`Table 15. Summary of Bosutinib Pharmacokinetic Parameters Following a Single Oral Dose
`of Bosutinib Either Alone or in Combination with Rifampin in Healthy Volunteers
`in Trial 3160A4-1106-US.... .....................................................................................35
`Table 16. Solubility of Bosutinib in Different Aqueous Media at 37°C Across the pH Range
`of 1 - 8 ..... .................................................................................................................36
`Table 17. Permeability of Bosutinib in Caco-2 Monolayers Incubated for 2 Hours at 37°C...36
`Table 18. Composition of Bosutinib 100 and 500 mg Film Coated Tablets.............................37
`Table 19. Bosutinib Mean Pharmacokinetic Parameters Following a Single Oral Dose of
`400 mg Bosutinib Administered Fasting or with a High Fat Meal in Healthy
`Volunteers. ................................................................................................................38
`Table 20. Summary of the LC/MS/MS Analytical Methods for Bosutinib and its Major
`Metabolites................................................................................................................40
`
`
`List of Figures
`
`Figure 1. Structural Formula of Bosutinib Monohydrate ...........................................................8
`Figure 2. Plot Showing that Probability of Major Cytogenetic Response at 24 Weeks Does
`Not Increase With Increasing Bosutinib Exposure ...................................................12
`Figure 3. Exposure-Response Plot for Grade 3+ Rash ...........................................................13
`Figure 4. Plot Showing That an Exposure-Response Relationship for Grade 3+ Diarrhea was
`Observed....................................................................................................................14
`Figure 5. A Plot Showing the Sponsor’s Exposure-Response Analysis for Diarrhea that
`Suggests an Exposure-Response Relationship Exists .............................................14
`Figure 6. Plots Showing no Exposure-Response Relationships Were Observed for Grade 3+
`Thrombocytopenia (Left Panel) or Neutropenia (Right Panel) ................................15
` Figure 7. Plots Showing no Exposure-Response Relationships Were Observed for Grade 3+
`Nausea (Left Panel) or Vomiting (Right Panel) ......................................................15
`Figure 8. Plot Showing No Exposure-Response Relationships Were Observed for Grade 3+
`Increases in Alanine Aminotransferases (ALT, Left Panel) or Aspartate
`Aminotransferases (AST, Right Panel).....................................................................16
`Figure 9. The Proposed Metabolic Pathways for Bosutinib Based on Metabolites Observed
`in Human Plasma, Urine and Feces in Trial # 3160A4-1112-US.............................22
`Figure 10. Bosutinib Individual and Mean AUC Values versus Dose after Administration of
`Single Ascending Oral Doses of Bosutinib to Healthy Subjects Under Fed
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`Reference ID: 3165861
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`Conditions (Trial # 3160A1-103-EU).......................................................................23
`Figure 11. Plot Showing Bosutinib Clearance is Reduced Approximately 30% in CML
`Patients with Moderate Renal Impairment ..............................................................25
`Figure 12. Plot Showing Bosutinib Clearance Is Correlated with Weight. ..............................26
`Figure 13. Plot Showing that Race or Gender Do Not Affect Bosutinib Clearance ...............26
`Figure 14. Plot Showing Age Does Not Affect Bosutinib CL..................................................27
`Figure 15. Mean Concentration versus Time Profile of Bosutinib in Plasma Following a
`Single 100 mg Oral Dose of Bosutinib Alone or in Combination with
`Ketoconazole (Keto) in Healthy Volunteers in Trial 3160A4-104-US ....................33
`Figure 16. Bosutinib Mean (±SD) Plasma Concentration-Time Profiles Following a Single
`Oral 400 mg Dose of Bosutinib Administered Fasting and with a High Fat Meal
`in Healthy Volunteers................................................................................................38
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`Reference ID: 3165861
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`1
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`Executive Summary
`
`
`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
`(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. The pivotal trial evaluated the efficacy of bosutinib 500 mg in 2nd
`line CP CML (N=288), 3rd line CP CML (N=118) and in AP and BP Ph+ CML (N=164). The
`primary efficacy endpoint was major cytogenetic response (MCyR) rate at Week 24 in imatinib-
`resistant 2nd line CP CML patients. The MCyR rate was 35.5% (90% CI: 29.7, 41.7) with a 1-
`sided p<0.001. The supportive trial (3160A4-3000-WW) was a phase 3 trial comparing the
`efficacy and safety of bosutinib to that of imatinib in patients with newly diagnosed (1st line) CP
`CML. In this trial, bosutinib failed to show superiority to imatinib with an adjusted odds ratio
`estimate of complete cytogenetic response (CCyR) at 1 year of 1.10 (95% CI: 0.74, 1.63). Data
`from a total of 15 single and multiple dose trials were submitted to support the Clinical
`Pharmacology Section of the NDA.
`
`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.
`
`1.1
`
`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.
`
`1.2 Post Marketing 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.
`
`Recommendations
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`Reference ID: 3165861
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`Summary of Clinical Pharmacology Findings
`
`
`1.3
`
`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
`(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, a hepatic impairment trial and
`four drug interaction trials. Multiple dose PK data were available from two dose escalation trials
`in patients with solid tumors and sparse PK data were also available from the pivotal phase 2
`trial.
`
`Bosutinib exhibits approximately linear PK in the dose range of 200 – 800 mg. The median Tmax
`in cancer patients ranged from 3 to 6 hours. The mean elimination half-life of bosutinib after a
`single dose in patients ranged from 19 to 30 hours. The mean accumulation ratio observed
`ranged from 2 – 3 at steady-state. In a food-effect trial, a high-fat meal caused a 2-fold increase
`in exposure. Food also increased tolerability to bosutinib in a dose escalation trial, as such,
`bosutinib was co-administered with food in patient trials. Based on an oral mass balance trial,
`radioactivity recoveries in feces and urine were 91% and 3%, respectively. The absolute
`bioavailability of bosutinib has not been determined.
`
`Bosutinib is primarily metabolized by CYP3A4. Concomitant ketoconazole (strong CYP3A4
`inhibitor) increased bosutinib Cmax 5-fold and AUC 9-fold. Concomitant rifampin (strong
`CYP3A4 inducer) decreased the Cmax and AUC of bosutinib by 86% and 94%, respectively.
`Therefore, the use of strong and moderate CYP3A4 inhibitors and inducers should be avoided.
`Simulation with Simcyp predicted that moderate CYP3A4 inhibitors could increase exposure to
`bosutinib 2 - 5 fold. A PMR will be issued in order to evaluate, in humans, the influence of
`moderate CYP3A4 inhibitors on the exposure to bosutinib so as to identify an appropriate dose
`for concomitant administration with such drugs. In vitro, bosutinib is a substrate and an inhibitor
`of P-gp. A 2-fold increase in exposures was observed in patients with hepatic impairment. A
`dose adjustment to 200 mg is recommended in patients with mild, moderate and severe hepatic
`impairment.
`
`No exposure-response relationships for effectiveness or safety were observed. No exposure-
`response relationship was observed for the primary endpoint of MCYR at 24 weeks in CML
`patients randomized to receive 500 mg bosutinib. No clinically meaningful exposure-response
`relationships were identified for grade 3 or higher rash, diarrhea, neutropenia, thrombocytopenia,
`nausea, vomiting and increases in liver transaminase levels. In a thorough QT trial bosutinib did
`not cause significant changes in placebo adjusted, baseline-corrected QTc.
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`Reference ID: 3165861
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`Signatures:
`
` Team Leader: Bahru Habtemarium, PharmD
`Reviewer: Elimika Pfuma, PharmD, PhD
`Division of Clinical Pharmacology 5
`Division of Clinical Pharmacology 5
` Team Leader: Rosane Charlab Orbach, PhD
`Reviewer: Elimika Pfuma, PharmD, PhD
`Genomics Group
`Genomics Group
` Team Leader: Christine Garnett, PharmD
`Reviewer: Justin Earp, PhD
`Division of Pharmacometrics
`Division of Pharmacometrics
`Cc: DDOP: RPM – D Hanner; MTL – V Kwitkowski; MO – K McGinn
`Reviewers - E Pfuma (DCP5 and GG), J Earp (PM)
`
`DCP-
`5:
`Team Leaders – B Habtemarium (DCP5), R Charlab (GG), C Garnett (PM)
`DCP5 DDD - B Booth DD - A Rahman
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`Reference ID: 3165861
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`2
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`QUESTION BASED REVIEW
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`2.1
`
`GENERAL ATTRIBUTES
`
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of the
`drug substance and the formulation of the drug product as they relate to the clinical
`pharmacology and biopharmaceutics review?
`
`Bosutinib is planned to be available as 100 and 500 mg debossed film-coated tablets for oral
`administration.
`
`Physical—chemical properties
`
`Structural formula:
`
`Figure 1: Structural Formula of Bosutinib Monohydrate
`
`
`
`Established names: Bosutinib monohydrate
`Molecular Weight: 548.46 (monohydrate)
`Molecular Formula: C26H29C12N503°H20 (monohydrate)
`Partition coefficient (log P): 3.1
`Dissociation Constant (pKa): 7.9 (pKal)
`Chemical Name: 3-Quinolinecarbonitlile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6—
`methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-, hydrate
`
`Melting Point Range: 100°C to 160°C
`Solubility: Bosutinib monohydrate has pH dependent solubility across the physiological pH
`range. Bosutinib is soluble at or below pH 5 and the solubility reduces above pH 5.
`
`2.1.2 What are the proposed mechanisms of action and therapeutic indications?
`
`Bosutinib is proposed for the treatment of chronic phase (CP), accelerated phase (AP) or blast
`phase (BP) Ph+ chronic myelogenous leukemia (CML) in adult patients with resistance or
`intolerance to prior therapy. CIVIL is causally linked to a cytogenetic abnormality resulting from
`a reciprocal translocation between the long arms of chromosomes 9 and 22. This results in the
`production of the Bcr-Abl oncoprotein, which exhibits constitutive tyrosine kinase activity.
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`Reference ID: 31 65861
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`Bosutinib is a tyrosine kinase inhibitor, specifically an inhibitor of Bcr-Abl and the Src-family
`kinases including Src, Lyn and Hck. In CML, bosutinib is believed to exert pharmacological
`action through the inhibition of Bcr-Abl kinase.
`
`2.1.3 What are the proposed dosage(s) and route(s) of administration?
`
`The applicant proposes an oral dosing regimen of 500 mg once daily to be taken with food.
`
`2.2 GENERAL CLINICAL PHARMACOLOGY
`
`2.2.1 What are the design features of the clinical pharmacology and clinical trials used to
`support dosing or claims?
`
`To support the approval of bosutinib, the sponsor submitted two key clinical trials; a pivotal trial
`phase 1/2 trial and a supportive phase 3 trial (Table 1). The pivotal trial was a two part phase 1/2
`trial. Part 1 was performed to identify the maximum tolerated dose (MTD) in patients with Ph+
`CML (N=18) and evaluated bosutinib at the oral daily doses of 400, 500 and 600 mg. In part 1 of
`the trial, 500 mg once daily was identified as the MTD. Part 2 was performed to evaluate the
`efficacy of bosutinib 500 mg once daily in 2nd line CP CML (N=288), 3rd line CP CML (N=118)
`and in AP and BP Ph+ CML (N=164). The primary efficacy endpoint was major cytogenetic
`response (MCyR) rate at Week 24 in imatinib-resistant 2nd line CP CML patients. The
`supportive trial (3160A4-3000-WW) was a phase 3 trial comparing the efficacy and safety of
`bosutinib (N=248) to that of imatinib (N=251) in patients with newly diagnosed (1st line) CP
`CML.
`
`Table 1: Summary of the Pivotal and the Supportive Efficacy Trials
`Trial Number
`Trial Description
`Treatment Groups
`3160A4-200-WW
`Part 1: Bosutinib
`Phase 1/2 open-label 2- part
`(pivotal)
`400, 500 and 600
`study in patients with Ph+
`mg
`leukemia
`
`
`Part 2: Bosutinib
`Part 1: dose escalation in
`CP CML (N=18)
`500 mg
`
`Part 2: efficacy study at the
`selected Phase 2 dose
`- CP CML 2nd line (N=288)
`- CP CML 3rd line (N=118)
`- AP and BP Ph+ CML
`(N=164)
`
`Trial Endpoints
`Part 1: MTD
`
`Part 2:
`
`CP CML 2nd/3rd line
`primary endpoint: Major
`cytogenetic response
`(MCyR) at 24 weeks
`
`AP and BP Ph+ CML
`primary endpoint:
`Overall hematologic
`response (OHR) by 48
`weeks.
`Rate of complete
`cytogenetic response
`(CCyR) at 1 year
`
`3160A4-3000-
`WW
`(supportive)
`
`Randomized, open-label,
`phase 3 study to compare
`the efficacy and safety of
`bosutinib to that of imatinib
`in subjects with newly
`diagnosed CP CML
`
`Bosutinib 500 mg
`QD (N=248)
`Imatinib 400 mg QD
`(N=251)
`
`
`Pharmacokinetic data are available from 15 trials conducted in healthy volunteers (HV) and
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`Reference ID: 3165861
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`patients including sparse PK in the pivotal trial.
`
`Table 2: Overview of Clinical Pharmacology Related Trials Submitted in the NDA
`Trial Number
`Trial Description
`Treatment Regimen
`(Population)
`
`3160A4-1109-US
`Single 500 mg dose of each formulation
`(Healthy)
`
`Relative BA of 3 new formulation
`tablets and a reference capsule and
`an oral solution given under fed
`conditions (N=40)
`BE comparing the proposed
`commercial test formulation to the
`phase 3 reference formulation given
`under fasting conditions (N=30)
`BE comparing the 500 mg proposed
`commercial test formulation to the
`Phase 3 reference formulation (N=31)
`Single dose PK and preliminary food
`effect study (N=41)
`Food effect study (N=24)
`
`Dose-escalation study in patients with
`advanced malignant solid tumors with
`expansion cohorts (N=151)
`Dose-escalation study in Japanese
`patients with advanced malignant
`solid tumors (N=25)
`Mass balance study (N=6)
`
`Thorough QT study (N=60)
`
`3160A4-1115-US
`(Healthy)
`
`3160A4-1120-US
`(Healthy)
`
`3160A1-103-EU
`(Healthy)
`3160A4-1110-US
`(Healthy)
`3160A1-100-US
`(Patients)
`
`3160A1-102-JA
`(Patients)
`
`3160A4-1112-
`US(Healthy)
`3160A4-105-US
`(Healthy)
`
`Single dose of each:
`100 mg x 3 Commercial test
`100 mg x 3 Phase 3 reference
`
`Single dose of each:
`500 mg Commercial test
`100 mg x 5 Phase 3 reference
`Bosutinib 200 - 800 mg
`
`Single doses of 400 mg (4 x 100 mg)
`under fed or fasting conditions
`Part 1 (dose-escalation): 50 to 600 mg
`daily (N=51)
`Part 2 (expansion): 400 mg QD (N=100)
`Daily doses taken with food ranging from
`100 - 400 mg
`
`A single 500 mg oral dose of bosutinib
`containing 0.01 μCi [14C] bosutinib
`Part A: A single dose of bosutinib 500 mg,
`placebo or moxifloxacin 400 mg in a fed
`state.
`Part B: A single dose of bosutinib 500 mg
`or placebo with both given concomitantly
`with ketoconazole 400 mg in a fed state.
`Single 200 mg dose
`
`Single dose of bosutinib 100 mg
`administered either alone or with
`ketoconazole (400 mg dose for 5 days)
`under fasting conditions
`Single dose of bosutinib 100 - 600 mg co-
`administered with multiple doses of
`ketoconazole (400 mg tablets) under fed
`conditions
`A single dose of bosutinib 500 mg
`administered either alone or with rifampin
`(600 mg for 8 days).
`A single dose of 400 mg bosutinib alone
`or co-administered with multiple doses of
`60 mg lansoprazole under fasting
`conditions
`
`3160A4-1111-EU
`(Healthy)
`
`3160A4-104-US
`(Healthy)
`
`Hepatic impairment study (N=27).
`The study enrolled six subjects in
`each group of Child Pugh A, B and C
`and 9 matched healthy volunteers in
`the control group
`Ketoconazole DDI (CYP3A4 Inhibitor)
`(N=24)
`
`3160A4-1114-EU
`(Healthy)
`
`Ketoconazole DDI (CYP3A4
`Inhibition) (N=48)
`
`3160A4-1106-US
`(Healthy)
`
`Rifampin DDI (CYP3A4 Induction)
`(N=24)
`
`3160A4-1108-US
`(Healthy)
`
`Lansoprazole DDI (pH altering
`proton-pump inhibitor) (N=24)
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`Reference ID: 3165861
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`2.2.2 What is the basis for selecting the response endpoints (i.e., clinical or surrogate
`endpoints) or biomarkers (collectively called pharmacodynamics (PD)) and how are they
`measured in clinical pharmacology and clinical trials?
`
`The primary endpoint for the pivotal trial was MCyR at 24 weeks in the imatinib-resistant
`second-line CP CML population. MCyR was the primary endpoint used in the pivotal trials for
`both currently approved tyrosine kinase inhibitors (dasatinib and nilotinib) in CP CML after
`prior imatinib failure. In the submitted pivotal trial, cytogenetic status was determined based on
`the ratio of the number of Ph+ cells to the number of cells analyzed. MCyR at week 24
`considered those with a partial and complete response at that specific time point.
`
`MCyR at 24 weeks was also used as the efficacy endpoint in third line CP CML. Overall
`hematologic response (OHR) was used as the efficacy end point in AP and BP Ph+ CML. OHR
`included complete hematologic responses (CHR), no evidence of leukemia (NEL), minor
`hematologic response (MiHR) and return to chronic phase (RCP). Hematologic responses were
`based on peripheral blood assessments and clinical assessments of extramedullary disease.
`
`In the pivotal trial, the primary efficacy endpoint was MCyR rate at Week 24 in imatinib-
`resistant second-line CP CML subjects. The MCyR rate was 35.5% (90% CI: 29.7, 41.7) with a
`1-sided p<0.001. For third-line CP CML patients, the MCyR at Week 24 was 26.9%. The
`overall hematologic response rate at 48 weeks was 55.1% in AP CML patients and 28.3% in BP
`CML patients. The supportive trial (3160A4-3000-WW) was a phase 3 trial in the 1st line setting
`in which bosutinib failed to show superiority to imatinib with an adjusted odds ratio estimate of
`complete cytogenetic response (CCyR) at 1 year of 1.10 (95% CI: 0.74, 1.63).
`
`2.2.3 Are the active moieties in the plasma (or other biological fluid) appropriately
`identified and measured to assess pharmacokinetic parameters and exposure response
`relationships?
`
`Yes. Plasma samples from clinical trials were assessed for the parent drug (bosutinib) which is
`the active moiety. Several of the clinical trials assessed exposures to the major metabolites, M2
`and M5, which are inactive (please refer to the pharmacology review for more details). M2 and
`M5 were the major metabolites found in plasma in the mass balance trial and pharmacokinetic
`trials such as 3160A4-1106-US. The mean AUC ratio of metabolites to parent drug was 0.196
`for M2 and 0.251 for M5.
`
`Exposure Response
`
`2.2.4 What are the characteristics of the exposure-response relationships (dose-response,
`concentration-response) for efficacy?
`
`No exposure-response relationship was observed for the primary endpoint of major cytogenetic
`response (MCYR) at 24 weeks (Figure 2) in CML patients randomized to receive 500 mg
`bosutinib. The efficacy analysis for the pivotal trial # 3160A4-200-WW used patients that were
`imatinib resistant or imatinib intolerant and had evaluable PK data (266 subjects). The sponsor
`conducted a logistic regression analysis of the data and their final logistic model indicates there
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`is no increase in the probability of response with increasing exposure. Details of the logistic
`regression analysis and exposure metric calculation are discussed starting on page 49 in the
`pharmacometrics review (Appendix 1).
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`Figure 2: Plot Showing that Probability of Major Cytogenetic Response at 24 Weeks Does Not Increase
`With Increasing Bosutinib Exposure
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`Symbols represent the calculated probability for each exposure bin. The red line is the
`sponsor’s model prediction
` (Source: Sponsor’s Study Report PMAR-217, Figure 33)
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`2.2.5 What are the characteristics of the exposure-response relationships (dose-response,
`concentration-response) for safety?
`
`An exposure-response relationship was observed for Grade 3+ rash (Figure 3). Logistic
`regression was applied to model the probability of having a Grade 3 or higher adverse event (e.g.
`rash) versus bosutinib exposure (AUC) using data from both trials 200 and 3000. Details of
`these clinical trials are described further on page 46 in the pharmacometrics review (Appendix
`1).
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`Figure 3: Exposure-Response Plot for Grade 3+ Rash
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`Text on the plot describes the logistic model equation and p-value for the coefficient on
`bosutinib exposure. Blue symbols are the probability of having grade 3+ rash by
`exposure bins. Ten exposure bins were assigned, each containing data from 75
`individuals. The solid line and green shaded area indicate the logistic model prediction
`and 90% confidence interval of the model prediction. Vertical bars denote the range of
`bosutinib AUC values in each exposure bin
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`Grade 3+ diarrhea events did not increase with increasing bosutinib exposures (Figure 4).
`Whereas, the sponsor’s analysis suggests there is an exposure-response relationship for Grade 1+
`diarrhea events (Figure 5). This may potentially be explained by the lower number of patients
`with Grade 3+ events (n=68) compared with the Grade 1+ events (n=567) creating more
`uncertainty in the analysis.
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`The primary differences between the reviewers and sponsor’s analyses were:
` The reviewer’s analysis evaluated Grade 3 events or higher
` The reviewer’s analysis calculated the individual bosutinib AUC values based on the time-
`averaged dose prior to the occurrence of the adverse event.
`AUCi = Dosei/CLi
`where the subscript i refers to the individual, Dose refers to the time-average dose prior to
`the adverse event and CL refers to bosutinib clearance.
`The sponsor’s analysis used the mode dose for the individual regardless of when the adverse
`event occurred.
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`Figure 4: Plot Showing That an Exposure-Response Relationship for Grade 3+ Diarrhea Was Observed
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`Blue symbols are the probability of having grade 3+ diarrhea by exposure bins. Ten
`exposure bins were assigned, each containing data from 75 individuals. Vertical bars
`denote the range of bosutinib AUC values in each exposure bin.
`
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`Figure 5: A Plot Showing the Sponsor’s Exposure-Response Analysis for Diarrhea that Suggests an
`Exposure-Response Relationship Exists
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`Symbols are calculated probability of Diarrhea grade 1+ for each AUC bin for pooled
`data from Studies 200 and 3000. Solid lines are predictions of the best model fittings.
`(Source: Sponsor’s Study Report PMAR-217, Figure 5)
`
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`No exposure-response was observed for grade 3+ thrombocytopenia (Figure 6), neutropenia
`(Figure 6), nausea (Figure 7), vomiting (Figure 7), increases in aspartate aminotransferases
`(Figure 8) or increases in alanine aminotransferases (Figure 8). These results are consistent
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`with the sponsor’s results for Grade 1+ events.
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`Figure 6: Plots Showing No Exposure-Response Relationships Were Observed for Grade 3+
`Thrombocytopenia (Left Panel) or Neutropenia (Right Panel)
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`Thrombocytopenia
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`Neutropenia
`
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` Blue symbols are the probability of having grade 3+ adverse event by exposure bins. Ten
` exposure bins were assigned, each containing data from 75 individuals. Vertical bars
` denote the range of bosutinib AUC values in each exposure bin.
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`
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`Figure 7: Plots Showing No Exposure-Response Relationships Were Observed for Grade 3+ Nausea
`(Left Panel) or Vomiting (Right Panel)
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`Nausea
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`Vomiting
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`
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`Blue symbols are the probability of having Grade 3+ adverse events by exposure bins.
`Ten exposure bins were assigned, each containing data from 75 individuals. Vertical
`bars denote the range of bosutinib AUC values in each exposure bin.
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`Figure 8: Plot Showing No Exposure-Response Relationships Were Observed for Grade 3+ Increases in
`Alanine Aminotransferases (ALT, Left Panel) or Aspartate Aminotransferases (AST, Right Panel)
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`
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`ALT Increased
`
`AST Increased
`
` Blue symbols are the probability of having grade 3+ adverse event by exposure bins. Ten
` exposure bins were assigned, each containing data from 75 individuals. Vertical bars
` denote the range of bosutinib AUC values in each exposure bin.
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`2.2.6 Does this drug prolong the QT or QTc interval?
`
`Bosutinib does not appear to prolong the QTc interval at clinically relevant exposures. The
`QT/IRT review concluded that in a study with a demonstrated abil