y meaningful changes in the exposure of either ramucirumab or its concomitant drugs in the approved combinations, including paclitaxel, docetaxel, and irinotecan (or its active metabolite, SN-38), were observed in patients with solid tumors.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been performed to test ramucirumab for potential carcinogenicity or genotoxicity.
Inhibition of VEGFR2 signaling in animal models was shown to result in changes to hormone levels critical for pregnancy, and, in monkeys, an increased duration of the follicular cycle. In a 39 week animal study, female monkeys treated with ramucirumab showed dose dependent increases in follicular mineralization of the ovary.
13.2 Animal Toxicology and/or Pharmacology
Adverse effects in the kidney (glomerulonephritis) occurred in monkeys at doses of 16-50 mg/kg (0.7-5.5 times the exposure in humans at the recommended dose of ramucirumab as a single agent).
A single dose of ramucirumab resulting in an exposure approximately 10 times the exposure in humans at the recommended dose of ramucirumab as a single agent did not significantly impair wound healing in monkeys using a full-thickness incisional model.
14 CLINICAL STUDIES
14.1 Gastric Cancer
Study 1 was a multinational, randomized, double-blind, multicenter study of CYRAMZA plus best supportive care (BSC) versus placebo plus BSC that randomized (2:1) 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]) who previously received platinum- or fluoropyrimidine-containing chemotherapy. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have ECOG PS of 0 or 1. Patients received either an intravenous infusion of CYRAMZA 8 mg/kg (n=238) or placebo solution (n=117) every 2 weeks. Randomization was stratified by weight loss over the prior 3 months (≥10% versus <10%), geographic region, and location of the primary tumor (gastric versus GEJ).
Demographic and baseline characteristics were similar between treatment arms. Median age was 60 years; 70% of patients were men; 77% were White, 16% Asian; the ECOG PS was 0 for 28% of patients and 1 for 72% of patients; 91% of patients had measurable disease; 75% of patients had gastric cancer; and 25% had adenocarcinoma of the GEJ. The majority of patients (85%) experienced disease progression during or following first-line therapy for metastatic disease. Prior chemotherapy for gastric cancer consisted of platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine-containing regimens without platinum (15%), and platinum-containing regimens without fluoropyrimidine (4%). In Study 1, patients received a median of 4 doses (range 1-34) of CYRAMZA or a median of 3 doses (range 1-30) of placebo.
Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive CYRAMZA as compared to patients randomized to receive placebo. Efficacy results are shown in Table 6 and Figure 1.
Table 6: Randomized Trial of CYRAMZA plus BSC versus Placebo plus |
