CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`203085Orig1s000
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`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
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`Clinical Pharmacology Review
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`NDA
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`NDA 203-085
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`\\CDSESUB1\EVSPROD\NDA203085\0000\
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`Type/Category
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`Brand Name
`
`Generic name
`
`Proposed Indication
`
`NME; Priority
`
`Stivarga
`
`Regorafenib
`
`Treatment of patients with metastatic colorectal cancer (mCRC)
`who have been previously treated with,
`
`, fluoropyrimidine-based chemotherapy, an anti-
`VEGF therapy, or an anti-EGFR therapy (if KRAS wild type).
`
`Dosage Form
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`Film-coated tablet, 40 mg
`
`Route of Administration
`
`Oral
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`Dosing Regimen and Strength 160 mg oral once daily for the first 21 days of each 28-day
`treatment cycle
`
`Applicant
`
`OCP Division
`
`OND Division
`
`Bayer HealthCare Pharmaceuticals, Inc.
`
`DCP 5
`
`DOP 2
`
`Submission Date
`
`April 27, 2012
`
`PDUFA
`
`October 27, 2012; Internal action goal, September 27, 2012
`
`Primary Reviewer
`
`Stacy S. Shord, Pharm.D.
`
`Team Leader
`
`Hong Zhao, Ph.D.
`
`NDA 203-085 Regorafenib/Stivarga
`
`Reference ID: 3194666
`
`Page 1 of 45
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`(b) (4)
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`(b) (4)
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`

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`Table of Contents
`1 EXECUTIVE SUMMARY ..............................................................................................................4
`1.1
`RECOMMENDATIONS ...........................................................................................................5
`1.2
`PHASE 4 REQUIREMENTS AND COMMITMENTS ...................................................................5
`SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
`1.3
`FINDINGS .............................................................................................................................8
`2 QUESTION BASED REVIEW .....................................................................................................10
`2.1
`GENERAL ATTRIBUTES ......................................................................................................10
`2.2
`GENERAL CLINICAL PHARMACOLOGY ..............................................................................11
`2.3
`INTRINSIC FACTORS...........................................................................................................20
`EXTRINSIC FACTORS..........................................................................................................26
`2.4
`2.5
`GENERAL BIOPHARMACEUTICS .........................................................................................32
`2.6
`ANALYTICAL SECTION ......................................................................................................36
`3 DETAILED LABELING RECOMMENDATIONS......................................................................37
`List of Tables
`Table 1. Summary of the Clinical Pharmacology and Clinical Studies ...................................................... 11
`Table 2. Summary of the QTcF interval measurements observed in Study 14387..................................... 14
`Table 3. The single and repeat dose (on cycle 1, day 21) mean pharmacokinetic parameters of
`regorafenib, M2 and M5 in patients administered 160 mg daily x 21 days ....................................... 15
`Table 4. The relative bioavailability of the initial tablet formulation relative to oral solution .................. 15
`Table 5. The percentage of a 120 mg radiolabeled oral dose of regorafenib identified in plasma and excreta
`................................................................................................................................................ 18
`Table 6. The accumulation of regorafenib, M2 (BAY 75-7495) and M5 (BAY 81-8752) ........................ 19
`Table 7. The inter-patient variability (%CV) observed for regorafenib, M2 and M5 following a single
`dose and repeat doses (cycle 1, day 21) ............................................................................................. 19
`Table 8. The intra-patient variability (%CV) observed for regorafenib, M2 and M5................................ 19
`Table 9. Pooled mean (%CV) exposure of patients < 65 years and ≥ 65 years. ........................................ 20
`Table 10. Pooled mean (%CV) exposure in men and women ................................................................... 21
`Table 11. The mean (%CV) exposure of regorafenib, M2 and M5 in Asian populations after repeat doses
`............................................................................................................................................................ 21
`Table 12. The point estimate and 90% CI for regorafenib, M2 and M5 measured in patients with mild
`renal impairment relative to normal renal function ............................................................................ 23
`Table 13. The mean (% CV) exposure as measured by AUC0-24h,ss of regorafenib, M2 and M5 in patients
`with solid tumors across five clinical studies following administration of 160 mg once daily for 21
`days .................................................................................................................................................... 24
`Table 14. The median (range) for regorafenib, M2 and M5 measured in patients with renal cell carcinoma
`(n=14) ................................................................................................................................................. 24
`Table 15. The point estimate and 90% CI for regorafenib, M2 and M5 in patients with mild (n=14) and
`moderate (n=4) hepatic impairment as compared to patients with normal (n=10) hepatic function.. 25
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`NDA 203-085 Regorafenib/Stivarga
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`Reference ID: 3194666
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`Page 2 of 45
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`Table 16. The mean trough concentrations (%CV) measured in patients with hepatocellular carcinoma
`and mild hepatic impairment and in patients with advanced solid tumors and normal hepatic function
`............................................................................................................................................................ 25
`Table 17. The point estimate and 90% CI for regorafenib, M2 and M5 measured in patients administered
`a single dose of regorafenib with and without a strong CYP3A4 inhibitor ....................................... 27
`Table 18. The point estimate and two-sided 90% CI for regorafenib, M2 and M5 measured in patients
`administered regorafenib with and without a strong CYP3A4 inhibitor............................................ 27
`Table 19. The Ki value determined by the applicant and the calculated R value based on observed steady-
`state concentrations of regorafenib, M2 and M5................................................................................ 29
`Table 20. The IC50 values determined by the applicant and the calculated R values based on observed
`steady-state concentrations of regorafenib and predicted gastrointestinal concentrations ................. 29
`Table 21. The Ki values determined by the applicant relative to the observed steady-state concentrations
`of regorafenib ..................................................................................................................................... 30
`Table 22. The point estimate and two-sided 90% CI for irinotecan and SN-38 measured in patients
`administered FOLFIRI with and without regorafenib........................................................................ 30
`Table 23. Permeability of regorafenib in Caco-2 cells ............................................................................... 32
`Table 24. The bioequivalence assessment between the ‘to-be-marketed’ tablet and the clinical trial tablet
`............................................................................................................................................................ 33
`Table 25. The mean pharmacokinetic parameters (%CV) of regorafenib, M2 and M5 after a high-fat and
`low-fat meal compared to fasted state in healthy volunteers ............................................................. 34
`Table 26. The relative exposure of regorafenib, M2 and M5 after a high-fat or a low-fat meal compared
`to fasted state in healthy volunteers .................................................................................................. 35
`Table 27. The accuracy and precision estimated for the quality control samples in the concentration range
`of 5 μg/L to 1600 μg/L in human plasma and urine........................................................................... 37
`List of Figures
`Figure 1. The QTcF measured in patients enrolled into Study 14387 after administration of placebo or
`regorafenib ......................................................................................................................................... 14
`Figure 2. The plasma concentration-time profiles of regorafenib following a single (left) and repeat dose
`(right) demonstrating multiple peak concentrations at ~ 3 hrs, 8 hrs and 24 hrs ............................... 16
`Figure 3. The metabolism of regorafenib after a single radiolabeled dose in four healthy men................. 17
`Figure 4. Dose-exposure relationships following a single dose and repeated doses of regorafenib ........... 18
`Figure 5. The relationship between race and exposure of regorafenib at steady-state................................ 22
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`NDA 203-085 Regorafenib/Stivarga
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`Reference ID: 3194666
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`Page 3 of 45
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`1
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`EXECUTIVE SUMMARY
`
`Regorafenib is a new molecular entity (NME) that inhibits multiple kinases. The proposed
`indication is for the treatment of patients with metastatic colorectal cancer (mCRC) who have
`been previously treated with,
`ma) fluoropyrimidine-based
`chemotherapy, an anti-VEGF therapy, or if KRAS wild type, an anti—EGFR therapy.
`(mm
`
`The proposed dose regimen is 160 mg as four 40 mg film-coated tablets
`administered orally once daily for the first 21 days of each 28-day treatment cycle. The
`bioequivalence (BE) of regorafenib between the ‘to—be-marketed’ formulation and clinical trial
`formulation was demonstrated after a single oral dose, but the exposure of the active metabolites
`M2 and M5 was clinically insignificantly higher for the ‘to-be-marketed’ formulation.
`
`A single clinical safety and efficacy trial was conducted in 760 patients with mCRC who were
`randomized 2:1 to receive oral regorafenib or placebo with best supportive care (BSC) until
`disease progression or unacceptable toxicity. Regorafenib resulted in a longer overall survival
`(OS) of 1.4 months compared to placebo [regorafenibz 6.4 mo. vs. placebo: 5.0 mo.; HR = 0.77;
`95% CI 0.64, 0.94; p=0.0102]. The OS benefit was independent of age, KRAS mutation status,
`and the number of previous therapies. Most patients received three or fewer previous therapies
`for metastatic disease. Regorafenib is associated with several adverse events (AE) commonly
`seen with drugs that interact with the same kinases: hepatotoxicity, hemorrhage, pahnar-plantar
`erythrodysesias, rash, hypertension, cardiac ischemia or infarction, gut perforation, diarrhea,
`mucositis, and hypophosphatemia.
`
`The clinical pharmacology studies included in this NDA are two dose escalation studies, three
`drug interaction studies, one food effect study and one BE study. The clinical safety and efficacy
`trial was completed earlier than anticipated with demonstrated OS benefit, while several clinical
`pharmacology studies including exposure—response (E-R) analyses, population pharmacokinetic
`(PopPK) analyses, an assessment of the risk of QT/QTc interval prolongation and an assessment
`of a pharmacokinetic (PK) drug interaction with cytochrome P450 probe substrates are still
`ongoing. Prior to the NDA submission, FDA agreed to the sponsor’s proposal to submit the
`reports of these ongoing studies in November 2012 under post marketing requirements (PIVIRs)
`and post marketing commitments (PMCs) if the applicant believes that there are no safety signals or
`evidence of important but incompletely characterized clinical pharmacologic effects that will preclude an
`adequate risk-benefit assessment.
`
`NDA 203-085 Regorafenib/Stivarga
`Reference ID: 31 94666
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`Page 4 of 45
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`1.1 RECOMMENDATIONS
`This NDA is acceptable from a clinical pharmacology perspective provided that the applicant
`and the FDA come to an agreement regarding the labeling language and the identified clinical
`studies to be conducted as PMRs or PMCs.
`1.2 PHASE 4 REQUIREMENTS AND COMMITMENTS
`1.2.1 Post Marketing Requirements (PMRs)
`The Office of Clinical Pharmacology requires the applicant to conduct the following PMRs.
`These studies are included in the action letter with milestones agreed upon after negotiation with
`the applicant.
`1. Complete a clinical trial evaluating the potential for regorafenib to prolong the QT/QTc
`interval in an adequate number of patients administered repeated doses of 160 mg of
`regorafenib and submit the final study report, along with a thorough review of cardiac safety
`data.
`2. Complete a clinical trial and submit the final study report to evaluate the effect of repeated
`doses of 160 mg of regorafenib on the pharmacokinetics of a probe substrate of CYP2C8,
`CYP2C9, CYP3A4 and CYP2C19.
`3. Conduct a multiple dose study to determine the appropriate dose of regorafenib in patients
`with severe renal impairment. Submit the final protocol for FDA review before conducting
`the trial.
`1.2.2 Post Marketing Commitments (PMCs)
`The Office of Clinical Pharmacology requires the applicant to conduct the following PMCs.
`These studies are included in the action letter with milestones agreed upon after negotiation with
`the applicant.
`1. Submit an integrative population pharmacokinetic analysis report to evaluate the effect of
`intrinsic and extrinsic factors on the pharmacokinetics of regorafenib and the active
`metabolites M-2 and M-5.
`2. Submit an exposure-response analysis for regorafenib and the active metabolites M-2 and M-
`5 for measures of both effectiveness and toxicity using data collected from the CORRECT
`trial (Study 14387).
`1.2.3 Additional Comments for the Applicant’s Consideration
`The following clinical pharmacology pertinent comments will be sent to the sponsor under the
`IND for the applicant to address during future development of this drug.
`1. Conduct a pharmacokinetic drug interaction study in subjects administered an oral P-
`glycoprotein probe substrate with and without regorafenib in accordance with the FDA draft
`Guidance for Industry: “Drug Interaction Studies — Study Design, Data Analysis, and
`Implications for Dosing and Labeling.” Submit the final protocol for FDA review before
`conducting the trial.
`
`NDA 203-085 Regorafenib/Stivarga
`
`Reference ID: 3194666
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`Page 5 of 45
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`2. Conduct a pharmacokinetic drug interaction study in subjects administered a cytochrome
`P450 (CYP) 2D6 probe substrate with and without regorafenib in accordance with the FDA
`draft Guidance for Industry: “Drug Interaction Studies — Study Design, Data Analysis, and
`Implications for Dosing and Labeling” if a drug interaction is demonstrated between
`regorafenib and a CYP2C8, CYP2C9, CYP3A4 or CYP2C19 probe substrate following the
`completion of the ongoing Study 12434. Submit the protocol for FDA review before
`conducting the trial.
`3. Conduct in vitro studies to determine if regorafenib and the active metabolites M-2 or M-5
`induce CYP1A2, CYP2B6 or CYP34 mRNA expression levels in accordance with the FDA
`draft Guidance for Industry “Drug Interaction Studies — Study Design, Data Analysis, and
`Implications for Dosing and Labeling.”
`4. Conduct a pharmacokinetic drug interaction study to determine the pharmacokinetics of a
`sensitive substrate or a substrate with a narrow therapeutic index of the cytochrome P450
`enzymes likely to be induced in humans if the calculated R3 value is less than 0.9 following
`the completion of the in vitro studies to assess the ability of regorafenib, M-2 or M-5 to
`induce cytochrome P450 enzymes. Submit the final protocol for FDA review before
`conducting the trial(s).
`5. Conduct a pharmacokinetic drug interaction study in subjects administered regorafenib with
`and without rifaximin in accordance with the FDA Guidance for Industry: “Drug Interaction
`Studies — Study Design, Data Analysis, and Implications for Dosing and Labeling.” Submit
`the final protocol for FDA review before conducting the trial.
`6. Submit a summary report and data files of the exploratory biomarker analyses completed
`during the clinical development of regorafenib, including genetic and nongenetic markers in
`various matrices (e.g., blood, plasma and tumor).
`Signatures:
`
`Stacy S. Shord, Pharm.D.
`Reviewer
`Division of Clinical Pharmacology 5
`
`Hong Zhao, Ph.D.
`Team Leader
`Division of Clinical Pharmacology 5
`
`Nam Atiqur Rahman, Ph.D.
`Division Director
`Division of Clinical Pharmacology 5
`
`Cc: DOP2: RPM-M Hughes; MO- S Pradhan, S Kaushik; MTL- S Lemery
`DCP-5: DDD - B Booth
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`NDA 203-085 Regorafenib/Stivarga
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`Reference ID: 3194666
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`Page 6 of 45
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`A Required OCP Office Level Briefing occurred on Wednesday, August 15, 2012. The attendees
`included Drs. Zineh, Abernethy, Rahman, Booth, Reynolds, Pacanowski and others.
`
`NDA 203-085 Regorafenib/Stivarga
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`Reference ID: 3194666
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`Page 7 of 45
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`1.3 SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
`FINDINGS
`Pharmacokinetics: Following a single 160 mg dose, regorafenib reached mean Cmax of 2.5
`μg/mL at a median time (Tmax) of 4 hrs and mean AUC of 70.4 μg*h/mL. At steady-state,
`regorafenib reached mean Cmax of 3.9 μg/mL and the mean AUC of 58.3 μg*h/mL. The
`coefficient of variation of Cmax and AUC is between 35% to 44%. Regorafenib underwent
`enterohepatic circulation with multiple peak plasma concentrations observed within 24 hrs after
`the oral administration. Regorafenib was highly protein bound (99.5%). It was primarily
`metabolized by CYP3A4 and UGT1A9 and about 71% of a single radiolabeled dose (24% as
`metabolites) was excreted in feces. The mean (range) elimination half-life (t½) was 28 (14 to 58)
`hrs. The metabolites M2 and M5 reached steady-state concentrations that were similar to
`regorafenib and demonstrated similar activity and degree of protein binding as regorafenib in the
`nonclinical and the in vitro studies. The mean (range) t½ for M2 was 25 (14 to 32) hrs and for
`M5 was 51 (32 to 70) hrs.
`Food Effect: Regorafenib is recommended to be administered with a low-fat meal. As compared
`to the fasted state, a low-fat breakfast increased the mean AUC of regorafenib, M2 and M5 by
`36%, 40% and 23%, respectively, whereas a high-fat meal increased the mean AUC of
`regorafenib by 48%, but decreased the mean AUC of M2 and M5 by 20% and 51%, respectively.
`Product Comparability: No clinically important differences in exposure were observed between
`the ‘to-be-marketed’ formulation and clinical trial formulation after administration of a single
`dose of 160 mg of regorafenib.
`Organ Impairment: No differences in the mean exposure of regorafenib and the metabolites M2
`and M5 were observed in 10 patients with mild renal impairment (CLcr 60 to 89 mL/min) as
`compared to 18 patients with normal renal function. The applicant is requested to conduct a
`multiple dose study to determine an appropriate dose for patients with severe renal impairment
`as a PMR.
`No differences in the exposure of regorafenib and the metabolites M2 and M5 were observed in
`14 patients with hepatocellular cancer (HCC) and mild hepatic impairment (Child-Pugh A) and 4
`patients with HCC and moderate hepatic impairment (Child-Pugh B) relative to 10 patients with
`solid tumors and normal hepatic function. Regorafenib has not been administered to patients
`with severe hepatic impairment (Child-Pugh C).
`Drug Interactions: The administration of ketoconazole 400 mg daily for 18 days with a single
`160 mg dose of regorafenib increased the mean AUC of regorafenib by 33% and decreased the
`mean AUC of M2 and M5 each by 93%. The administration of rifampin 600 mg daily for 9 days
`with a single 160 mg dose of regorafenib decreased the mean AUC of regorafenib by 50% and
`increased the mean AUC of M5 by 264%; the mean AUC of M2 was similar with and without
`rifampin.
`Regorafenib or the active metabolites M2 or M5 inhibited CY2B6, CYP2C8, CYP2C9,
`CYP2C19, CYP2D6, or CYP3A4 in vitro. The effect of regorafenib on the PK of CYP2C8,
`CYP2C9, CYP2C19 and CYP3A4 probe substrates are being evaluated in an ongoing study.
`Regorafenib did not induce cytochrome P450 activity in vitro; however, it is not known if
`regorafenib, M2 or M5 induce CYP1A2, CYP2B6, and/or CYP3A4 mRNA expression levels.
`Regorafenib M2 and M5 inhibited UGT1A1 and UGT1A9 in vitro. When irinotecan was
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`NDA 203-085 Regorafenib/Stivarga
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`Reference ID: 3194666
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`Page 8 of 45
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`administered five days after the last dose of seven daily doses of regorafenib, the mean AUC of
`SN-38 increased by 44% and the mean AUC of irinotecan increased by 28%.
`Regorafenib is not a substrate for P-gp, BCRP, OATP1B1, and OATP1B3 in vitro. It inhibits P-
`gp and BCRP in vitro. Regorafenib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3 and
`OCT2 in vitro.
`Exposure-Response and Population Pharmacokinetic Analyses: The applicant plans to submit
`these analyses post marketing.
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`NDA 203-085 Regorafenib/Stivarga
`
`Reference ID: 3194666
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`Page 9 of 45
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`2
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`2.1
`
`QUESTION BASED REVIEW
`
`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 related
`
`to clinical pharmacology and biopharmaceutics review?
`
`The proposed drug product is available as 40 mg film-coated tablets. Each tablet contains 40 mg
`of regorafenib which corresponds to 41.49 mg of regorafenib monohydrate. The structural
`formula for the drug substance regorafenib monohydrate is:
`
`F
`
`F
`
`Cl
`
`0
`
`@131” °
`min F
`’
`.Hp
`
`,CH
`
`Regorafenib monohydrate has a molecular weight of 501 g/mol.
`
`Regorafenib monohydrate is practically insoluble in water
`
`(mo
`
`(m4)
`
`The applicant claims that
`Regorafenib showed a high permeability across Caco-2 cells.
`regorafenib is a BCS class 2 compound with high permeability and low solubility.
`
`2.1.2
`
`What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`including VEGFR1,VEGFR2,VEGFR3, TIE2, KIT,
`Regorafenib inhibits multiple kinases,
`RET, RAF- 1, BRAF, BRAFV600E, PDGFR, and FGFR. Regorafenib inhibited VEGFR2,
`VEGFR3, TIE2, PDGFRB, KIT (wild-type and mutant), RET (mutant), BRAF (mutant) and
`FGFR with ICso values ranging from 3 nM to 200 nM. The activation of the MAPK pathway
`monitored by ERK phosphorylation was inhibited by regorafenib with ICso values ranging from
`40 nM to 400 nM. These values appear to be at least 20-fold lower than the observed steady-
`state regorafenib concentrations as measured at the proposed dose in the dose escalation trial.
`
`The M2 and M5 metabolites of regorafenib inhibited some of the same kinases as regorafenib,
`such as VEGFR2, TIE2, KIT (mutant and wild-type) and BRAF (mutant) at IC5o values similar
`to regorafenib. These metabolites exhibited similar anticancer activity compared to regorafenib
`in tumor models of colorectal cancer.
`
`The proposed indication is for “the treatment of patients with mCRC who have been previously
`treated with,
`(mu) fluoropyrimidine-based chemotherapy, an anti-
`VEGF therapy, or if KRAS wild type, an anti—EGFR therapy.” FDA modified the proposed
`indication to “the treatment of patients with mCRC who have been previously treated with
`
`NBA 203-085 Regorafenib/Stivarga
`Reference ID. 3194666
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`Page 10 of 45
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`fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and,
`if KRAS wild type, an anti-EGFR therapy.”
`2.1.3 What are the proposed dosage(s) and route(s) of administration?
`The proposed dose is 160 mg once daily (QD) for the first 21 days of each 28-day treatment
`cycle. The proposed drug product will be available as 40 mg film-coated tablets.
`2.2 GENERAL CLINICAL PHARMACOLOGY
`2.2.1
`What are the design features of the clinical pharmacology and clinical
`studies used to support dosing or claims?
`Table 1 lists the relevant clinical pharmacology and clinical studies included in the application. The
`applicant proposes to submit the final study reports and datasets for PopPK analyses, E-R
`analyses, Study 12434 and Study 14814 in November 2012; these clinical pharmacology studies
`were not completed before the submission of the application as the clinical safety and efficacy
`trial was completed earlier than anticipated.
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`Table 1. Summary of the Clinical Pharmacology and Clinical Studies
`Study
`Study
`Dose and
`Study Population
`Number
`Design
`Administration
`11650
`Dose
`10 mg to 220
`escalation
`mg QD x 21
`days
`
`Advanced solid
`tumors (n = 76)
`
`Assessment
`
`Status
`
`Pharmacokinetics; a post-
`hoc subgroup analysis
`was conducted in patients
`with mild renal
`impairment
`Biomarkers
`Pharmacokinetics; a post-
`hoc subgroup analysis
`was conducted in patients
`with mild and moderate
`hepatic impairment
`Biomarkers
`Pharmacokinetics in
`Asian (Japan) patients
`
`Pharmacokinetics in
`Asian (Hong Kong,
`Singapore) patients
`Drug interaction with
`irinotecan, fluorouracil
`and oxaliplatin
`
`Completed
`
`Completed
`
`Completed
`
`Ongoing
`
`Completed
`
`11651
`
`Dose
`escalation
`
`20 mg to 140
`mg QD daily x
`28 days
`
`Advanced solid
`tumors (n = 84)
`
`13172
`
`Open label
`
`14996
`
`Open label
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`11656
`
`Open label
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`12434
`
`Open label
`
`160 mg QD x
`21 days
`
`160 mg QD x
`21 days
`
`160 mg QD on
`days 4-10 and
`18-24 with
`mFOLFOX6 or
`FOLFIRI
`160 mg QD x
`21 days
`
`Advanced
`refractory tumors
`(n = 16)
`Advanced
`refractory tumors
`(n = 8)
`Metastatic
`colorectal cancer
`(n = 45)
`
`Advanced solid
`tumors (n=16)
`
`Drug interaction with
`substrates of cytochrome
`P450 enzymes
`
`Ongoing
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`NDA 203-085 Regorafenib/Stivarga
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`Reference ID: 3194666
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`Page 11 of 45
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`Study
`Number
`14814
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`14656
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`12437
`
`12436
`
`Study
`Design
`Open label
`
`Open label,
`randomized,
`crossover
`Open label,
`randomized,
`crossover
`Open label
`
`12435
`
`Open label
`
`Dose and
`Administration
`160 mg QD x
`21 days
`160 mg x 1
`dose in each
`period
`160 mg x 1
`dose in each
`period
`120 mg 14C-
`radiolabeled
`regorafenib x 1
`dose
`160 mg x 1
`dose
`
`Study Population
`
`Assessment
`
`Status
`
`Advanced solid
`tumors (n=54)
`Healthy men
`(n=24)
`
`Healthy men
`(n=48)
`
`Healthy men
`(n=4)
`
`QTc interval prolongation Ongoing
`
`Food effect
`
`Completed
`
`Relative bioavailability
`
`Completed
`
`ADME
`
`Completed
`
`Healthy men
`(n=24)
`
`Drug interaction with
`ketoconazole
`
`Completed
`
`Completed
`
`Completed
`
`Completed
`
`Completed
`
`
`
`
`
`
`
`15524
`
`Open label
`
`160 mg x 1
`dose
`
`Healthy men
`(n=24)
`
`Drug interaction with
`rifampin
`
`14596
`
`11726
`
`Open label
`(phase 2)
`
`160 mg once
`daily x 21 days
`
`Open label
`(phase 2)
`
`160 mg once
`daily x 21 days
`
`14387 Randomized,
`double blind,
`placebo
`controlled
`
`160 mg once
`daily x 21 daily
`
`Pharmacokinetics in
`White and Korean
`patients
`Pharmacokinetics
`
`Hepatocellular
`carcinoma
`(n=36)
`Renal cell
`carcinoma
`(n=48)
`Metastatic
`colorectal cancer
`(n=705)
`
`Overall survival
`Progression free survival
`Overall response rate
`Disease control rate
`Patient reported outcomes
`Duration of response
`Duration of stable disease
`Safety
`Pharmacokinetics
`Biomarkers
`What is the basis for selecting the response endpoints or biomarkers and how
`are they measured in clinical pharmacology and clinical studies?
`The primary endpoint of the clinical safety and efficacy trial was OS defined as the time (days)
`from randomization to death due to any cause. Patients alive at the time of analysis were
`censored at their last date known to be alive. As stated in the FDA Guidance for Industry
`“Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics”, OS is considered
`the most reliable cancer endpoint, and when studies can be conducted to adequately assess
`survival, it is usually the preferred endpoint. The secondary endpoints included progression free
`survival (PFS), overall response rate (ORR) and disease control rate (DCR).
`
`2.2.2
`
`NDA 203-085 Regorafenib/Stivarga
`
`Reference ID: 3194666
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`Page 12 of 45
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`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. Regorafenib and the active metabolites M2 and M5 were appropriately identified and
`measured in human plasma samples to assess the PK parameters [see Section 2.6 Analytical
`Methods].
`2.2.4 Exposure-response
`2.2.4.1
`What are the characteristics of the exposure-response relationships (dose-
`response, concentration-response) for efficacy?
`The applicant proposes to submit an E-R analysis for Study 14387 post marketing.
`Based on the initial analysis conducted in Study 11650, no clear E-R relationship was observed
`for regorafenib, M2 or M5 between exposure (AUC and Cmax) and selected indices of safety or
`clinical activity. The absolute and relative changes from baseline for plasma VEGF levels
`indicate an overall increase in systemic levels and for sVEGFR2 levels indicate an overall
`decrease in systemic levels. A dose-response relationship was observed for sVEGFR2 levels as
`sVEGFR levels declined relative to baseline with a greater effect observed for daily doses of
`≥ 60 mg.
`2.2.4.2
`
`What are the characteristics of the exposure-response relationships (dose-
`response, concentration-response) for safety?
`See Section 2.2.4.1. Exposure-response.
`2.2.4.3 Does this drug prolong the QT or QTc interval?
`Regorafenib, M2 and M5 inhibited the hERG K+ current with an IC50 value of 27 μM [PH-
`33109], 1.4 μM [PH-35502] and 1.8 μM [PH-35519], respectively. Regorafenib demonstrated
`no effect on the cardiac action potential in rabbit Purkinje fibers [PH-33827] and no effect on
`ECG intervals in Beagle dogs after oral or intravenous administration [Reports PH-33963, PH-
`35619, PH-34580, PH-34182, A45739]. M2 and M5 demonstrated no effect on QT intervals in
`Beagle dogs after intravenous infusions [PH-35628 and PH-35620].
`The applicant included an interim analysis of the QT/QTc intervals recorded from 25 patients
`with advanced solid tumors enrolled in Study 14814. The final study report for this dedicated
`cardiovascular safety study will be submitted post marketing. No changes in the QTcF interval
`were observed throughout treatment in patients with mCRC enrolled into the clinical safety and
`efficacy trial (Figure 1, Table 2).
`
`NDA 203-085 Regorafenib/Stivarga
`
`Reference ID: 3194666
`
`Page 13 of 45
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`Table 2. Summary of the QTcF interval measurements observed in Study 14387
`
`Figure 1. The QTcF measured in patients enrolled into Study 14387 after administration of
`placebo or regorafenib
`
`
`
`
`
`2.2.4.4
`
`Is the dose and dosing regimen selected by the applicant consistent with the
`known relationship between dose-concentration-response, and is there any
`unresolved dosing or administration issues?
`The applicant did not conduct an E-R analysis in the clinical safety and efficacy trial. Two
`individual dose escalation studies with either intermittent (the first 21 days of each 28-day
`treatment cycle) or continuous daily dosing were completed. The applicant selected the
`intermittent dosing regimen based on the following considerations:
`• The safety profile is similar for the intermittent and continuous dosing.
`• The intermittent dosing leads to higher total dose/cycle, higher steady-state concentrations
`and a robust DCR.
`
`NDA 203-085 Regorafenib/Stivarga
`
`Reference ID: 3194666
`
`Page 14 of 45
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`• The intermittent dosing provides patients with an opportunity to recover partially from
`potential adverse events.
`2.2.5 What are the PK characteristics of the drug and its major metabolite?
`2.2.5.1 What are the single dose and multiple dose PK parameters?
`In Study 11650, the following parameters were calculated for patients administered a dose of 160
`mg once daily for 21 days after a light breakfast. PK samples