CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203085Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`NDA 203085
`
`Cross—Discipline Team Leader Review
`
`
`Date
`10 Sep 2012
`, M.D., M.H.S.
`From
`Steven Leme
`rm_——
`
`
`PDUFA Goal Date
`27 Oct 2012
`
`(b) (4)
`
`Proprietary Name /
`Established Name
`
`D . R .
`osmg egimen
`
`Proposed Indication(s)
`
`Recommended:
`
`.
`.
`Stivarga / regorafemb
`
`160 mg regorafenib (four 40 mg tablets) taken orally once
`dail
`for the first 21 da 3 of each 28-da c cle.
`
`Regorafenib is indicated for the treatment of patients with
`metastatic colorectal cancer (CRC) who have been
`previously treated with,
`fluoropyrimidine-based chemotherapy, an anti-VEGF
`thera o
`, and, if KRAS wild pe, an anti-EGFR thera o
`Approvalpendingfinal agreement on labeling and Post-
`Marketm Re mrements
`
`Table of Contents
`
`1. Introduction .............................................................................................................................. 4
`
`1.1 One versus two trials ...................................................................................................... 4
`
`1.2 Clinical-pharmacology submission................................................................................ 5
`1.3 Food effects .................................................................................................................... 6
`
`2. Background .............................................................................................................................. 6
`2.] Disease and therapy related issues ................................................................................. 6
`2.2 US. regulatory history ................................................................................................... 9
`2.3 Application history....................................................................................................... ll
`3. CMC ....................................................................................................................................... 12
`
`3.] Drug substance review ................................................................................................. 12
`3.2 Drug product review .................................................................................................... 12
`3.3 Biopharmaceutics review ............................................................................................. 13
`3.4 Manufacturing inspections ........................................................................................... l3
`4. Nonclinical Pharmacology/Toxicology ................................................................................. l3
`5. Clinical Pharmacology ........................................................................................................... 14
`5.1 General clinical pharmacology considerations ............................................................ 14
`5.1.1 Dose selection ........................................................................................................... 14
`
`5.1.2 Pharmacokinetics ...................................................................................................... 15
`
`5.1.3 Food effects ............................................................................................................... 16
`
`5.2 Drug-drug interactions ................................................................................................. 17
`5.3 Demographic interactions/special populations ............................................................ 17
`5.4 Thorough QT study or other QT assessment ............................................................... 17
`5.5 Biomarker assessments ................................................................................................ 17
`
`Page 1 of 41
`
`Reference ID: 3186716
`
`1
`
`

`

`Cross Discipline Team Leader Review
`
`
`
`NDA 203085
`
`6. Clinical Microbiology............................................................................................................18
`7. Clinical/Statistical-Efficacy ...................................................................................................18
`7.1 Background of clinical program ..................................................................................18
`7.2 Design of Bay 73-4506/14387.....................................................................................18
`7.2.1 Primary endpoint.......................................................................................................18
`7.2.2 Secondary endpoints .................................................................................................18
`7.2.3 Eligibility criteria......................................................................................................19
`7.2.4 General study design/treatment plan.........................................................................19
`7.2.5 Statistical design and analysis issues ........................................................................20
`7.3 Summary results...........................................................................................................22
`7.3.1 Demographics ...........................................................................................................22
`7.3.2 Disposition................................................................................................................23
`7.3.3 OS analyses...............................................................................................................23
`7.3.4 Secondary endpoints .................................................................................................26
`8. Safety .....................................................................................................................................27
`8.1 Adequacy of database ..................................................................................................27
`8.2 Deaths, SAEs, discontinuations due to AEs, general AEs, and results of laboratory
`tests ....................................................................................................................................28
`8.2.1 Deaths .......................................................................................................................28
`8.2.2 SAEs .........................................................................................................................28
`8.2.3 Drop-outs and discontinuations due to adverse events.............................................29
`8.2.4 Common adverse events ...........................................................................................29
`8.2.5 Laboratory tests.........................................................................................................30
`8.3 Special safety concerns................................................................................................31
`8.3.1 Drug-demographic interactions ................................................................................31
`8.3.2 Additional in-depth analyses of specific events........................................................32
`8.4 Discussion of primary reviewer’s findings and conclusions .......................................32
`9. Advisory Committee Meeting................................................................................................33
`10. Pediatrics..............................................................................................................................33
`11. Other Relevant Regulatory Issues........................................................................................34
`11.1 Application Integrity Policy (AIP).............................................................................34
`11.2 Financial disclosures..................................................................................................34
`11.3 GCP issues .................................................................................................................34
`11.4 OSI audits...................................................................................................................35
`11.5 Other discipline consults............................................................................................35
`11.5.1 DRISK.....................................................................................................................35
`11.5.2 DMEPA...................................................................................................................35
`11.5.3 Pediatric and Maternal Health Staff review............................................................35
`11.5.4 Predictive Safety consult.........................................................................................35
`11.6 Drug name review......................................................................................................36
`12. Labeling ...............................................................................................................................36
`13. Recommendations/Risk Benefit Assessment.......................................................................38
`13.1 Recommended regulatory action ...............................................................................38
`13.2 Risk-benefit assessment.............................................................................................39
`13.3 Recommendation for postmarketing Risk Evaluation and Management Strategies..40
`13.4 Recommendation for other postmarketing requirements and commitments .............40
`
`Page 2 of 41
`
`Reference ID: 3186716
`
`2
`
`

`

`Cross Discipline Team Leader Review
`
`
`
`NDA 203085
`
`
`
`Table of Figures
`Figure 1 K-M curves for OS, Bay 73-4506/14387 ....................................................................24
`Figure 2 K-M curves for PFS, Bay 73-4506/14387...................................................................27
`
`
`Table of Tables
`Table 1 Summary of efficacy results ...........................................................................................4
`Table 2 FDA approved drugs for the treatment of patients with CRC ........................................7
`Table 3 Regimens used to treat mCRC........................................................................................8
`Table 4 Amendments to NDA 203085 (as of the date of the completion of this review) .........11
`Table 5 Amendments to Bay 73-4506/14387 ............................................................................21
`Table 6 Demographics, Bay 73-4506/14387 .............................................................................22
`Table 7 Disease characteristics at baseline, Bay 73-4506/14387 ..............................................22
`Table 8 Patient disposition, Bay 73-4506/14387.......................................................................23
`Table 9 OS analyses (ITT), Bay 73-4506/14387.......................................................................24
`Table 10 Subgroup analyses for OS, Bay 73-4506/14387.........................................................25
`Table 11 PFS analyses (ITT), Bay 73-4506/14387 ...................................................................26
`Table 12 Response rate (ITT), Bay 73-4506/14387 ..................................................................27
`Table 13 SAEs, Bay 73-4506/14387 .........................................................................................28
`Table 14 AEs leading to permanent discontinuation (≥ 1%), Bay 73-4506/14387...................29
`Table 15 Common AEs, Bay 73-4506/14387............................................................................30
`Table 16 Hematologic findings, Bay 73-4506/14387................................................................31
`Table 17 Liver function tests, Bay 73-4506/14387 ...................................................................31
`
`Page 3 of 41
`
`Reference ID: 3186716
`
`3
`
`

`

`Cross Discipline Team Leader Review
`
`NDA 203085
`
`1. Introduction
`
`FDA received NDA 203085 from Bayer on 27 Apr 2012 requesting marketing authorization
`(regular approval) for regorafenib (proposed trade-name Stivarga) for the treatment of patients
`with metastatic colorectal cancer (CRC) who have been previously treated with,
`ma)
`fluoropyrimidine—based chemotherapy, an anti—VEGF therapy, and,
`if KRAS wild type, an anti-EGFR therapy.
`
`Disclaimer: Any data or information described below that Bayer does not own (for example,
`summary data from other drugs used to treat patients with mCRC or other cancers) is included
`for descriptive purposes only. This information was not relied upon or necessary to make a
`decision regarding this application.
`
`The following section describes the primary issues identified during the review of this
`application:
`
`1.1 One versus two trials
`
`The primary issue considered during the review of this application was whether the results of a
`single adequate and well-controlled trial were suflicient to support approval. FDA Guidance
`1 Llflpi//www.fda.gov/downloads/Drugs/GuidanceComplianceReglilatoglnformation/Guidance
`s/ucm078749.pdf) identified characteristics that can contribute to the conclusion that results
`from a single study can support an efficacy claim. The characteristics identified were (a) large
`multicenter study; (b) consistency across study subsets; (c) multiple studies in a single study;
`((1) multiple endpoints involving different events; and (e) statistically very persuasive findings.
`Results of the Bay73—4506/11650 trial submitted in support of this NDA satisfied all of these
`characteristics except (c).
`
`Bay 73-4506/11650 was a large, randomized (2:1), multi-national trial that randomized 760
`patients with previously treated mCRC. Patients in Bay 73-4506/11650 received regorafenib
`plus best supportive care or placebo plus best supportive care. Table 1 (data obtained from the
`statistical review) summarizes the efficacy results from Bay 73-4506/11650. The results
`(demonstrating that regorafenib prolonged overall survival in patients with previously treated
`mCRC) were statistically robust and supported by consistent results in subgroup analyses.
`
`Table 1 Summa
`
`of efficac results
`
`— “‘“‘“‘°"“’
`
`N = 505
`
`N = 255
`
`Overall survival
`# of events
`
`275
`
`157
`
`1.7
`
`Median (in mos.) ”- 5-0
`Stratified HR 95% CI
`0.77 0.64, 0.94
`n value two-sided
`
`Pro 14 ession free survival (FDA ana sis)
`# of events
`
`231
`
`Median in mos.
`
`Page 4 of 41
`
`Reference ID: 3186716
`
`4
`
`

`

`Cross Discipline Team Leader Review
`
`NDA 203085
`
`N = 255 Stratified HR 95% C
`— “mm"
`
`0.49 0.42, 0.58
`
`N = 505
`
`The May 1998 FDA Guidance document also states that reliance on a single study will
`generally be limited to situations in which a trial has demonstrated a clinically meaningful
`effect on mortality, irreversible morbidity, or prevention of a disease with a potentially serious
`outcome and confirmation of the results in a second trial would be practically or ethically
`impossible.
`
`Bay 73-4506/11650 established that patients receiving regorafenib experienced a modest
`improvement in overall survival compared to placebo. Although one can reasonably argue
`whether a second trial could ethically be conducted in the third-line setting based on a median
`1.4 month improvement in OS, modest survival benefits have resulted in approval of cancer
`drugs in other settings (especially for patients who have terminal cancer and no adequate
`alternative therapies). Physicians and patients will need to individually consider whether the
`modest improvement in OS is of sufficient magnitude to offset the increased toxicity conferred
`by regorafenib.
`
`Unfortunately, biomarkers have not been identified that will allow for the selection of certain
`groups of patients who will benefit from treatment (or perhaps more importantly, who will not
`benefit from treatment). Given the modest effect size observed in Bay 73-4506/11650, this
`reviewer encourages Bayer to conduct additional research into identifying potential biomarkers
`that will allow for better selection of patients for treatment with regorafenib (i.e., to maximize
`benefit or to minimize harms in patients who will not benefit). At this time, however, based
`on the lack of a suitable candidate biomarker, a specific PMC cannot be recommended to
`conduct a pivotal clinical trial using a biomarker.
`
`1.2 Clinical—pharmacology submission
`
`This application did not contain exposure—response analyses fiom pivotal trial Bay 73-
`4506/14387, population pharmacokinetic analyses from Bay 73-4506/14387, final results from
`all drug-interaction studies, or final results from the dedicated cardiovascular safety study to
`assess effects on QT/QTc.
`
`OCP and DOP2 agreed to exercise regulatory discretion regarding the lack of complete
`pharmacology information in this NDA based on the following: completion of pivotal trial
`Bay 73-4506/14387 earlier than anticipated based on the pre—planned stopping rule; overall-
`survival effect in patients with late-stage metastatic colorectal cancer (without available
`treatment options); no QTc interval effects were observed in the analysis of preliminary data;
`and agreement by Bayer to submit this information (fiom ongoing and nearly complete
`studies) as PMRs and PMCs. Although not optimal, DOP2 and OCP were able to make a
`determination of the safety and effectiveness of regorafenib for this late-stage population (with
`an overall survival effect) based on the information submitted in the NDA.
`
`Page 5 of 41
`
`Reference ID: 3186716
`
`5
`
`

`

`Cross Discipline Team Leader Review
`
`
`
`NDA 203085
`
`1.3 Food effects
`The label proposed by Bayer instructs patients to take regorafenib with a low-fat meal. FDA
`initially acknowledged the uncertainty regarding food effects on the pharmacokinetics of
`regorafenib in a 22 Jan 2010 letter to Bayer.
`
`During the review of this application, OCP analyzed the results of a food effects study
`conducted in 24 healthy men. The study was a randomized, open-label, three-way crossover
`study to determine the effect of a high-fat breakfast, a low-fat breakfast, and fasting state on
`the PKs of a single 160 mg dose of regorafenib. Each study period was separated by a 14-day
`washout period and PK samples were collected up to 336 hours.
`
`OCP found that after a high-fat meal, the mean AUC of regorafenib was increased by 48% and
`the mean AUC of two active metabolites, M2 and M5, were decreased by 20% and 51%,
`respectively, resulting in an overall exposure approximately 8% lower as compared to the
`fasted state. OCP found that the low-fat breakfast increased the mean AUC of regorafenib by
`36% and the mean AUC of M2 and M5 by 40% and 23%, respectively, resulting in overall
`exposure approximately 33% higher as compared to the fasted state.
`
`Based on the available data, this reviewer agrees that the label should instruct patients to take
`regorafenib with a low-fat meal because patients enrolled in Bay 73-4506/14387 (pivotal trial)
`took regorafenib with a low-fat meal. Review staff recommended inclusion of examples of
`low-fat meals (that were contained within the Bay 73-4506/14387 protocol) in product
`labeling so that patients will be able to understand what types of foods constitute a low-fat
`meal.
`
`Due to the wide variability of diets in the U.S., these low-fat dosing instructions may introduce
`the possibility of increased variability in the exposure to regorafenib. Nevertheless, substantial
`evidence for effectiveness only exists for treatment with a low-fat meal. Additionally, in
`regards to regorafenib, substantial inter-patient variability in exposure also occurs in the
`fasting state (part of the reasoning to administer drugs with a narrow therapeutic index in the
`fasting state is to reduce variability).
`2. Background
`2.1 Disease and therapy related issues
`Bayer requested marketing authorization for regorafenib for the treatment of patients with
`metastatic colorectal cancer (mCRC) who have been previously treated with,
`
` fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and,
`if K-Ras wild type, an anti-EGFR therapy. In general, because mCRC is an incurable disease
`[with the notable exception of patients who have oligometastatic disease (usually hepatic)], the
`goal of treatment for these patients is to prolong life and/or improve quality of life (refer to the
`clinical review for details regarding the epidemiology of mCRC).
`
`Table 2 shows FDA approved drugs (in alphabetical order) for the treatment of patients with
`colorectal cancer. The table shows that FDA granted regular approval for most drugs intended
`to treat patients with mCRC based on demonstrated effects on overall survival (OS). For
`
`Page 6 of 41
`
`Reference ID: 3186716
`
`6
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`
`NDA 203085
`
`brevity, drugs no longer marketed in the US. (e.g., levamisole); no longer (or rarely) used in
`practice for mCRC [e.g., vincristine (component of MOF with fluorouracil and methyl-
`CCNU)]; indicated as a palliative regional intra-arterial treatment (e.g., floxuridine); approved
`more than 20 years ago (e.g., fluorouracil and leucovorin); or approved imder the 505(b)(2)
`pathway (e.g., levoleucovorin) were not included in the table.
`
`Table 2 FDA a t roved dru_s for the treatment of natients with CRC
`Date
`Indication
`A »
`. roved
`
`21V-
`
`03 Aug 12
`
`nd .
`.
`mCRC With FOLFIRI 2 hne
`
`mCRC with 5-FU based ctx 1‘
`line
`mCRC with 5-FU based ctx
`
`2'"! line
`1" line treatment of mCRC
`when FP therapy alone
`preferred
`Single-agent adjuvant
`treatment for Dukes‘ C colon
`
`cancer when FP therapy alone
`preferred
`
`Single agent. EGFR-
`expressing mCRC: intolerant
`to irinotecan ctx
`
`EGFR—expressing mCRC in
`combination with irinotecan in
`
`pts refractory to irinotecan ctx
`
`Single agent. EGFR—
`expressing mCRC after failure
`of both irinotecan and
`
`oxaliplatin ctx
`
`Capecitabine
`
`15 Jun 05
`
`12 Feb 04*
`
`02 Oct 07
`
`Improved OS [HR 0.816, p=0.0032 (ziv-
`aflib + FOLFIRI vs. placebo +
`FOLFIRI)]
`Improved OS [HR 0.66, p< 0.001 (bev +
`
`Improved OS [HR 0.77, p=0.001 (bev +
`FOLFOX4 vs. FOLFOX4 alone
`
`NI for OS to 5FU/LV
`
`NI for DFS to 5FU/LV
`
`Durable objective responses: ORR
`25.8% (irinotecan-refractory group)
`when administered with irinotecan and
`
`11.4% as monotherapy
`Durable objective responses: ORR
`25.8% (irinotecan-refractory group)
`when administered with irinotecan and
`
`11.4% as monotherapy
`Com'erted tofill] approvalfor single—
`agent indication: Improved OS [HR
`0.77, p=0.0046 (cetuximab + BSC vs.
`BSC)]
`Com'erted to fill] approvalfor cemximab
`+ irinotecan indication: Improved OS
`(K—Ras wild-type group) [HR 0.80. 95%
`CI 0.67. 0.94 (cetuximab + FOLFlRI vs.
`FOLFIRI)] plus supportive evidence
`from external trials
`
`Com'erted fofilll approval: Improved
`OS: irinotecan (every three weeks) vs.
`BSC 2ml line in two trials
`
`Durable objective responses
`
`Improved OS in 2 studies of irinotecan +
`5FU/LV vs. 5FU/LV
`
`
`
`06 Jul 12
`
`K—Ras mutation-negative.
`EGFR-expressing. mCRC
`with FOLFIRI 1“ line
`
`22 Oct 98
`
`mCRC. recurred or progressed
`following 5-FU based therapy
`
`Irinotecan
`
`14 Jun 96*
`
`Irinotecan
`
`20 Apr 00
`
`mCRC. recurred or progressed
`following 5-FU based therapy
`mCRC 1 line therapy with
`5FU + LV
`mCRC with 5-FU/LV recurred
`
`Oxaliplatin
`
`09 Aug 02*
`
`or progressed after first-line 5-
`FU/LV and irinotecan
`
`Improved ORR compared to 5FU/LV
`
`Page 7 of 41
`
`Reference ID: 3186716
`
`

`

`Cross Discipline Team Leader Review
`
`NBA 203085
`
`Date
`
`
`
`A o uroved
`
`Oxaliplatin
`
`09 Jan 04
`
`.
`fi
`.
`.
`mCRC mm LV ional 5_FU +
`
`Oxaliplatin
`
`04 Nov 04
`
`Panitumumab
`
`27 Sep 06*
`
`Adjuvant treatment of stage III
`colon cancer with infusional
`S-FU/LV
`Estgififfiggfis‘sii:
`p gr
`.
`.
`.
`.
`g
`FP. oxaliplatin. and mnotecan
`ctx
`
`Com'erted rofilll approval: Improved
`OS compared to bolus-IFL regimen
`(previously untreated patients)
`
`.
`.
`Improvement 3135135714de to
`mfi‘s”
`Improved PFS and ORR versus best
`supportive care (p < 0.0001. non-
`.
`proportional KM hazard curves)
`
`*Accelerated approval
`Abbreviations: ctx = chemotherapy: 5-FU = fluorouracil; OS = overall survival; bev = bevacizumab: IFL = bolus
`irinotecan plus fluorouracil regimen; BSC = best supportive care: LV = leucovorin
`
`Table 1 showed that most drugs approved for the treatment of patients with mCRC are labeled
`in combination with other drugs. Table 3 lists regimens described by the NCCN
`://www.nccn.or rofessionals/ h sician ls/ df/colon. df accessed 12 Jul 2012) for the
`
`
`
`first- and second-line treatment of patients with mCRC (note this reviewer modified the table
`to include ziv—aflibercept following the 03 Aug 2012 approval). Inclusion of these regimens in
`this review does not necessarily indicate endorsement by this reviewer or the Agency;
`however, the table lists regimens offered to patients in the United States.
`
`Table 3 Re_' u ens used to treat mCRC
`
`FOLFIRI; or in'notecan; or FOLFIRI
`
`cetuximab or panitumumab (only if
`
`+ cetuximab or panitummnab (only if
`FOLFOX or CapeOX i
`bevacizumab or FOLFOX KRAS WT); or irinotecan +
`i panitumumab (only if
`cetuximab or panitumumab (only if
`KRAS WT)
`KRAS WT); or FOLFIRI +
`bevacizumab or ziv-aflibercept
`FOLFOX or CapeOX or irinotecan +
`
`FOLFIRI + bevacizumab
`or FOLFIRI
`i cetuximab or
`
`panitumumab (only if
`KRAS WT)
`
`5FU/LA i bevacizumab
`
`or capecitabine i
`bevacizumab
`
`FOLFOXIRI
`
`Ifnot able to tolerate combination,
`
`single agent cetuximab or
`anitumumab on]
`if KRAS WT
`
`FOLFOX or CapeOX or FOLFIRI or
`in'notecan i oxaliplatin
`
`Single agent cetuximab or
`panitumumab (only if KRAS WT) :t
`irinotecan.
`
`Patients with mCRC who have progressed following a second-line of treatment (in the
`metastatic setting) have few beneficial treatment options. Best supportive care or participation
`in clinical trials are two options described for these patients in treatment guidelines.
`
`Page 8 of 41
`
`Reference ID: 3186716
`
`8
`
`

`

`Cross Discipline Team Leader Review
`
`
`
`NDA 203085
`
`Currently, two anti-VEGF therapies are approved for the treatment of patients with mCRC:
`bevacizumab and ziv-aflibercept. However, multiple small molecule tyrosine kinase inhibitors
`approved for the treatment of patients with other cancers exhibit anti-VEGF properties. Drugs
`that target the VEGF pathway cause a characteristic pattern of adverse events that include
`hypertension, proteinuria, thromboembolic events, hemorrhage, and reversible posterior
`leukoencephalopathy (RPLS).
`
`2.2 U.S. regulatory history
`The following summarizes the pertinent regulatory history and meetings held in relation to this
`NDA. Meetings held to discuss
` were not
`summarized in this review.
`
`03 Sep 2009 (Type B meeting): FDA and Bayer held this meeting to discuss a proposed
`clinical trial in patients with mCRC. FDA recommended that Bayer revise the primary
`endpoint for the proposed trial
` to overall survival.
`
`FDA agreed that Bayer can randomize patients in the control arm to placebo as long as the
`patients “failed” all approved drugs or drug combinations for the proposed indications. FDA
`stated that for a single randomized trial to support an NDA, the trial should be well designed,
`well conducted, internally consistent, and provide statistically persuasive efficacy findings so
`that a second trial would be ethically or practically impossible to perform.
`
`FDA recommended that Bayer do the following in regards to the clinical pharmacology
`program: (1) evaluate the PKs of active metabolites (e.g., M2 and M5) in addition to
`regorafenib; (2) use a ketoconazole dose of 400 mg daily in the evaluation of CYP 3A4-related
`effects; (3) evaluate the PKs of active metabolites (e.g., M2 and M5) in the drug-drug
`interaction (DDI) studies; (4) extend sampling times beyond 12 hours for midazolam and
`beyond 96 hours for warfarin when conducting the appropriate DDI studies; and (5) conduct a
`DDI study using repaglinide or rosiglitazone as a probe substrate of CYP 2C8. FDA
`recommended that Bayer evaluate the effects of hepatic impairment on regorafenib PKs using
`the proposed 160 mg dosing regimen (three out of four weeks). FDA also provided
`recommendations regarding hepatic impairment study designs.
`
`22 Jan 2010 (SPA no agreement letter): FDA sent this SPA no agreement letter based upon
`a 08 Dec 2009 SPA request submitted by Bayer for the following clinical protocol: “A
`Randomized, Double-blind, Placebo-controlled Phase III Study of Regorafenib Plus BSC
`versus Placebo Plus BSC in Patients with Metastatic Colorectal Cancer (CRC) Who Have
`Progressed after Standard Therapy.” The primary endpoint of the trial was overall survival
`(OS).
`
`In the letter, FDA recommended that Bayer conduct a futility analysis earlier than the planned
` information fraction and conduct a single interim analysis for efficacy at a later time-
`point [FDA discussed the rationale for this recommendation during the 03 Sep 2009 meeting:
`specifically, Bayer intended to initiate this phase 3 trial after enrolling a limited number of
`patients (with mCRC) with few responses in earlier studies]. FDA also expressed uncertainty
`regarding how any potential modifications in the administration of regorafenib with respect to
`
`Page 9 of 41
`
`Reference ID: 3186716
`
`9
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`
`
`
`NDA 203085
`
`food would influence exposure response. FDA agreed to the proposed patient population in
`that patients must have progressed during or within 3 months following the last administration
`of approved standard therapies (depending on the approval status in each of the participating
`countries, the therapies must include a fluoropyrimidine drug, oxaliplatin, irinotecan,
`bevacizumab, and cetuximab or panitumumab (if K-Ras wild-type).
`
`09 Apr 2010 FDA responses to Bayer questions: FDA agreed with Bayer’s revised plan to
`conduct (for the proposed phase 3 trial) a futility analysis at 30% of the planned events with a
`second analysis for futility and efficacy at 70% of the planned events (with stopping rules
`based on O’Brien-Fleming boundaries).
`
`24 Jan 2011 FDA email to Bayer regarding QTc protocol: FDA provided comments
`regarding a proposal to evaluate the effects of regorafenib on QTc intervals. FDA stated that
`the proposed dose (not specified in the email) and the proposed size of the study were
`acceptable (specifically, the size of the study was acceptable to exclude large QTc effects).
`FDA recommended that Bayer collect additional ECG/PK samples of both the parent
`compound and the major metabolites at the time of Cmax.
`
`10 Jun 2011 Fast Track letter: FDA granted Fast Track designation for the “investigation of
`regorafenib for the treatment of patient with metastatic colorectal cancer (CRC) after failure of
`standard therapies.”
`
`23 Aug 2011 (Type B pre-NDA meeting): FDA and Bayer met to discuss the contents of a
`planned NDA submission. FDA stated that the non-clinical program appeared acceptable to
`support the NDA. FDA agreed to Bayer’s proposals regarding which information to include in
`Modules 2 and 5 of the NDA. Bayer agreed to include tables, figures, appendices, and datasets
`in Module 5. FDA agreed to this proposal following FDA guidance
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
`s/UCM136174.pdf) regarding exceptions to the normally required NDA format (this NDA was
`primarily based on the results of a single study).
`
`Bayer agreed to an FDA request to include data from combination or healthy volunteer studies
`in the ISS if patients enrolled in the studies experienced regorafenib-related serious adverse
`events. FDA agreed to accept datasets in STDM and analysis formats.
`
`Bayer stated that enrollment into the pivotal trial occurred faster than expected and that patient
`recruitment into studies 12434 and 14814 (DDI and QTc studies) was not completed. Bayer
`proposed to provide interim reports from these studies. FDA stated that this approach was
`generally acceptable, but recommended that Bayer try to submit final study reports in the NDA
`submission. FDA strongly recommended submission of the QT study results in the NDA.
`
`03 Mar 2012 FDA letter to Bayer: FDA provided comments regarding the final version of
`the statistical analysis plan submitted to the Agency on 07 Feb 2012. FDA did not agree with
`the proposed methods for imputation for death based on partial information. FDA also
`recommended limiting PFS events to those defined by objective pathologic or radiologic
`findings.
`
`Page 10 of 41
`
`Reference ID: 3186716
`
`10
`
`

`

`Cross Discipline Team Leader Review
`
`NDA 203085
`
`16 Mar 2012 FDA letter to