CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203085Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`
` Stivarga (regorafenib)
`
`Date: September 10, 2012
`To: File for NDA 203085
`From: John K. Leighton, PhD, DABT
`
`Acting Director, Division of Hematology Oncology Toxicology
`
`Office of Hematology and Oncology Products
`
`
` I
`
` have examined pharmacology/toxicology supporting review of Drs. Goheer and
`McDougal and secondary memorandum and labeling provided by Dr. Helm. I
`concur with Dr. Helm’s conclusion that Stivarga may be approved and that no
`additional nonclinical studies are needed for the proposed indication.
`
`Reference ID: 3186473
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN K LEIGHTON
`09/10/2012
`
`Reference ID: 3186473
`
`

`

`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`
`Application number:
`Supporting document/s:
`
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`
`Review Division:
`
`Reviewer:
`
`203-085
`IND 75,642, EDR Location:
`\\CDSESUB1/EVSPROD\NDA203085\203085.enx
`April 30, 2012
`April 30, 2012
`Regorafenib (Stivarga®)
`Metastatic colorectal cancer
`Bayer Healthcare Pharmaceuticals, Inc.
`340 Changebridge Road
`Pine Brook, NJ 07058
`Division of Hematology Oncology Toxicology
`(Division of Oncology Products 2)
`M. Anwar Goheer, Ph.D.
`Andrew McDougal, Ph.D., D.A.B.T.
`Supervisor/Team Leader: Whitney S. Helms, Ph.D.
`Division Director:
`John Leighton, Ph.D.
`(Patricia Keegan, M.D.)
`Monica L. Hughes
`
`Project Manager:
`Disclaimer
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203-085 are owned by Bayer or are data for which
`Bayer has obtained a written right of reference.
`Any information or data necessary for approval of NDA 203-085 that Bayer does not
`own or have a written right to reference constitutes one of the following: (1) published
`literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as
`described in the drug’s approved labeling. Any data or information described or
`referenced below from a previously approved application that Bayer does not own (or
`from FDA reviews or summaries of a previously approved application) is for descriptive
`purposes only and is not relied upon for approval of NDA 203-085
`
`Reference ID: 3186302
`
`1
`
`

`

`Reviewers: Anwar Goheer, Ph.D.
`NDA # 203085
` Andrew McDougal, Ph.D., D.A.B.T.
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 8
`1.1
`INTRODUCTION.................................................................................................... 8
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 8
`1.3 RECOMMENDATIONS.......................................................................................... 11
`1.3.3
`LABELING...................................................................................................... 11
`
`2 DRUG INFORMATION .......................................................................................... 11
`2.1 DRUG............................................................................................................... 11
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS ....................................................... 12
`2.3 DRUG FORMULATION ......................................................................................... 12
`2.4 COMMENTS ON NOVEL EXCIPIENTS NONE .......................................................... 13
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 13
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 14
`2.6
`2.7 REGULATORY BACKGROUND: ............................................................................. 14
`3 STUDIES SUBMITTED.......................................................................................... 14
`3.1
`STUDIES REVIEWED........................................................................................... 14
`3.2
`STUDIES NOT REVIEWED ................................................................................... 18
`PREVIOUS REVIEWS REFERENCED...................................................................... 22
`3.3
`4 PHARMACOLOGY................................................................................................ 22
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 22
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 34
`4.3
`SAFETY PHARMACOLOGY................................................................................... 35
`5 PHARMACOKINETICS/ADME/TOXICOKINETIC................................................. 55
`5.1
`PK/ADME........................................................................................................ 55
`TOXICOKINETICS (INCLUDED IN TOXICITY STUDIES) ............................................... 71
`5.2
`6 GENERAL TOXICOLOGY..................................................................................... 72
`6.1
`SINGLE-DOSE TOXICITY..................................................................................... 72
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 72
`7 GENETIC TOXICOLOGY .................................................................................... 105
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)..................... 105
`7.1
`7.2
`IN VITRO ASSAYS IN MAMMALIAN CELLS............................................................ 108
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)................ 112
`7.3
`7.4 OTHER GENETIC TOXICITY STUDIES.................................................................. 120
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 154
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 154
`9.1
`EMBRYONIC FETAL DEVELOPMENT .............................................................................. 154
`PRENATAL AND POSTNATAL DEVELOPMENT.................................................................. 173
`
`Reference ID: 3186302
`
`2
`
`

`

`Reviewers: Anwar Goheer, Ph.D.
`NDA # 203085
` Andrew McDougal, Ph.D., D.A.B.T.
`SPECIAL TOXICOLOGY STUDIES................................................................. 173
`10
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 174
`
`APPENDIX/ATTACHMENTS........................................................................... 185
`
`11
`
`12
`
`
`Reference ID: 3186302
`
`3
`
`

`

`Reviewers: Anwar Goheer, Ph.D.
`NDA # 203085
` Andrew McDougal, Ph.D., D.A.B.T.
`Table of Tables
`
`Table 1: Kinase IC50 values for regorafenib, M-2 and M-5 (report # A57121) ............... 23
`Table 2: Selected KD values for regorafenib (report # A58227)..................................... 26
`Table 3: Regorafenib inhibited cell proliferation in vitro (report # A58229).................... 29
`Table 4: M-2 slightly increased body temperature in a rat behavioral safety
`pharmacology study (report # PH-35438) ....................................................... 42
`Table 5: Dog PK parameters following single intraduodenal doses of regorafenib (report
`# PH-33963).................................................................................................... 46
`Table 6: Dog PK parameters following intravenous infusion of regorafenib (report # PH-
`35619)............................................................................................................. 48
`Table 7: Blood glucose levels in rats after acute oral dosing with regorafenib (report #
`PH-33925)....................................................................................................... 53
`Table 8: Regofaneib slowed the intestinal transit of barium sulfate in rats (report # PH-
`33841)............................................................................................................. 54
`Table 9: Binding of BAY 73-4506 to plasma proteins of selected species..................... 57
`Table 10: Stability in plasma of different species at 37 °C after 2 h of incubation. ....... 57
`Table 11: Binding of BAY 73-4506 to human plasma proteins at different pH.............. 58
`Table 12: Reversibility of protein binding of BAY 73-4506 in vitro................................ 58
`Table 13: In vitro partitioning of BAY 73-4506 between plasma and blood cells .......... 58
`Table 14: Qualitative Distribution of Regorafenib ......................................................... 60
`Table 15: Pharmacokinetic parameters of pregnant Wistar rats.................................... 63
`Table 16: Equivalent concentrations (µg-eq/L) of radioactivity of pregnant Wistar rats
`and fetuses at various observation times ...................................................... 64
`Table 17: Ratios of equivalent concentrations and AUCs of radioactivity in selected
`organs / body fluids of pregnant Wistar rats and fetuses .............................. 64
`Table 18: Metabolite profiles after 60 minute incubations with liver microsomes of
`different species ............................................................................................ 65
`Table 19: Metabolite profiles after 180 minute incubations with liver microsomes of
`different species ............................................................................................ 65
`Table 20: Equivalent concentrations [μg-eq/L] of total radioactivity in milk and plasma.
`...................................................................................................................................... 68
`Table 21: Summary PK parameters of total radioactivity derived from equivalent
`concentrations [μg-eq/L] in milk and plasma, and corresponding milk/plasma
`concentration ratios....................................................................................... 69
`Table 22: Comparison of cumulative excretion data of radioactivity in per cent of the
`administered dose......................................................................................... 70
`Table 23: Body Weights (26 Week Rat, Main Groups)................................................. 73
`Table 24: Main Group Hematology (26 Week Rat) ....................................................... 75
`Table 25: Main Group Clinical Chemistry (26 Week Rat)............................................. 76
`Table 26: Histological Findings (26-Week Rat) ............................................................. 77
`Table 27: Summary of Pharmacokinetic Parameters on Day 1 and 182 (Rat 26-Week)
`...................................................................................................................................... 77
`Table 28: Mean body weights (kg) 13 week dog .......................................................... 79
`Table 29: Clinical chemistry (Med ± S.D) ...................................................................... 80
`Table 30: Summary of organ-to-body weight ratios (Mean±S.D.) (13 week dog).......... 81
`
`Reference ID: 3186302
`
`4
`
`

`

`NDA # 203085
`
`Reviewers: Anwar Goheer, Ph.D.
`
`Andrew McDougal, Ph.D., D.A.B.T.
`
`Table 31: 13 Week Dog Histological Findings ............................................................... 81
`Table 32: Toxicokinetics (13-week Dog) ...................................................................... 84
`Table 33: Blood pressure (mmHg) on week 51 of treatment (52 Week Dog Study) ...... 87
`Table 34: ECG Parameters (Week 51 of treatment relative to start date-52 Week Dog
`Study) ............................................................................................................ 88
`Table 35: Clinical test of nervous system function in the dog ........................................ 89
`Table 36: Hematology Findings (52-Week Dog) .......................................................... 90
`Table 37: Clinical Chemistry-Week 52 Values (52 Week Dog) .................................... 90
`Table 38: Mean values of thyroid hormone analysis, males and females combined (52
`Week Dog) .................................................................................................... 91
`Table 39: Bone Marrow Smear Findings (52-Week Dog) ............................................. 91
`Table 40: Gross Pathology (52 Week Dog) .................................................................. 92
`Table 41: The exposure to BAY73—4506 on day 354 (52-week dog) ............................ 95
`Table 42: Cumulative and mean daily food intake (M-5 Study) ..................................... 97
`Table 43: Histological Findings - Terminal sacrifice (M-5 Study) .................................. 98
`Table 44: Toxicokinetics (M-5 Study) ........................................................................... 99
`Table 45: Mean Food Intake (M-2 Study) ................................................................... 101
`Table 46: Hematology Findings (M-2 Study) .............................................................. 101
`Table 47: Clinical Chemistry (M-2 Study) .................................................................... 102
`Table 48: Toxicokinetics (M-2 Study) ......................................................................... 103
`Table 49: Clinical Observations after the First Administration of Regorafenib ............ 114
`Table 50: Clinical Observations after the Second Administration of Regorafenib ....... 115
`Table 51: Mouse micronucleus assay - Negative control ........................................... 118
`Table 52: Mouse micronucleus assay - 2 x 500 mglkg BAY 73-4506 ......................... 118
`Table 53: Mouse micronucleus assay - 2 x 1000 mglkg BAY 73-4506 ....................... 118
`Table 54: Mouse micronucleus assay — 2 x 2000 mglkg BAY 73—4506 ...................... 119
`Table 55: Mouse micronucleus assay — 1 x 20 mglkg i.p. cyclophosphamide ........... 119
`Table 56: Summary of In Vivo Micronucleus assay results ........................................ 119
`Table 57: Summary of mean values without 89 in M-2 Ames Assay ......................... 121
`Table 58: Summary of mean values with S9 in M-2 Ames Assay .............................. 121
`Table 59: First experiment without 39 Mix (M-5 Ames) ............................................... 126
`Table 60: First experiment with 89 Mix (M-5 Ames) ................................................... 126
`Table 61: Final experiment without S9 Mix (M-5 Ames) ............................................. 126
`Table 62: Final experiment with 89 Mix (M-5 Ames) .................................................. 127
`Table 63: Survival index — 4 hours treatment (M-5 CHO) ........................................... 128
`Table 64: Mitotic index — 4 hours treatment (M-5 CHO) .............................................. 129
`Table 65: Aberrations without SQ mix — 4 hours treatment, 18 hours harvest (M-5 CHO)
`.................................................................................................................................... 129
`
`Table 66
`
`Table 67
`
`Table 68
`
`Table 69
`
`Table 70
`
`Table 71
`
`Table 72
`
`: Aberrations with 89 mix — 4 hours treatment, 18 hours harvest (M-5 CHO) 130
`: Aberrations without and with S9 mix — 4 hours treatment, 30 hours harvest
`(M-5 CHO)................................................................................................... 131
`: Survival index — 18 hours treatment (M-5 CHO) .......................................... 132
`: Mitotic index — 18 hours treatment (M-5 CHO) ........................................... 132
`: Aberrations without SQ mix — 18 hours treatment (M-5 CHO) .................... 133
`: Direct plate incorporation without 89 (
`m" 134
`: Direct plate incorporation with 89 (
`"’m’ 134
`
`Reference ID: 31 86302
`
`5
`
`

`

`NDA # 203085
`
`Reviewers: Anwar Goheer, Ph.D.
`
`Andrew McDougal, Ph.D., D.A.B_T.
`
`M“) 135
`Table 73: Preincubation test without 89 (
`"’"" ................................... 135
`Table 74: Pre-incubation test with $9(
`“m ........... 137
`Table 75: Summary of mean values without 89 mix (
`Table 76: Experiment 1 - Direct plate incorporation - Mean vales with and without 39
`mix (
`“’"" __________________________________________________________________________________ 139
`Table 77: Experiment 2 (preincubation for 20 min.) — Mean vales with and without 89
`mix (
`W" .................................................................................. 140
`Table 78: Experiment 1 — Summary of mean values without and with 89 mix ........... 142
`Table 79: Experiment 2 - Summary of mean values without and with SQ mix
`“’m’
`143
`"M" ............................................ 145
`Table 80: Mitotic Index-4 hrs (
`W" 146
`Table 81: Survival Index-4 hrs (
`“M"
`Table 82: Chromosomal Aberration w/o metabolic Activation—4 hrs
`........................................................................................................ 147
`
`“m
`Table 83: Chromosomal Aberration with metabolic Activation-4 hrs
`........................................................................................................ 147
`Table 84: Chromosomal Aberrations with and without metabolic Activation—4 hrs (:2;
`............................................................................... 148
`Table 85: Bone marrow micronucleus test (
`m“) 151
`Table 86: Liver Comet Assay with high doses of
`W" ................................. 152
`Table 87: Liver Comet Assay with low doses of
`M“) 153
`Table 88: Regorafanib affected body weight gain in pregnant rats (report # PH-36547)
`.................................................................................................................................... 1 57
`
`Table 89: Placental changes noted in pregnant rats receiving regorafenib (report # PH-
`36547) ......................................................................................................... 1 58
`Table 90: Regorafenib caused post-implantation losses in pregnant rats (report # PH-
`36547) ......................................................................................................... 1 59
`Table 91: Regorafenib exposure associated with rat fetal external anomalies (report #
`PH-36547) ................................................................................................... 1 61
`Table 92: Regorafenib exposure associated with rat fetal visceral anomalies (report #
`PH-36547) ................................................................................................... 1 61
`Table 93: Regorafenib exposure associated with rat fetal skeletal anomalies (report #
`PH-36547) ................................................................................................... 1 62
`Table 94: The initiation of regorafenib-dosing was associated with a transient increase
`in food consumption in pregnant rabbits (report # PH-36036) ..................... 166
`Table 95: PK summary for pregnant rabbits (report # PH—36036) ............................... 167
`Table 96: Regorafenib caused adverse placental changes in pregnant rabbits (report #
`PH-36036) ................................................................................................... 1 68
`Table 97: Selected reproductive endpoints from regorafenib-treated pregnant rabbits
`(report # PH-36036) .................................................................................... 169
`Table 98: Selected malformation data (external and visceral malformations) from the
`rabbit embryofetal study (report # PH-36036) ............................................. 171
`Table 99: Selected fetal skeletal observations from the rabbit embryofetal study (report
`# PH-36036) .................................................................................................. 172
`
`Reference ID: 31 86302
`
`6
`
`

`

`Reviewers: Anwar Goheer, Ph.D.
`NDA # 203085
` Andrew McDougal, Ph.D., D.A.B.T.
`Table of Figures
`
`Figure 1: Regorafenib (10 mg/kg/day orally) prolonged survival in mice bearing
`implanted hepatomas (report # A58231)....................................................... 33
`Figure 2: Slight transient plasma sodium elevation in regorafenib-treated dogs (report #
`PH-3393)......................................................................................................... 46
`Figure 3: Assumed metabolic fate of the parent drug.................................................... 66
`Figure 4: Radioactivity from Regorafenib in Rat Plasma and Milk................................ 68
`Figure 5: Body Weight (M-2 Study) ............................................................................. 100
`
`
`Reference ID: 3186302
`
`7
`
`

`

`Reviewers: Anwar Goheer, Ph.D.
`NDA # 203085
` Andrew McDougal, Ph.D., D.A.B.T.
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`New Drug Application (NDA) 203-085 was submitted to the U.S. Food and Drug
`Administration for evaluation for full approval of regorafenib (Stivarga®) for the
`treatment of patients with metastatic colorectal cancer. Regorafenib is a new molecular
`entity kinase inhibitor, which inhibits multiple membrane bound and intracellular kinases
`involved in a wide range of normal cellular functions and in pathologic processes such
`as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.
`The recommended dose of regorafenib for the treatment of metastatic colorectal cancer
`(CRC) is 160 mg (4 tablets) daily for 3 weeks followed by 1 week off therapy to
`comprise a cycle of 4 weeks. Nonclinical pharmacology, pharmacokinetic and
`toxicology studies have been submitted to support the approval of regorafenib for the
`proposed indication.
`
`1.2 Brief Discussion of Nonclinical Findings
`Nonclinical primary pharmacology studies were designed to evaluate the
`mechanism of action and activity of regorafenib. Regorafenib and two metabolites of the
`drug present at high levels in human serum, M-2 and M-5, were tested in either
`biochemical assays or in cellular assays examining the phosphorylation of downstream
`targets. Kinases inhibited at the lowest concentrations of regorafenib included RET and
`several RET variants, PTK5, VEGFR-1,-2, and -3, FGFR-1 and -2, DDR2, SAPK2, Lyn,
`Tie2, Abl, TrkA, EphA2, KIT and several Kit variants, c-RAF, BRAF, and BRAFV600E.
`With each of these kinases, both the M-2 and M-5 metabolites showed inhibitory activity
`that was similar to and occasionally higher than the activity of the regorafenib parent
`compound.
`Regorafenib also exhibited activity in in vivo studies performed in mice and rats.
`An in vivo experiment specifically examining potential anti-VEGF activity was conducted
`with both regorafenib and the M-2 and M-5 metabolites. At a dose level of 1 mg/kg,
`regorafenib and each of its metabolites were able to prevent VEGF-induced reduction of
`blood pressure in cathetized Wister rats. Non-VEGF specific effects of regorafenib on
`angiogenesis were also analyzed using magnetic resonance imaging (MRI) to
`determine the amount of tumor blood vessel development in regorafenib-treated rats
`implanted with exogenous tumors. Decreased MRI signals in tumors from rats treated
`with either regorafenib or the M-2 metabolite suggest that the drug has anti-angiogenic
`activity. Regorafenib also showed anti-tumor activity, primarily inhibition of tumor
`growth, in several mouse tumor implant models including some investigating the drug’s
`activity against CRC cell lines.
`Target organs for regorafenib-mediated toxicity identified in toxicology studies
`conducted using rats and dogs included the liver, kidney, adrenal gland, thyroid,
`pancreas, gastrointestinal tract, hematopoietic/lymphoid system, reproductive system,
`and skeletal system. Findings of changes in dentin and epiphyseal growth plates were
`present in both species. These changes have been associated with many VEGF
`inhibitors and may be relevant to a pediatric population. Evidence of gastrointestinal
`
`Reference ID: 3186302
`
`8
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`

`

`Reviewers: Anwar Goheer, Ph.D.
`NDA # 203085
` Andrew McDougal, Ph.D., D.A.B.T.
`toxicity included findings of liquid feces/blood in the feces, vomiting of whitish/yellowish
`mucus/foam/watery liquid/food mash in the 13-week dog study at doses resulting in
`regorafenib exposures approximately 50% of the exposure in humans. A single dose
`study in rats also demonstrated decreases in gastric motility following administration of
`regorafenib. In the hematopoietic system there were findings of bone marrow
`hypocellularity, atrophy of the spleen, lymph nodes, and thymus in rats at doses
`resulting in exposures similar to the exposure in humans at the recommended daily
`dose. In dogs, thymic atrophy was observed at the high dose levels in all studies;
`atrophy was also observed in lymph nodes. Both rats and dogs had histopathological
`findings in the liver along with elevations in liver enzymes noted in short and long term
`repeat dose toxicology studies. Hematological changes including neutropenia,
`thrombocytopenia, and lymphopenia as well as elevations in liver enzymes were seen
`clinically and hepatotoxicity is included in a black box warning for Stivarga.
`
`Skin toxicity was observed in dogs at all dose levels of regorafenib administration
`in a 13-week study. Toxicity was evidenced by histopathological findings of
`dyskeratosis, hyperkeratosis, acanthosis, and dermatitis, along with hair growth arrest.
`Similarly, in a 52-week study, dogs displayed dose-dependent increases in findings of
`fur and skin/mucosa alteration (hair loss, abscess like lesions). Administration of
`regorafenib to both rats and dogs also resulted in increases in thyroid stimulating
`hormone (TSH). In rats this change was accompanied by an increase in thyroxine (T4)
`levels at doses approximately 40% higher than those observed in humans. In dogs the
`change in TSH (up to 7 fold higher than levels in control animals) was not accompanied
`by increases triiodothyronine (T3) and (T4) but was observed in high dose animals from
`Week 6 onwards in a 52-week study; at this dose level regorafenib exposure in dogs
`was approximately 53% of the human exposure at the recommended daily dose. Skin
`toxicity and rising TSH levels have been reported clinically as well.
`
`Renal toxicity was observed in all repeat-dose toxicology studies conducted with
`regorafenib. Renal findings in rats and dogs included glomerulpathy, tubular
`degeneration/regeneration, tubular dilation, and interstitial fibrosis. No renal toxicity was
`noted in 1-month studies with either the M-2 or the M-5 metabolite which suggests that
`differences in metabolism between humans, rats, and dogs leading to significantly
`higher human exposures to M-2 and M-5 compared to the species used for toxicological
`assessment may account for higher levels of renal toxicity seen in animals compared to
`humans in trials conducted to support marketing.
`Cardiovascular safety was examined in both single and repeat-dose toxicology
`studies in dogs. In repeat-dose studies conducted in rats there histopathological
`findings in the heart including perivascular/interstial edema and pericarditis in the 4-
`week rat study and thickening of the atrioventricular valve in the 26-week rat study. In
`dogs none of the studies revealed significant changes in ECG parameters. In in vitro
`experiments regorafenib itself showed low potential for QTc prolongation with no
`prolongation of action potential duration in a Purkinje fiber assay and an IC50 of 27μM in
`the hERG assay; however, the M-2 and M-5 metabolites had IC50s of 1.1 and 1.8 μM,
`respectively, in the hERG assay suggesting a considerably higher potential for QTc
`prolongation. The M-2 and M-5 metabolites were not present in rats or dogs at
`significant levels, thus the animal studies may have underpredicted the potential for
`regorafenib induced QTc prolongation in humans. To address this issue, single dose
`
`Reference ID: 3186302
`
`9
`
`

`

`Reviewers: Anwar Goheer, Ph.D.
`NDA # 203085
` Andrew McDougal, Ph.D., D.A.B.T.
`cardiovascular safety studies in dogs were conducted using each of the metabolites;
`however, there were no clearly adverse effects noted for either metabolite in these
`studies and in 1-month repeat-dose toxicology studies conducted in mice using each of
`the metabolites, no unique toxicities compared to those observed in animals
`administered regorafenib were identified.
`Dedicated studies examining fertility and pre- and post-natal development were
`not conducted to support the treatment of patients with advanced cancer. In general
`toxicology studies, female rats administered regorafenib at dose levels resulting in
`exposures similar to those observed in humans at the clinically recommended dose had
`histopathological findings of increased necrotic corpus lutea and atrophy in the ovaries
`and uterus. Males in the same dose group had increases in histopathological findings
`of mononuclear infiltration and cellular debris as well as decreased weight of the testes,
`prostate, and seminal vesicles compared to control animals. Findings in the
`epididymides had not resolved by the end of the recovery period; there were also
`findings of tubular atrophy and degeneration in the testes and atrophy of the seminal
`vesicles noted at the end of the 4 week recovery period in these animals. Similarly, in
`13-week studies conducted in male dogs at dose levels ≥ 400 mg/m2 (approximately
`half of the human exposure at the clinically recommended dose of 160 mg/day by AUC)
`had histopathological findings of retarded maturation of the testes along with
`aspermia/oligospermia in the epididymides. In females, findings of reduced follicular
`development and increased follicular degeneration were noted at the same dose levels.
`These findings suggest that regorafenib could affect fertility in humans.
`Embryofetal studies were conducted in Wistar rats and Himalayan rabbits. In
`both species, at doses resulting in exposures significantly lower than the human
`exposure at the recommended daily dose, there were increases in post-implantation
`loss and teratogenic effects including skeletal and cardiovascular malformations and
`renal findings of dilation of the renal pelvis or hydronephrosis. Total resorption of litters
`in rats was sometimes observed at dose levels resulting in exposures as low as
`approximately 10% of the exposure in humans at the recommended dose. Pregnancy
`category D is recommended.
`In a distribution study in pregnant rats that were administered radiolabelled
`regorafenib there was clear exposure to the fetus. Exposure in the fetal adrenal glands
`exceeded the maternal blood concentration. Fetal brain concentration exceeded the
`maternal brain concentration by 2-fold indicating significantly higher penetration of the
`blood/brain barrier in the fetus compared to the dam. In the mammary gland exposure
`was approximately 2-fold higher than that in maternal blood correlating with a finding of
`high levels of radiolabelled regorafenib or its metabolites secreted in milk observed in a
`dedicated excretion study performed in rats. These studies suggest a high risk for
`neonatal exposure to regorafenib in breast milk from women taking Stivarga.
`
`Regorafenib was not mutagenic in in vitro or in vivo assessments of genotoxicity;
`however, the M-2 metabolite was clastogenic in an in vitro assay suggesting that the
`drug may have mutagenic potential in humans. No carcinogenicity studie