g chromosome aberration in Chinese hamster V79 cells.
Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans.
13.2 Animal Toxicology and/or Pharmacology
In a chronic 26 week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals.
14 CLINICAL STUDIES
The clinical efficacy and safety of Stivarga were eva luated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 1) in 760 patients with previously treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); supportive efficacy outcome measures included progression-free survival (PFS) and objective tumor response rate.
Patients were randomized to receive 160 mg regorafenib orally once daily (n=505) plus Best Supportive Care (BSC) or placebo (n=255) plus BSC for the first 21 days of each 28-day cycle. Stivarga was administered with a low-fat breakfast that contains less than 30% fat [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. Treatment continued until disease progression or unacceptable toxicity.
In the all-randomized population, median age was 61 years, 61% were men, 78% were White, and all patients had baseline ECOG performance status of 0 or 1. The primary site of disease was colon (65%), rectum (29%), or both (6%). History of KRAS eva luation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one patient with KRAS mutation-negative tumors received panitumumab or cetuximab.
The addition of Stivarga to BSC resulted in a statistically significant improvement in survival compared to placebo plus BSC (see Table 3 and Figure 1).
Table 3: Efficacy Results from Study 1
Stivarga + BSC
(N=505)
Placebo + BSC
(N=255)
Overall Survival
Number of deaths, n (%)
275 (55%)
157 (62%)
Median Overall Survival (months)
6.4
5.0
95% CI
(5.8, 7.3)
(4.4, 5.8)
HR (95% CI)
0.77 (0.64, 0.94)
Stratified Log-Rank Test P-value a,b
0.0102
Progression-free Survival
Number of Death or Progression, n (%)
417 (83%)
231 (91%)
Median
