reater than 60 ms increase in ΔQTcF and 4.3% of patients had QTcF greater than 500 ms. Cases of Torsades de pointes and sudden death have been reported [see Boxed Warning and Warnings and Precautions (5.1, 5.11)].
13. NONCLINICAL TOXICOLOGY
13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with vandetanib.
Vandetanib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo rat micronucleus assay.
Based on nonclinical findings, male and female fertility may be impaired by treatment with vandetanib. In a fertility study in male rats, vandetanib had no effect on copulation or fertility rate when undosed females were mated with males administered 1, 5, or 20 mg/kg/day of vandetanib (approximately 0.03, 0.22, or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). There was a slight decrease in the number of live embryos at 20 mg/kg/day and an increase in preimplantation loss at >5 mg/kg/day. 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 (approximately 1.8 times the AUC in patients with cancer at the recommended human dose) for 1 month.
13.2. Animal Pharmacology and/or Toxicology
In an animal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strength compared with controls. This suggests that CAPRELSA slows but does not prevent wound healing. The appropriate interval between discontinuation of CAPRELSA and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined.
Nodular masses were observed in a 6-month toxicology study in rats during treatment with ≥5 mg/kg/day vandetanib (approximately 0.22 or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). Masses were palpable during clinical assessments as early as week 13, were observed in multiple organs, and were associated with hemorrhagic or inflammatory findings.
14. CLINICAL STUDIES
A double-blind, placebo-controlled study randomized patients with unresectable locally advanced or metastatic medullary thyroid cancer to CAPRELSA 300 mg (n=231) versus Placebo (n=100).
The primary objective was demonstration of improvement in progression-free survival (PFS) with CAPRELSA compared to placebo. Other endpoints included eva luation of overall survival and overall objective response rate (ORR). Centralized, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression based on the investigator’s assessment, patients were discontinued from blinded study treatment and given the option to receive open-label CAPRELSA. Nineteen percent (44/231) of the patients initially randomized to CAPRELSA opted to receive open-label CAPRELSA after disease progression, and 58% (58/100) of the patients initially randomized to placebo opted to receive open-label CAPRELSA after disease progression.
The result of the PFS analysis, based on the central review RECIST assessment, showed a statisticall |
