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CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 022405Orig1s000 PHARMACOLOGY REVIEW(S) MEMORANDUM Vandetanib Date: March 25, 2011 To: File for NDA 22405 From: John K. Leighton, PhD, DABT Associate Director for Pharmacology/Toxicology Office of Oncology Drug Products I have examined pharmacology/toxicology supporting review and labeling provided by Drs. Gehrke and Dorsam and supervisory memorandum provided by Dr. Verbois. I concur with their conclusions that vandetanib may be approved for the proposed indication with the carcinogenicity studies to be provided as described in the Action Letter. Reference ID: 2923639 --------------------------------------------------------------------------------------------------------- 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 03/25/2011 Reference ID: 2923639 MEMORANDUM Date: March 25, 2011 From: S. Leigh Verbois, Ph.D. Supervisory Pharmacologist Division of Drug Oncology Products To: File for NDA #022405 Vandetinib Re: Approvability of Pharmacology and Toxicology Non-clinical studies that investigated the pharmacology and toxicology of vandetinib provided to support NDA 022405 for the treatment of patients with unresectable locally advanced or metastatic medullary thyroid cancer were reviewed in detail by Brenda Gehrke, Ph.D., and Robert Dorsam, Ph.D. The supporting information included studies of orally administered vandetinib that investigated the drug’s pharmacology, toxicokinetics and ADME, safety pharmacology, general toxicology (rat and dog), and genetic toxicity (in vivo and in vitro). Reproductive and developmental toxicology studies were conducted in rats to assess the effects of vandetanib on fertility, embryofetal development, and pre- and post-natal development. The studies cited in the review consist primarily of original research conducted by the applicant. The pharmacology studies submitted to the NDA demonstrate that vandetinib is a tyrosine kinase inhibitor which binds multiple receptor tyrosine kinases including VEGF, EGF, RET, BRK, TIE2, and members of EPH and SRC family of kinases. These kinases were inhibited at concentration lower than levels than that achieved in the plasma clinically. Based on this, the pharmacological classification of vandetinib is a kinase inhibitor. Drug induced toxicity, including gastrointestinal, cardiovascular, toxicity, skin, spleen, and teeth and bone (in rats) toxicity were observed non-clinically. These findings were well characterized non-clinically. Cardiovascular toxicity was highly discussed throughout the review process and manifested both in toxicology studies as well as safety pharmacology studies as prolongation of QT interval. Vandetinib was not mutagenic or clastogenic when tested in the Ames assay or the in vitro cytogenetic assay using human lymphocytes and an in vivo rat micronucleus assay, respectively. Although carcinogencity studies have not been initiated to date, evidence of masses was detected in the repeat dose rat study in multiple organs. Masses were detected at both clinical observation and gross pathology. Given the proposed patient indication which has an extended life expectancy, studies are required to assess the risk of carcinogenicity. Vandetinib may impair fertility in males and females. In a fertility study in male rats, vandetanib had no effect on copulation or fertility rate at doses approximately 0.03 to 0.38 times the AUC in patients with cancer at the recommended human dose of 300 mg/day. However, there was a slight decrease in the number of live embryos at 20 Reference ID: 2923745 mg/kg/day (120 mg/m2) and an increase in preimplantation loss at >5 mg/kg/day (30 mg/m2). In a female fertility study, there was a trend towards increased estrus cycle irregularity, a slight reduction in pregnancy incidence and an increase in implantation loss. In a repeat-dose toxicity study in rats, there was a decrease in the number of corpora lutea in the ovaries of rats administered 75 mg/kg/day vandetanib (450 mg/m2; approximately 1.8 times the AUC in patients with cancer at the recommended human dose) for 1 month. Vandetanib is embryotoxic, fetotoxic, and teratogenic to rats, at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day. When vandetanib was administered to female rats prior to mating and through the first week of pregnancy, there were increases in pre-implantation loss, post-implantation loss and early embryolethality resulting in a significant reduction in the number of live embryos. This dose administered to rats during organogenesis, caused an increase in post-implantation loss including embryofetal death. Vandetanib caused total litter loss when administered at a dose of 25 mg/kg/day (150 mg/m2/day) during organogenesis until expected parturition. When administered during organogenesis, vandetanib doses of greater than 1 mg/kg/day (greater than 0.03 the Cmax in patients with cancer at the recommended human dose), caused malformations of the heart vessels and delayed ossification of the skull, vertebrae and sternum, indicating delayed fetal development. A no effect level for these malformations was not identified in this study. In a rat pre- and post-natal development study, at doses producing maternal toxicity (1 and 10 mg/kg/day; 6 and 60 mg/m2/day) during gestation and/or lactation, vandetanib, decreased pup survival, and/or reduced post-natal pup growth. Reduced post-natal pup growth was associated with a delay in physical development. In the pre- and post-natal development study, it was determined that vandetinib was excreted in rat milk and found in the plasma of pups. Vandetinib was found in the plasma of pups pre-dosing and eight hours post-dosing indicating the persistence of vandetinib in plasma of dams, persistant excretion into breast milk or residence in breast milk or slow excretion of pups. Given the long half life of the drug it likely the first and last. Because the potential benefit from the use of the vandetinib in pregnant women in this patient population may outweigh the potential risk to the developing fetus, Pregnancy Category D is recommended for this patient population. Recommendations: I concur with Drs. Gehrke’s and Dorsam’s conclusion that pharmacology and toxicology data support the approval of NDA 022405 for vandetinib. There are no outstanding nonclinical issues related to the approval of vandetinib for the proposed indication. The following information should be conveyed in the approval letter regarding the PMRs: 1. To evaluate the potential for a serious risk of carcinogenicity, it is necessary to assess the potential for carcinogenicity by conducting a long-term (2 year) rodent carcinogenicity study in the rat. Submit the carcinogenicity protocol for a Special Protocol Assessment prior to initiating the study. Notify the Agency in writing at least 30 Reference ID: 2923745 days prior to submission of the study that a carcinogenicity protocol will be arriving. Submit the carcinogenicity protocol and questions regarding the protocol with sufficient time prior to the anticipated initiation of the study to allow for meaningful discourse with the Agency and resolution of any issues before study initiation. Clearly mark in bold black letters as a REQUEST FOR SPECIAL PROTOCOL ASSESSMENT. Once the study has been completed, submit the final study report and a prior approval labeling supplement containing proposed labeling to update package inserts to reflect study findings. 2. To evaluate the potential for a serious risk of carcinogenicity, it is necessary to assess the potential for carcinogenicity by conducting a rodent carcinogenicity study in the mouse. Submit the carcinogenicity protocol for a Special Protocol Assessment prior to initiating the study. Notify the Agency in writing at least 30 days prior to submission of the study that a carcinogenicity protocol will be arriving. Submit the carcinogenicity protocol and questions regarding the protocol with sufficient time prior to the anticipated initiation of the study to allow for meaningful discourse with the Agency and resolution of any issues before study initiation. Clearly mark in bold black letters as a REQUEST FOR SPECIAL PROTOCOL ASSESSMENT. Once the study has been completed, submit the final study report and a prior approval labeling supplement containing proposed labeling to update package inserts to reflect study findings. Reference ID: 2923745 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- SANDI L VERBOIS 03/25/2011 Reference ID: 2923745 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION Application number: 022405 Supporting document/s: 0000 Applicant’s letter date: July 7, 2010 CDER stamp date: July 7, 2010 Product: Vandetanib Indication: Unresectable locally advanced or metastatic medullary