CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202570Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY
`GENOMICS GROUP REVIEW
`
`
`202570
`March 30, 2011
`Pfizer, Inc
`Crizotinib
`ALK-positive advanced NSCLC
`Rosane Charlab Orbach, Ph.D.
`Issam Zineh, Pharm.D., M.P.H.
`
`NDA/BLA Number
`Submission Date
`Applicant Name
`Generic Name
`Proposed Indication
`Primary Reviewer
`Secondary Reviewer
`
`
`
`Background
`
` 1
`
`
`The EML4-ALK fusion gene has been identified as an oncogenic driver in a small subset of non-
`small cell lung cancer (NSCLC). Crizotinib is an oral, ATP-competitive small molecule receptor
`tyrosine kinase (RTK) inhibitor of ALK (including ALK oncogenic fusion variants) and of the c-
`Met/Hepatocyte growth factor receptor (c-Met/HGFR). Pre-clinical studies suggest activity
`against other targets such as RON. As part of it’s development program, the sponsor used an
`enrichment strategy in early phase clinical studies leading up to a restricted entry (ALK+) phase
`2 study to support accelerated approval. The key purpose of this memo is to assess whether data
`support targeted use of crizotinib solely in ALK+ patients and outline outstanding issues from a
`pharmacogenomics perspective.
`
` 2
`
`
`
`Submission Contents Related to Genomics
`
`
`In addition to a phase 1 study of all-comers (A8081001) that initially identified a small subset of
`NSCLC patients with ALK+ to have achieved stable disease, the sponsor conducted an ALK+
`restricted-entry expansion cohort and a single-arm trial in ALK+ patients (A8081005). Data
`from these trials were submitted in the NDA.
`
` 3
`
`
`
`Key Issues and Summary of Findings
`
`
`3.1 Overview of Patient Selection Issue
`
`Although initially developed against c-Met, crizotinib showed pre-clinical and clinical activity
`against ALK. Due to ALK emergence as a potentially relevant oncogenic target at the time,
`crizotinb development was shifted to target ALK+ NSCLC. The test used in the registration trial
`to select ALK+ patients is a FISH with break-apart probes, which identifies ALK rearrangement
`events. The FISH assay cannot distinguish between the different fusion partners or rearranged
`variants of ALK. There are limited data in ALK- NSCLC patients in this NDA.
`
`3.2 Outstanding Issues
`
`3.2.1 Crizotinib Effect in ALK- patients
`Preliminary data on 23 ALK- patients were submitted to FDA on June 10th, 2011. Some
`patients who tested ALK- by the Vysis ALK Break Apart FISH assay tested ALK+ by other
`
`
`
`Reference ID: 3006911
`
`1
`
`

`

`diagnostic tests. Seven of 19 ALK- patients with response data experienced either an
`investigator response or a single assessment of partial response. This 35% response rate, if
`confirmed, suggests crizotinib may be effective in patients without diagnostically-defined ALK+
`status. It is not clear if responders are false negatives (e.g., due to an inappropriate assay cut-off)
`or if crizotinib is inhibiting other oncogenic targets relevant to ALK negative NSCLC (see
`clinical review for details).
`
`3.2.2 Resistance
`As with other TKI inhibitors, resistance to crizotinib due to secondary mutations has been
`described (PMID: 21791641; 21502504). Tumor sample acquisition at progression is planned
`(A8081005). These, perhaps, can be used to identify molecular resistance mechanisms. Key
`review questions regarding acquired resistance as a determinant of overall crizotinib efficacy will
`be addressed contingent on the additional data obtained from two phase 3 trials intended to
`support crizotinib’s full approval (i.e., A8081007 and A8081014) in which OS and PFS will be
`key endpoints.
`
`3.2.3 Safety
`A potential for drug-induced liver injury was noted. TKI-induced liver injury has been observed
`to have a genetic component (PMID: 21245432). From the current submission, it is unknown
`whether germline DNA was collected and is available for patients that experienced crizotinib-
`associated ALT elevations. Germline DNA collection from all future crizotinib studies for safety
`assessment will be requested through IND.
`
`
`
`Summary and Conclusions
`
` 4
`
`
`Crizotinib exhibited significant activity in the population studied (see clinical review for details).
`This activity will be confirmed with meaningful clinical endpoints in two efficacy studies as part
`of crizotinib’s full registration program. Outstanding issues include whether (1) crizotinib is also
`effective in ALK- patients, (2) resistance mechanisms will limit crizotinib efficacy in the
`definitive efficacy trials, and (3) genetic determinants of crizotinib-associated liver dysfunction
`can be identified in order to enhance risk/benefit balance.
`
`
`
`Recommendations
`
` 5
`
`
`The data support accelerated approval of crizotinib for ALK+ NSCLC from the Genomics
`perspective. A comment to the IND regarding DNA collection for safety pharmacogenetics and
`a post-marketing commitment to generate additional data in the ALK- patients are warranted.
`
`5.1
`
`Given the potential activity of crizotinib in the ALK- population based on the sponsor’s
`preliminary data, a definitive study of crizotinib efficacy in this population is warranted. PMC to
`test crizotinib in ALK- NSCLC has been discussed with the team. No further recommendations
`from the Genomics Group for PMC/PMRs.
`
`5.2
`
`Post-marketing studies
`
`Label Recommendations
`
`
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`Reference ID: 3006911
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`

`
`None.
`
`
`___________________________________
`Rosane Charlab Orbach, Ph.D.
`Reviewer, Genomics Group, OCP
`
`
`
`___________________________________
`Issam Zineh, Pharm.D., M.P.H.
`Associate Director, Genomics Group, OCP
`
`
`
`Reference ID: 3006911
`
`3
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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/
`----------------------------------------------------
`
`ROSANE CHARLAB ORBACH
`08/26/2011
`
`ISSAM ZINEH
`08/26/2011
`Concu
`
`Reference ID: 3006911
`
`

`

`
`
`NDA
`Submission Date
`Brand Name
`Generic Name
`Dosage Form / Strength
`Related IND
`Applicant
`OCP Reviewer
`Pharmacometrics Reviewer
`OCP Team Leader
`
`Pharmacometrics Team Leader
`OCP Division
`ORM Division
`Submission Type; Code
`Dosing Regimen
`Indication
`
`
`
`
`Clinical Pharmacology Review
`202570
`March 30, 2011
`Xalkori®
`Crizotinib; PF-02341066
`Oral Capsules/ 200 mg, 250 mg
`73544
`Pfizer Inc.
`Pengfei Song, Ph.D.
`Anshu Marathe, Ph.D.
`Qi Liu, Ph.D.
`Christine Garnett, Pharm.D.
`Division of Clinical Pharmacology 5
`Division of Drug Oncology Products
`Original NDA; 505 (b)(1); New Molecular Entity
`250 mg Orally Twice Daily (BID)
`Treatment of Anaplastic Lymphoma Kinase (ALK)-
`Positive Advanced Non-Small Cell Lung Cancer (NSCLC)
`
`
`
`Table of contents
`1 Executive Summary.............................................................................................................6
`1.1
`Recommendations....................................................................................................7
`1.2
`Post-Marketing Requirements (PMRs) and Commitments (PMCs)........................7
`1.3
`Clinical Pharmacology Summary ............................................................................8
`2 Question Based Review.....................................................................................................10
`2.1
`General Attributes..................................................................................................10
`2.2
`General Clinical Pharmacology .............................................................................11
`2.3
`Intrinsic Factors .....................................................................................................31
`2.4
`Extrinsic Factors ....................................................................................................35
`2.5
`General Biopharmaceutics.....................................................................................44
`2.6
`Analytical Section..................................................................................................49
`3 Detailed Labeling Recommendations................................................................................53
`4 Pharmacometric Review....................................................................................................60
`
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`Reference ID: 2998079
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`NDA 202570 Clinical Pharmacology Review - Crizotinib
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`List of Tables
`Table 1. PH-dependent aqueous solubility of crizotinib...............................................................
` 10
`12
`Table 2. Crizotinib studies for pharmacokinetic analysis.............................................................
`
`Table 3. Summary of Crizotinib PK parameters in studies with a single 250 mg oral dose of
`19
`crizotinib....................................................................................................................
`
`Table 4. Summary of PF-06260182 PK parameters in studies following a single 250 mg oral
`19
`dose of crizotinib .......................................................................................................
`
`Table 5. Summary of crizotinib pharmacokinetic parameters in trial 1001 with multiple 250 mg
`20
`oral doses of crizotinib in patients with advanced solid tumors................................
`
`Table 6. Summary of crizotinib lactam (PF-06260182) pharmacokinetics parameters in trial 1001
`21
`following a multiple 250 mg twice daily oral dose of crizotinib...............................
`
`Table 7. Pharmacokinetics of crizotinib (PF-02341066) in 6 healthy male subjects receiving a
`single oral 250-mg dose of crizotinib containing approximately 100 μCi of
`[14C]crizotinib............................................................................................................
`
`24
`Table 8. Inhibition of crizotinib (PF-02341066) metabolism at 10 μM in human liver
`microsomes by selective Cytochrome P450 inhibitors..............................................
`
`25
`Table 9. AUC and Cmax after single and multiple doses of crizotinib during the dose escalation
`phase of trial 1001 .....................................................................................................
`
`27
`Table 10. Pharmacokinetic parameters of crizotinib during the dose escalation phase of trial 1001
`...................................................................................................................................
`
`29
`Table 11. Median trough concentration (ng/mL) of crizotinib and active metabolite PF-06260182
`following multiple 250 mg oral doses of crizotinib (trials 1001 and 1005)..............
`
`30
`Table 12. Pharmacokinetic parameters of crizotinib in Asian and non-Asian patients................
`
`31
`Table 13. Inhibitory effect of crizotinib on CYP isozymes in human liver microsomes .............
`
`36
`Table 14. Summary of CYP3A induction potential of crizotinib three lots of cryoperserved
`37
`human hepatocytes.....................................................................................................
`
`Table 15. Permeability and bi-directional transport of crizotinib (PF-02341066) using wild-type,
`38
`human MDR1 or BCRP-transfected Madin-Darby canine kidney (MDCK) cells....
`
`Table 16. Effect of multiple doses of ketoconazole on the pharmacokinetics of single dose of
`crizotinib and active metabolite PF-06260182..........................................................
`
`39
`Table 17. Pharmacokinetic parameters of crizotinib and active metabolite with and without
`multiple doses of ketoconazole..................................................................................
`
`40
`Table 18. Effect of multiple doses of rifampin (600 mg once daily) on the single-dose
`pharmacokinetic parameters of crizotinib and active metabolite PF-06260182 .......
`
`41
`Table 19. Single-dose pharmacokinetic parameters of crizotinib and active metabolite PF-
`
`06260182 with and without rifampin (600 mg once daily) .......................................
`42
`Table 20. Pharmacokinetic parameters of plasma midazolam for pre- and post-crizotinib co-
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`Reference ID: 2998079
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`administration ............................................................................................................
` 43
`44
`Table 21. Summary of Caco-2 cell permeability data for crizotinib ............................................
`
`45
`Table 22. Composition of clinical and to-be-marketed commercial crizotinib dosage forms......
`
`Table 23. Summary of plasma crizotinib pharmacokinetic parameters following 50 mg IV and
`46
`250 mg oral doses of crizotinib .................................................................................
`
`Table 24. Summary of plasma PF-06260182 pharmacokinetic parameters following 50 mg IV
`46
`
`and 250 mg oral doses of crizotinib...........................................................................
`Table 25. Summary of the bioequivelence between commercial image capsule (CIC), and
`immediate release tablet (IRT), between CIC and powder in capsule (PIC) following
`47
`
`250 mg oral doses of crizotinib in 35 healthy subjects..............................................
`Table 26. Summary of the bioequivelence between immediate release tablet (IRT), and powder
`47
`
`in capsule (PIC) following 250 mg oral doses of crizotinib in healthy subjects.......
`Table 27. Summary of the effects of a standard high-fat meal on the pharmacokinetics
`parameters of crizotinib following a 250 mg oral dose of crizotinib in patients with
`48
`
`advanced solid tumors ...............................................................................................
`Table 28. Summary of the effect of a standard high-fat meal on the pharmacokinetics of
`48
`
`crizotinib following a 250 mg oral dose of crizotinib in healthy subjects ................
`Table 29. Summary of bioanalytical studies associated with clinical pharmacology studies and
`49
`
`efficacy/safety clinical studies...................................................................................
`
`
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`Reference ID: 2998079
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`NDA 202570 Clinical Pharmacology Review - Crizotinib
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`List of Figures
`Figure 1: The proportion of patients with ORR versus mean steady state trough concentrations of
`crizotinib in trials 1005 and 1001. Solid black symbols represent the observed
`percentage of patients responding to treatment in each Ctrough,ss quartile. The vertical
`black bars represent the 95% confidence interval. The exposure range in each
`Ctrough,ss quartile is denoted by the horizontal black line. Mean Ctrough,ss represents the
`arithmetic mean of the observed Ctrough,ss in various cycles after steady state was
`reached.......................................................................................................................
` 14
`Figure 2: Kaplan-Meier plots for PFS for patients in various quartiles (Q1, Q2, Q3 and Q4)
`based on the mean steady state trough concentrations. Ctrough,ss represents the
`arithmetic mean of the observed Ctrough in various cycles after steady state was
`15
`reached.......................................................................................................................
`
`Figure 3: The probability of patients with A) Grade 2+ liver related AEs (left panel) and B)
`Grade 2+ respiratory related AEs (right panel)–steady state Ctrough of crizotinib in
`trials 1001 and 1005. Solid black symbols represent the observed percentage of
`patients experiencing AEs in each Ctrough quartile. The black bars represent the 95%
`confidence interval. The solid red line represents the mean logistic regression
`prediction. The shaded area represents the 95% confidence interval. The exposure
`16
`
`range in each Ctrough quartile is denoted by the horizontal black line........................
`Figure 4: The time-concentration profiles of crizotinib in patients (N=46) with advanced tumors
`following single 250 mg oral dose under fasting conditions on Day-7, on a normal
`18
`scale (left) and on a semi-log scale (right) ................................................................
`
`Figure 5: The time-concentration profiles of crizotinib on Day 15 of Cycle 1 in patients (N=156)
`21
`with advanced solid tumors following 250 mg twice daily oral dose in trial 1001...
`
`Figure 6: Mean radioactive dose recovered in urine and feces after a single 250-mg (100-μCi)
`oral dose of [14C]-crizotinib to six healthy male subjects .........................................
`23
`
`Figure 7: Mean (±SD) concentration-time profiles of crizotinib and total radioactivity in plasma
`23
`in healthy subjects (N=6)...........................................................................................
`
`26
`Figure 8: Proposed metabolic pathways of crizotinib in rat, dog, and human .............................
`
`Figure 9: Crizotinib Cmax (left) and AUC (right) in the lead-in period (Day -7) or Day 1 increased
`with dose with a slope of 0.74 (0.44, 1.03) for Cmax and 0.72 (0.37, 1.08) for AUC
`from 50 to 300 mg single dose of crizotinib. The shaded area is the 90% confidence
`interval of the slope. ..................................................................................................
`
`28
`Figure 10: Crizotinib Ctrough (left) and AUCtau (right) on Day 15 of Cycle 1 following twice daily
`oral doses of crizotinib increased with doses, with a slope of 2.21 (0.50, 3.92) for
`Cmax and 2.06 (0.64, 3.48) for AUCtau from 200 to 300 mg twice daily of crizotinib
`in 13 patients with advanced solid tumors.................................................................
`
`28
`Figure 11: Cycle-independent steady state trough concentrations of crizotinib in patients with
`advanced solid tumors following 250 mg twice daily oral doses of crizotinib (Trial
`1001)..........................................................................................................................
`
`30
`Figure 12: The effect of sex on the Ctrough, ss of crizotinib in patients with ALK-positive NSCLC
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`Reference ID: 2998079
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`NDA 202570 Clinical Pharmacology Review - Crizotinib
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`

` 32
`following oral 250 mg of crizotinib twice daily........................................................
`Figure 13: The effect of renal function on the Ctrough,ss. Each dot represents one patient baseline
`creatinine clearance (CLcr), which was defined as normal renal function (CLcr ≥ 90
`mL/min, N=33), mild (60 mL/min ≤ creatinine clearance (CLcr) < 90 mL/min, N=47
`), moderate (30 mL/min ≤ CLcr < 60 mL/min, N=27), and severe (CLcr < 30
`33
`mL/min, N=1) renal impairment................................................................................
`
`Figure 14: The box-plot of mean crizotinib trough concentration at steady-state versus renal
`function groups. Based on each patient’s baseline creatinine clearance (CLcr), renal
`function groups are defined as normal renal function (CLcr ≥ 90 mL/min, N=33),
`mild (60 mL/min ≤ creatinine clearance (CLcr) < 90 mL/min, N=47 ), moderate (30
`mL/min ≤ CLcr < 60 mL/min, N=27), and severe (CLcr < 30 mL/min, N=1) renal
`34
`impairment.................................................................................................................
`
`Figure 15: Effect of pre-incubation with crizotinib on CYP3A activity (left) and Kitz-Wilson
`37
`plot (right) for CYP3A inactivation in human liver microsomes..............................
`
`Figure 16: The time-concentration profiles of crizotinib in healthy subjects (N=15) on a normal
`scale (left) and on a semi-log scale (right), following a single 150 mg oral crizotinib
`dose alone or coadministered with 200 mg ketoconazole twice daily in a two-
`40
`treatment, two period, one-sequence crossover design .............................................
`
`Figure 17: The time-concentration profiles of crizotinib in healthy subjects (N=15) on a normal
`scale (left) and on a semi-log scale (right), following a single 150 mg oral crizotinib
`dose alone or coadministered with 600 mg rifampin once daily in a two-treatment,
`41
`two-period, one-sequence crossover design ..............................................................
`
`Figure 18: The time-concentration profiles of midazolam in patients with advanced solid tumor
`on a normal scale (left) and on a semi-log scale (right), following a single midazolam
`oral dose of 2 mg administered alone on Day -7 or concurrently with crizotinib on
`Day 29 at dose levels of 100 mg once daily, 250 mg twice daily, and 300 mg twice
`43
`daily ...........................................................................................................................
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`Reference ID: 2998079
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`NDA 202570 Clinical Pharmacology Review - Crizotinib
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`1 EXECUTIVE SUMMARY
`
`Crizotinib, a new molecular entity, is a small-molecule kinase inhibitor. The applicant seeks an
`accelerated approval of crizotinib for the treatment of anaplastic lymphoma kinase (ALK)-
`positive advanced non-small cell lung cancer (NSCLC). The proposed dosage of crizotinib is
`250 mg administered orally twice daily (BID), continuously, with or without food. Results from
`two single-arm trials (A8081005 and A8081001) in patients with ALK-positive NSCLC are
`submitted to support the accelerated approval. Objective response rate (ORR), the primary
`efficacy endpoint, was 50% (N=136) and 61% (N=119) in trials A8081005 and A8081001,
`respectively.
`Exposure-response (ER) analyses indicated a lower ORR in the lowest quartile of steady state
`trough concentrations (Ctrough,ss) compared to other quartiles (24% vs > 70% in trial A8081001,
`and 47% vs > 60 in trial A8081005). The proposed dosage appears acceptable, as even the
`lowest quartile of Ctrough,ss in pivotal trial A8081005 showed an ORR of 47%, compared to 10-
`24% using historical controls. ER analyses utilizing data from confirmatory trials A8081007 and
`A8081014 may provide further information on the appropriateness of 250 mg BID dose.
`Following oral administration of crizotinib, Cmax is reached within 4 to 6 hours, with a mean T1/2
`of 42 hours. Absolute oral bioavailability is 43%. Crizotinib can be dosed without regard to
`food, as a standard high-fat meal reduces AUCinf and Cmax by only 15%.
`Crizotinib demonstrated non-linear pharmacokinetics (PK) in terms of dose proportionality and
`time-dependence. The steady state systemic exposure of crizotinib appears to increase with doses
`in a greater-than-proportional manner in the dose range of 200-300 mg BID. Following
`crizotinib 250 mg BID, steady state is reached within 15 days and stayed stable, with a median
`accumulation ratio of 4.5. However, apparent clearance (CL/F) at steady state (64 L/hr) was
`lower than that after a single dose (100 L/hr), likely due to auto-inhibition of CYP3A by
`crizotinib.
`Following the oral administration of a single 250 mg radiolabeled crizotinib dose to healthy
`subjects, 63% (53% unchanged) and 22% (1.3% unchanged) of the administered dose was
`recovered in feces and urine, respectively. No dose adjustment is needed for mild or moderate
`renal impairment, as mean Ctrough,ss in these two groups are similar to that in normal renal
`function group. The effects of severe renal impairment and hepatic impairment are unknown.
`Crizotinib is predominantly metabolized by CYP3A4/5 in vitro, at the same time, it is also a
`reversible and time-dependent inhibitor of CYP3A. Furthermore, crizotinib is possibly a CYP3A
`inducer, as crizotinib increases CYP3A4 mRNA levels by up to 29 fold, with no increase in
`CYP3A enzyme activity. In vivo, crizotinib (at steady-state) increases AUC of midazolam by
`3.7 fold compared to midazolam alone. Due to the time-dependent PK of crizotinib, the effects
`of strong inducers or inhibitors of CYP3A4 on the PK of crizotinib at steady-state can not be
`predicted, because the drug interaction studies that the sponsor has conducted only evaluated
`single dose PK of crizotinib.
`The aqueous solubility of crizotinib is pH dependent. No drug interaction study has been
`conducted with gastric pH elevating agents.
`
`Reference ID: 2998079
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`NDA 202570 Clinical Pharmacology Review - Crizotinib
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`1.1 RECOMMENDATIONS
`The Office of Clinical Pharmacology has reviewed NDA 202570. This NDA is acceptable from
`a clinical pharmacology perspective, provided that the Applicant and the Agency come to a
`mutually satisfactory agreement regarding the labeling language, the post-marketing
`requirements and post-marketing commitments.
`1.2 POST-MARKETING REQUIREMENTS (PMRS) AND COMMITMENTS (PMCS)
`The following issues should be addressed as PMRs:
`1. Conduct a multiple dose trial in humans to determine how to adjust the crizotinib dose
`when it is coadministered with a strong CYP3A inhibitor (e.g., ketoconazole).
`2. Conduct a multiple dose trial in humans to determine how to adjust the crizotinib dose
`when it is coadministered with a strong CYP3A inducer (e.g., rifampin).
`3. Conduct a multiple dose trial to determine the appropriate crizotinib dose in patients with
`various degrees of hepatic impairment.
`4. Conduct a multiple dose trial to determine the appropriate crizotinib dose in patients with
`severe renal impairment.
`5. Conduct a trial in humans to determine how to dose crizotinib with regard to gastric pH
`elevating agents (i.e., a proton-pump inhibitor, an H2-receptor antagonist, and/or an
`antacid).
`6. Complete the ECG sub-study in trial A8081007 and submit the final study report, along
`with a thorough review of cardiac safety data to address any potential impact of crizotinib
`on QTc interval prolongation in patients.
`7. Submit the study report on the ongoing in vitro evaluations of induction potential of
`crizotinib on CYP2B and CYP2C enzymes.
`The following issue should be addressed as a PMC:
`1. Conduct exposure-response analysis utilizing data from confirmatory trials A8081007
`and A8081014 to further evaluate the appropriateness of 250 mg BID dose for all
`patients.
`Signatures:
`Qi Liu, Ph.D.
`Pengfei Song, Ph.D.
`Team Leader
`Reviewer
`Division of Clinical Pharmacology 5
`Division of Clinical Pharmacology 5
`Christine Garnett, Pharm.D.
`Anshu Marathe, Ph.D.
`Pharmacometrics Team Leader
`Pharmacometrics Reviewer
`Division of Pharmacometrics
`Division of Pharmacometrics
`Cc: DDOP: CSO - Diane Hanner; MTL - Virginia E. Maher; MO - Shakun Malik
`
`DCP-5: DDD - Brian Booth; DD – Nam Atiqur Rahman
`
`Reference ID: 2998079
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`NDA 202570 Clinical Pharmacology Review - Crizotinib
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`

`1.3 CLINICAL PHARMACOLOGY SUMMARY
`
`Crizotinib, a new molecular entity, is a small-molecule kinase inhibitor. In this original NDA,
`single-arm trials A8081005 and A8081001 were submitted to support an accelerated approval of
`crizotinib for the treatment of ALK-positive advanced NSCLC. The proposed dosage of
`crizotinib is 250 mg administered BID, continuously, with or without food. Objective response
`rate (ORR) in trials A8081005 and A8081001 was 50% and 61%, respectively.
`ER analyses indicated a lower ORR in the lowest quartile of Ctrough,ss compared to other quartiles
`(24% vs >70% in trial A8081001 and 47% vs > 60 in trial A8081005). The proposed dosage
`appears acceptable, as even the lowest quartile of in pivotal trial A8081005 showed an ORR of
`47%, compared to 10-24% of historical controls. ER analyses in the ongoing Phase 3 trials
`A8081007 and A8081014 may provide further information on the appropriateness of 250 mg
`BID dose.
`Crizotinib appears to be associated with concentration-dependent QT interval prolongation. Due
`to ECG acquisition and interpretation issues, large increase in QT interval (i.e., ~20 ms) can not
`be reliably excluded.
`Following oral administration of crizotinib, Cmax was reached at 4 to 6 hours, with a terminal
`half-life of 42 hours in patients. The absolute oral bioavailability is 43%. Crizotinib can be
`dosed without regard to food, as a standard high-fat meal reduces AUCinf and Cmax by only 15%.
`Crizotinib demonstrated non-linear PK in humans in terms of dose proportionality and time-
`dependence. The steady state systemic exposure of crizotinib appears to increase with doses in a
`greater-than-proportional manner in the dose range of 200-300 mg BID. Following 250 mg
`crizotinib BID, steady state is reached within 15 days with an accumulation ratio of 4.5, and the
`exposure stayed stable over the treatment period of 112 days. However, apparent clearance
`(CL/F) at steady state (64 L/hr) was lower than that after a single dose (100 L/hr), likely due to
`auto-inhibition of CYP3A by crizotinib.
`In the mass balance trial with a single 250-mg dose of [14C] crizotinib, the mean recovery of
`administered dose was 85%, with 63% (53% unchanged) in feces and 22% (1.3% unchanged) in
`urine. No dose adjustment is needed for mild or moderate renal impairment, as mean Ctrough,ss in
`these two groups are similar to that in normal renal function group. The effects of severe renal
`impairment and hepatic impairment are unknown.
`Crizotinib is predominantly metabolized by CYP3A4/5 in vitro. At the same time, crizotinib is
`also a reversible inhibitor and a time-dependent inhibitor of CYP3A. Furthermore, crizotinib is
`possibly a CYP3A inducer, as crizotinib increases CYP3A4 mRNA levels by up to 29 fold, with
`no increase in CYP3A enzyme activity. In vivo, crizotinib at steady-state increases the AUC of
`midazolam by 3.7 fold, compared to midazolam alone. For a single dose of crizotinib,
`coadminstration of ketoconazole (a strong CYP3A inhibitor) increases the crizotinib AUC by 3.2
`fold, while rifampin (a strong CYP3A inducer) decreases the crizotinib AUC by 82%. However,
`due to time-dependent inhibition on CYP3A by crizotinib, the effects of strong CYP3A inducers
`and inhibitors on the steady-state PK of crizotinib are unclear.
`Crizotinib is not an inducer of CYP1A2. The potential of crizotinib to induce CYP2B or CYP2C
`in vitro is currently being evaluated by the sponsor. In vitro, crizotinib is a substrate and an
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`Reference ID: 2998079
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`inhibitor of P-glycoprotein (P-gp). It is not a substrate of breast cancer resistance protein (BCRP)
`or hepatic uptake transporters.
`As the aqueous solubility of crizotinib is pH dependent, with higher pH resulting in lower
`solubility. Drugs that elevate the gastric pH may decrease the solubility of crizotinib and
`subsequently reduce its bioavailability. No formal drug interaction study has been conducted yet.
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`Reference ID: 2998079
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`2 QUESTION BASED REVIEW
`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 clinical
`pharmacology and biopharmaceutics review?
`Crizotinib, the drug substance, is a white to pale yellow powder. The drug product Xalkori® is
`supplied as hard gelatin capsules containing 200 mg or 250 mg of crizotinib. The following is a
`brief summary of the physico-chemical properties of crizotinib:
`Physico-chemical properties of crizotinib
`• Structure:
`
`
`
`NH
`
`N
`
`N
`
`Cl
`
`N
`
`NH2
`
`O
`
`Cl
`
`
`
`F
`• Established Name: Crizotinib, PF-02341066
`• Molecular Weight: 450.34 Daltons
`• Molecular Formula: C21H22Cl2FN5O
`• LogP: 4.28
`• LogD at pH 7.4: 1.65
`• PKa: 9.4 (piperidinium cation) and 5.6 (pyridinium cation)
`• Chemical Name (CAS): (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-
`4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine
`• Solubility: Crizotinib solubility in aqueous media decreases with increasing pH (Table 1).
`
`
`Table 1. PH-dependent aqueous solubility of crizotinib
`
`
`
`Source: Table 3.2.S.1.3-1 of Module 3 Quality
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`Reference ID: 2998079
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`2.1.2 What are the proposed mechanisms of action and therapeutic indications?
`Crizotinib is a small-molecule inhibitor of c-mesenchymal-epithelial transition factor/hepatocyte
`growth factor receptor (c-Met/HGFR) and ALK tyrosine kinases. The proposed indication of
`crizotinib is for the treatment of ALK-positive advanced NSCLC.
`2.1.3 What are the proposed dosage and route of administration?
`The proposed dosage of crizotinib is 250 mg oral capsules twice daily (BID), continuously, with
`or without food.
`2.2 GENER