CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203756Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Division Director Summary Review
`
`_ November 20, 2012
`
`From
`Patricia Keegan
`
`Division Director Summary Review
`Subject
`NDA #
`NDA 203756
`
`Exelixis Inc.
`Applicant Name
`
`Date of Submission
`May 21, 2012 (receipt date May 29, 2012)
`November 29, 2012
`
`PDUFA Goal Date
`
`COMETRIQ
`Proprietary Name /
`
`cabozantinib
`Established (USAN) Name
`Dosage Forms / Strength
`
`Proposed Indication(s) COMETRIQ 20-mg gelatin capsules; grey capsules
`
`with “XL184 20mg” printed in black on the capsule
`
`COMETRIQ 80-mg gelatin capsules: Swedish orange
`with “XLl84 80mg” printed in black on the capsule
`
`COMETRIQ is indicated for the treatment of patients
`with progressive unresectable locally advanced or
`metastatic medull
`th oid cancer
`
`Recommended Action for NME:
`
`NDA 203 756;“0
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`Reference ID: 3222683
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`Division Director Summary Review
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`Material Reviewed/Consulted
`
`Names of discipline reviewers
`OND Action Package, including:
`Regulatory Project Manager Review Gina Davis
`Medical Officer Review
`Ruthann Giusti
`Statistical Review
`Yuan-Li Shen
`Pharmacology Toxicology Review
`Margaret Brower
`CMC Review
`Minerva Hughes, William M. Adams, Li-Shan Hsieh
`Microbiology Review
`Denise Miller
`Clinical Pharmacology Review
`Jun Yang
`OPDP
`Carole Broadnax & Karen Munoz-Nero
`OMP/DMPP Review
`Karen Dowdy
`DMHS Review
`Jeanine Best
`OSI
`Roy Blay
`CDTL Review
`Suzanne Demko
`OSE/DMEPA
`James Schlick
`OSE/DRISK
`Joyce Weaver
`QT/IRT Consult
`Satjit Brar
`OND=Office of New Drugs
`OMP=Office Medical Policy
`DMPP=Division of Medical Policy Program
`OPDP= Office of Prescription Drug Promotion
`PMHS= Pediatric and Maternal Health Staff
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`OSI=Office of Scientific Investigations
`DRISK=Division of Risk Management
`CDTL=Cross-Discipline Team Leader
`
`
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`Division Director Summary Review
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`Introduction
`
`
`1.
`
`Cabozantinib is a small molecule inhibitor of multiple receptor-based tyrosine kinases,
`including RET, MET, and VEGFR2. The clinical development program of cabozantinib in
`medullary thyroid cancer (MTC) is as a targeted therapy, based on the known correlation
`between mutation in the RET gene and both the hereditary and sporadic forms of MTC.
`Cabozantinib has the same mechanism of action (inhibition of RET tyrosine kinase) as that of
`another drug, vandetinib, which was approved for the treatment of metastatic medullary
`thyroid cancer in 2011, based on a similarly designed trial and endpoints (progression-free
`survival and durable objective response rate) as that provided in the NDA for cabozantinib.
`
`The NDA is supported by a single, well-conducted, placebo-controlled, randomized (2:1),
`multi-national trial, Protocol XL184-301, which enrolled 330 patients with metastatic
`medullary thyroid cancer. Assessment for RET mutation was not a requirement of the protocol
`but was assessed retrospectively in approximately 70% of patients with “research-use only”
`assays. Protocol XL184-301 demonstrated that treatment with cabozantinib results in a
`statistically significant and clinically important improvement in progression free survival [HR
`0.28 (95% CI: 0.19, 0.40); p<0.0001], with an estimated median PFS of 11.2 months for
`cabozantinib treatment as compared to an estimated median PFS of 4 months for patients
`receiving no treatment (placebo arm). The favorable results from the cabozantinib arm were
`robust based on various sensitivity analyses and consistent within relevant patient subgroups,
`including subgroups retrospectively identified as RET mutation positive, RET mutation
`negative, and RET mutation status unknown. In addition, there was a significantly higher
`overall response rate (27%) for cabozantinib-treated patients as compared to no responses in
`the placebo arm.
`
`In a planned interim analysis, conducted after 44% of the total deaths for the final analysis of
`survival, and in an unplanned analysis conducted at FDA’s request and submitted at the 120-
`day update, with 75% of the planned deaths for the final analysis, there was no evidence of
`significant improvement in overall survival for cabozantinib-treated patients. The estimated
`median survival times were 26 months for cabozantinib-treated patients and 20.3 months for
`placebo-treated patients.
`
`The safety database of 289 patients included the results of the major efficacy trial and two
`additional, single-arm trials in patients with various cancers, treated with cabozantinib 140 mg
`daily. In the major efficacy trial, dose modifications occurred in the majority (86%) of
`patients; the most common adverse reactions resulting in dose modification were palmar-
`plantar erythrodysesthia syndrome, weight loss, decreased appetite, fatigue, diarrhea,
`stomatitis, asthenia and nausea.
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`There was no difference in overall survival between the two treatment arms, although four
`deaths in the cabozantinib arm were considered probably related to treatment (1 death due to
`fatal hemorrhage, 2 deaths in patients with esophageal fistula formation, and 1 death due to
`respiratory failure in a patient with hemorrhage and possible fistula). The most common
`serious adverse reactions of cabozantinib are gastrointestinal (GI) perforations, GI and non-GI
`fistulas, thrombotic events, hemorrhage, wound complications, hypertension, osteonecrosis,
`and reversible posterior leukoencephalopathy syndrome. The most common (≥ 30%) adverse
`reactions of cabozantinib are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome,
`weight loss, decreased appetite, nausea, fatigue, oral pain, dysgeusia, oral pain, depigmentation
`of hair, and hypertension.
`
`
`The major issue considered during this review was the acceptability of the proposed dose in
`light of the adverse reaction profile and given the lack of a clear exposure-response
`relationship in exploratory analyses conducted by the Clinical Pharmacology reviewers.
`Based on this concern, a post-marketing trial will be required to explore the safety and activity
`of a lower dose of cabozantinib.
`
`2. Background
`
`Indicated population/available therapy
`Medullary thyroid cancer arises from the parafollicular cells of the thyroid and is reported to
`account for 3-5% of estimated 56, 460 cases of cancers of the thyroid gland estimated to occur in
`2012. 1,2 Approximately one-quarter of MTC are hereditary and mutations of the RET (REarranged
`during Transfection) gene occur in 95% of these hereditary MTC cases, while the proportion of
`sporadic MTC with RET mutations is reportedly lower (25%)3. Mutation of RET leads to
`constituitive activation of receptor tyrosine kinases, with downstream activation of pathways
`involved in cell proliferation. Cabozantinib is designed to target this pathway common to
`hereditary MTC and some cases of sporadic MTC,
`
`Dr.Guisti notes in her review that doxorubicin is approved for the treatment of thyroid cancer,
`however the basis for this approval is not clear from current records and it is uncertain whether this
`approval applies to medullary thyroid cancer.
`
`On April 6, 2011 Caprelsa (vendetanib), a small molecule inhibitor of the RET, the VEGFR2, and
`other kinases, was approved for “the treatment of symptomatic or progressive medullary thyroid
`cancer in patients with unresectable locally advanced or metastatic disease. Use of vandetanib in
`patients with indolent, asymptomatic or slowly progressing disease should be carefully considered
`because of the treatment related risks of vandetanib.”
`
`
`1 http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/HealthProfessional/page7
`2 Pitt SC, Moley JF: Medullary, Anaplastic, and Metastatic Cancers of the Thyroid. Semin Oncol 37 (6): 567-579,
`2010.
`3 Liu Z, Falola J, Zhu X, et al: Antiproliferative effects of Src inhibition on medullary thyroid cancer. J Clin
`Endocrinol Metab 89:3503-3509, 2004.
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`Vandetanib is a small molecule that inhibits multiple kinases including members of the epidermal
`growth factor receptor (EGFR) family, vascular endothelial cell growth factor (VEGF) receptors,
`rearranged during transfection mET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH
`receptors kinase family, and members of the Src family of tyrosine kinases.
`
`The approval was based on a single, double-blind, placebo-controlled, randomized (2: 1) trial
`
`conducted in 331 patients with unresectable locally advanced or metastatic medullary thyroid
`
`cancer. The primary eflicacy endpoint was progression-free survival, with supportive endpoints of
`
`overall survival and overall objective response rate. Tumor-based endpoints were determined by a
`
`centralized, independent blinded imaging review. At the time of investigator-determined disease
`
`progression, the treatment blind for the individual patient was broken and all patients were offered
`treatment with vandetanib. Following investigator-determined disease progression, 19% of the 231
`patients initially randomized to vandetanib and 58% of the 100 patients initially randomized to
`
`placebo chose to take vandetanib.
`
`The trial demonstrated a statistically significant improvement in progression-free survival [HR
`0.35 (95% CI: 0.24, 0.53); p<0.0001], with a median PFS time of 16.4 months in the control arm
`and median not reached at the time of the final PFS analysis in the vandetinib arm, and a
`significantly higher overall response (44% vs. 1%) for patients randomized to vandetanib
`compared to those randomized to placebo. At the time of the PFS analysis, based on 100 PFS
`events, at which time the estimated median PFS time was 6.4 months in the placebo arm and
`estimated median PFS time in the vandetinib arm not reached, the survival data were not mature.
`
`Vandetanib was approved under a Risk Evaluation and Mitigation Strategy (REMS) with
`elements to assure safe use (ETASU) based on the risks of Torsades de pointes and sudden
`death due QT prolongation. In addition, Vandetanib labeling contains Warnings and Precautions
`describing the following additional clinically important adverse reactions: skin reactions and
`Stevens-Johnson Syndrome, interstitial lung disease, ischemic cerebrovascular events,
`hemorrhage, heart failure, diarrhea, hypothyroidism, hypertension, Reversible Posterior
`Leukoencephalopathy Syndrome, drug interactions, renal impairment, hepatic impairment, and
`Pregnancy Category D.
`
`Regulatory History of the Cabozantinib Development Program
`
`Clinical investigations for the medullary thyroid cancer development program were conducted
`primarily under IND
`(m4)
`(m4)
`\"1 \‘U
`
`hile development program for medullary thyroid cancer (IND 113446)
`
`July 13, 2005:
`
`"”“’
`
`March 6, 2008: An EOP2 meeting for the medullary thyroid development program was held
`on March 6, 2008 Key agreements reached were:
`. Progression-free survival may be an acceptable efficacy endpoint, depending on the
`magnitude of the treatment effect and riskzbenefit ratio
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`(cid:131) PFS should be evaluated both by investigators and by blinded central review; the primary
`analysis of PFS will be based on central review-determined PS events
`(cid:131) The trial was to detect a 50% improvement in PFS (HR 0.667) assuming median PFS
`times of 8 months in the placebo arm and 12 months in the treatment arm.
`(cid:131) FDA recommended against an interim analysis of PFS after 50% of the planned events due
`to concerns that the interim data may not produce an accurate and reliable estimate of the
`true treatment effects.
`(cid:131) The protocol will permit patients in the placebo arm to cross over to open-label therapy at
`the time of investigator-determined disease progression; given the unblinding at the time of
`disease progression, the analysis plan should detail how such patients will be handled in
`the analysis of PFS.
`(cid:131) The trial should be powered to detect an improvement in overall survival; FDA accepted
`Exelixis’ proposal to conduct an interim analysis of survival at the time of the final PFS
`analysis. Exelixis will file an NDA based on the final PFS analysis and interim analysis of
`survival
`(cid:131) Claims derived from subject self-assessent and quality of life instruments need to be based
`on data collected with a validated instrument for this purpose.
`
`
`The adequacy of the clinical pharmacology program for cabozantinib to support an NDA was
`discussed during EOP2 meetings (March 6, 2008
`
` May 2009) and at the December 12, 2010 pre-NDA
`
`meeting.
`
`June 6, 2008: SPA agreement letter issued for Protocol XL184-301, which provided the
`following answers to Exelixis’ questions
`• Sponsor’s Question 1: Since the discussion with the Agency on 06 March 2008, Exelixis
`has re-evaluated the assumptions made for both treatment groups in XL184-301. The
`current study is designed to detect a larger increase in PFS (75% improvement, median 14
`months for XL184 versus 8 months for placebo), and OS (50% improvement, median 33
`months for XL184 versus 22 months for placebo), at the time of final analysis. To
`maximize the ability to evaluate the effect of XL184 on overall survival, subjects on the
`placebo arm will not be allowed to cross-over to receive XL184 upon disease progression.
`In addition, Exelixis does not plan on conducting an interim analysis on PFS…Exelixis
`believes that [data from Protocol XL184-001] support the proposed assumptions of a 75%
`and 50% improvement for PFS and OS, respectively, in the XL184 versus placebo groups.
`Does the Agency agree with the proposed assumptions for PFS and OS?
`
`FDA response: The available data appear to be too limited to allow for accurate estimates
`of PFS and OS improvements. We therefore neither agree nor disagree with your
`assumptions, but simply view them as a reflection of the amount of risk you are willing to
`accept. The magnitude of improvement in PFS and/or OS required for drug approval will be
`a review issue.
`
` Sponsor Question 2: Given the current assumptions for PFS and OS, and the concern for
`long-term repeated exposure to radiation, tumor assessments will be conducted every 12
`weeks...Does the Agency agree with this proposal?
`
` (cid:131)
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`FDA response: Yes, this is acceptable.
`
`I Question 3: Subjects with MTC who have either measurable or non-measurable disease
`will be eligible for Study XL184-301. The primary efficacy endpoint of progression-free
`survival will be based on modified RECIST criteria (provided as Appendix C in the
`protocol, as well as in the Independent Review Committee Charter), which defines how
`progression will be determined in subjects with MTC with measurable and non-measurable
`disease. Does the Agency agree with the proposal to include subjects with non-measurable
`disease?
`
`FDA Response: Because PFS is the primary endpoint, including patients with non-
`measurable disease is problematic. It adds to the heterogeneity of the patient population
`and it essentially creates two different sets of progression criteria on which the primary
`endpoint is based. We would therefore need assurance that the overall results are consistent
`between these two patient populations if general claims are to be made that apply to both
`populations...You may wish to minimize the number of patients enrolled with non-
`measurable disease for the reasons described above. Alternatively, if a substantial number
`of patients with non-measurable disease are allowed in the study, then the randomization
`should be stratified by patients’ measurable disease status in order to prevent an imbalance
`between the treatment groups.
`
`I
`
`Sponsor Question 5: As discussed with the Agency on 06 March 2008, Exelixis is planning
`to evaluate subject self-assessment parameters and disease-related symptom burden with
`XL184 treatment as compared with placebo, as per the MD Anderson Symptom Inventory
`(MDASI) Thyroid Module as an exploratory study objective. The MDASI Thyroid Module
`consists of 13 elements from the widely-used MDASI Core Module with 6 additional items
`developed specifically for the symptoms of patients with thyroid cancer. Supportive
`documentation for both the Core and Thyroid Modules is provided in this submission.
`Does the Agency agree that the MDASI Thyroid Module is an appropriate instrument to
`measure subject self-assessment parameters and disease-related symptom burden, “(4)
`
`FDA response: No. We do not agree. Insufficient information was submitted to support the
`validity of the MDASI thyroid module as a measure of disease-related symptom burden :2}
`
`December 12, 2010: A pre-NDA meeting was held for the medullary thyroid indication and
`the following key agreements were reached:
`I
`Safety experience will be supported by the pharmacokinetic data and clinical study reports
`from Protocols XL184-001 and XL184-301, a QTc evaluation substudy conducted within
`Protocol XL184-301, a P—gp in vitro study report, population PK analysis based on data
`obtained in Protocols XLl84-001, XLl84-201, XLl84-203, and XL184-301.
`I FDA recommended that, in addition, a food effect study, organ impairment studies and
`drug-drug interaction studies should also be submitted in the NDA
`I The proposed approach to data presentation in the ISE and 188 were acceptable to FDA
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`I FDA agreed that since the daily 100 mg (freebase) dose of XLlS4 administered in Protocol
`XLl84-203 was lower than the daily 140 mg (freebase) dose (expressed as 175 I-malate
`salt weight) administered in the Protocol XL 184-301), but rather was equivalent to a daily
`dose of 125 mg (I—malate salt weight), expedited safety reports for patients treated under
`Protocol XL 184-203 were not required for submission in the NDA.
`
`April 8, 2011: Fast-track designation was granted for “the investigation of XL184 for patients
`with unresectable, locally advanced, or metastatic medullary thyroid carcinoma (MTC)”.
`
`November 29, 2010: Orphan drug designation was granted for cabozantinib for the treatment
`of follicular, medullary and anaplastic thyroid carcinoma and metastatic or locally advanced
`papillary thyroid cancer.
`
`March 4, 2011: A pre—NDA CMC meeting was held
`I FDA accepted Exelixis’ proposal to include Quality information in the NDA only for the
`two XL184 capsule strengths of
`(mo which were administered in the
`Protocol XL 184-301;
`M"
`I FDA agreed that the proposal to manufacture higher dose commercial capsules containing
`80 mg (freebase weights) XL184 was reasonable, based on Exelisis justification that the
`difference between the clinical and planned commercial dosage strength (79 mg versus 80
`mg) is small relative to the variance in mean exposures in subjects administered 175 mg
`(salt)/ 139 mg (freebase) and therefore not clinically relevant.
`I The proposed starting materials appeared to be acceptable
`I
`In response to the request for a biowaiver, FDA stated that as long as the to—be-marketed
`formulation is sufficiently similar to the clinical trial formulation(s), in terms of
`M“)
`and proper controls are applied, 3 BE study would not be needed. Alternatively,
`
`the sponsor may choose to conduct a BE study.
`I Regarding qualification of genotoxic impurities, Exelixis was advised to follow the
`appropriate ICH guidanees and that impurities can be managed individually.
`I The proposed specifications for drug substance and drug product and the stability testing
`data package appeared to be reasonable.
`(m4)
`
`December 20, 2011: A second preNDA meeting was held at which the high-level summary
`results for safety and efficacy were available. Key agreements reached were:
`I Agreement on the schedule for the rolling submission and contents of each submission
`I Agreement on the content and format of the data to be included in the Quality, Clinical
`Pharmacology, Clinical, and Non-clinical sections
`I Agreement on the contents of the 120—day safety update, to include an unplanned interim
`analysis of overall survival
`
`The NDA was submitted as a rolling submission
`
`0 Non-clinical module submitted Dec. 21, 2011
`
`0 Quality module submitted March 9, 2012
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`• Last components of Quality module (stability data), last components of the Administrative
`module (proposed labeling), and Clinical data (efficacy, safety, pharmacokinetics)
`submitted May 25, 2012, and received May 29, 2012.
`3. CMC
`
` I
`
` concur with the conclusions reached by the chemistry reviewer regarding the acceptability of
`the manufacturing of the drug product and drug substance. There were no microbiology
`deficiencies noted in the NDA submission. Manufacturing site inspections were acceptable.
`Stability testing supports an expiry of 24 months at ambient room temperature. All quality and
`compliance reviewers recommended approval and there are no outstanding CMC issues that
`preclude approval.
`
`Cabozantinib, also referred to as XL184, is a synthetically-derived molecule; data provided in
`the application support that the manufacturing process is appropriately controlled and
`specifications for process intermediates and final product are adequately justified. The drug
`product, COMETRIQ, will be marketed in oral hard gelatin capsules containing 20 mg or 80
`mg of cabozantininb freebase (roughly equivalent to 25 mg or 100 mg cabozantinib l-malate
`salt) in blister packs providing a 7-day supply of capsules providing a daily dose of 140 mg,
`100mg, or 60 mg cabozantinib, or bottles containing 20-mg capsules.
`4. Nonclinical Pharmacology/Toxicology
`
` I
`
` concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
`no outstanding pharm/tox issues that preclude approval.
`
`As noted in Dr. Brower’s review, cabozantinib is a small molecule tyrosine kinase inhibitor
`(TKI) which inhibits multiple receptor- -based tyrosine kinases including RET, MET, VEGFR
`2, VEGFR1, VEGFR3, FLT3, TIE2, Axl, TrkB and KIT at IC50 concentrations that are
`achievable in human subjects. The application also provided proof-of-concept data for RET
`inhibition in murine xenograft models, where cabozantininb administration was documented to
`inhibit RET phosphorylation in medullary thyroid cells in a dose-dependent manner.
`
`The nonclinical development program was adequate to support the NDA, containing
`nonclinical studies assessing the pharmacology, safety pharmacology, chronic toxicology, and
`reproductive toxicology of cabozantinib. The pharmacology of cabozantinib itself was similar
`to that in humans, with the dog appearing to most closely approximate human
`pharmacokinetics, however the concentration of active metabolites of cabozantinib were
`substantially lower in animals than in humans requiring that a post-marketing study be
`required for to assess the potential genotoxicity, in an in vitro mutagenicity assay, of the M4
`metabolite.
`
`The most common toxicities of cabozantinib were predicted by chronic toxicology studies.
`Effects observed in dedicated studies in rats and dogs evaluating the effects of cabozantinib on
`fertility suggest that fertility may be impaired in cabozantinib-treated males and females. In
`safety pharmacology trials, cabozantinib did not inhibit hERG channel activity at relevant
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`concentrations and no effects on cardiovascular parameters were observed in dogs. In safety
`pharmacology studies conducted in rats, behavioral and physiological changes were not
`observed following single doses of up to 300 mg/kg cabozantinib and single doses of 900
`mg/kg cabozantinib had no effects on respiratory parameters.
`
`Cabozantinib was not mutagenic or clastogenic. Genotoxic impurities were considered
`adequately characterized, in light of the indicated patient population, in accordance with ICH
`S9. The four major metabolites of cabozantinib were not mutagenic but have not been
`assessed for induction of chromosomal aberrations. However, based on the potential for long-
`term survival in some patients with medullary MTC (median survival from diagnosis is X), the
`non-clinical review team has identified the requirement for 2-year carcinogenicity studies in
`rats and mice.
`
`Embryofetal development studies were conducted in rats and rabbits. In both species, there
`was increased risk of post-implantation losses at cabozantinib exposures of < 1% (rats) and 9-
`11% (rabbits) of the human exposure at the recommended dose of 140 mg compared to
`controls. Additional findings includes cardiac anomalies, and dose-dependent increases in
`skeletal variations in rats and a dose-dependent decrease in fetal body weight, increases in the
`incidence of visceral variations and malformations including reduced spleen size and missing
`lung lobes in rabbits at exposures significantly lower than the human exposure at the
`recommended dose. Reproductive toxicity findings suggest that male and female fertility can
`be impaired by treatment with cabozantinib. Based on these findings, product labeling
`identifies this product as Pregnancy Category D. In addition, based on the potential for
`extended survival in some patients with medullary thyroid cancer, and the known
`pharmacologic effects of inhibition of MET and VEGF pathways which may result in altered
`bone development, a post-marketing requirement for a pre/post-natal developmental toxicity
`study has been identified.
`5. Clinical Pharmacology
`
` I
`
` concur with the conclusions reached by the clinical pharmacology/biopharmaceutics reviewer
`that there are no outstanding clinical pharmacology issues that preclude approval.
`
`The pharmacokinetics of cabozantinib capsules and cabozantinib “powder in bottle” dosage
`forms were evaluated in healthy subjects and in patients with cancer. The application also
`contained the results of a population PK (PopPK) analysis of cabozantinib performed with data
`from 289 patients with solid tumors in clinical trials evaluating the regimen of 140 mg
`cabozantinib capsules. In the population PK analysis, the half-life of cabozantinib at steady
`state was approximately 55 hours, the oral volume of distribution is approximately 349 L, and
`clearance (CL/F) was estimated to be 4.4 L/hr. The median Tmax was approximately
`2-4 hours in cancer patients following a single oral dose. Mass balance studies in healthy
`subjects demonstrated that 54% of administered radioactivity was recovered in the feces and
`27% was recovered in the urine. The dose proportionality of the cabozantinib capsules has not
`been evaluated, however dose-proportional AUC and Cmax were observed with the “powder
`in bottle” dosage form. Absolute oral bioavailability of cabozantinib capsule has not been
`determined. Significant increases in Cmax (41%) and AUC (57%) were observed when
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`cabozantinib was administered with a high-fat, high calorie meal in healthy subjects, thus
`product labeling states that cabozantinib should be taken without food/
`
`The Clinical Pharmacology review team recommended that the dosing regimen in product
`labeling be based on pharmacokinetic modeling, with a proposed starting dose of 100 mg
`daily, to be increased to 140 mg or decreased to 60 mg based on observed toxicity. This
`recommendation was based on the observation that 86.4% of the patients in the major efficacy
`trial required dose modification (interruption, reduction, or termination), on exposure-response
`analyses suggesting that progression-free survival was similar across all quartiles for
`cabozantinib exposure, and a correlation observed between model-predicted steady state
`exposure (AUCSS PRED) and time to first dose medication (shorter time with higher exposure).
`It is noted that there was no correlation between exposure and the incidence of the most
`common adverse reactions resulting in dose modification (palmar-plantar erythrodysesthesia
`or diarrhea). Dr. Jun concluded that “These E-R relationships for efficacy and safety suggest
`that a lower dose might be effective with improved tolerability; therefore, label should include
`a starting dose of 100 mg with a provision to increase the dose to 140 mg or decreased to 60
`mg as tolerated.”
`
`Given the exploratory nature of the exposure-response analysis performed using the results for
`sparse PK sampling techniques in 200 patients per Table 5 of Dr. Jun’s review, it is my
`opinion that the data are inadequate to support a recommended dose that has not been studied.
`As an alternative, the clinical and clinical pharmacology review teams have agreed that a trial
`to confirm that an alternative dosing regimen is safer and retains sufficient efficacy be required
`under the provisions of 505(o).
`
`The results of the population PK analyses do not identify clinically relevant differences in
`exposures based on gender, age, or race (White versus non-White) and that the effect of mild
`and moderate renal impairment on clearance of cabozantinib is minimal. Since cabozantinib is
`cleared by the kidneys and metabolized, via CYP3A4, in the liver and formal studies of the
`pharmacokinetics of cabozantinib in patients with renal or hepatic organ impairment have not
`been conducted, the clinical pharmacology reviewer has stated that post-marketing trials to
`evaluate the pharmacokinetics of cabozantinib in patients with severe renal impairment and in
`patients with hepatic impairment are required. Pending the completion of the hepatic
`impairment trial, product labeling contains a Warning that cabozantinib is not indicated for the
`treatment of patients with hepatic impairment. In addition, product labeling contains
`recommendations to avoid use of strong CYP3A4 inducers or inhibitors in patients receiving
`cabozantinib, and proposes specific recommendations for dose modification based on the
`dedicated drug interactions studies of cabozantinib in patients taking strong CYP3A4 inducers
`or inducers. Dedicated studies have shown that cabozantinib exposure is increased by 38%
`when administered to subjects taking a strong CYP3A4 inhibitor and that cabozantinib
`exposure is decreased by 77% in subjects taking a strong CYP3A4 inducer.
`
`Population PK studies were inconclusive regarding the effects of gastric pH modifying agents
`on cabozantinib pharmacokinetics. Since the solubility of cabozantinib is pH-dependent, the
`clinical pharmacology review team has stated that a post-marketing trial to conduct a dedicated
`
`NDA 203756/0
`
`Division Director Summary Review
`
`Page 11 of 25
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`Reference ID: 3222683
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`study assessing the effects on pH modifying agents on cabozantinib pharmacokinetics also be
`required.
`
`The effects of cabozantinib on the QT interval were assessed in a dedicated substudy within
`the major efficacy trial. The IRQT consultant’s assessment of this substudy was that no large
`increases in mean QT interval (>20 ms) were detected at steady state (pre-dose on Cycle 2,
`Day 1) compared to baseline values in the 166 cabozantinib-treated patients assessed on C2D1.
`The mean change was 11.3 ms (90% CI: 8.7, 13.95). There were no new changes in cardiac
`wave form morphology or new rhythms in patients with increased QT interval and no
`cabozantinib -treated patient had a QTcF >500 ms. These results have been described in the
`Clinical Pharmacology section of product labeling, however based on these data, no Warnings
`or Precautions are required.
`6. Clinical Microbiology
`
` I
`
` concur with the conclusions reached by the clinical microbiology reviewer that there are no
`outstanding sterility issues that preclude approval.
`
`7. Clinical/Statistical-Efficacy
`
`There were no issues raised during the review regarding the adequacy of the development
`program and efficacy data submitted to the NDA. Prior to submission of NDA 203756, the
`FDA met with Exelixis during an EOP2 meeting and preNDA meeting to discuss the scope
`and adequacy of the development program in medulla