Nivolumab (Nivo) is a human IgG4 programmed death receptor-1 (PD-1) monoclonal antibody that blocks the interaction between PD-1 and its ligands, releasing PD-1 pathway-mediated inhibition of the anti-tumor immune response. Nivo has demonstrated significant improvement in overall survival (OS) in the phase III trial (ONO4538-12) for patients (pts) in salvage line treatment of advanced gastric cancer (AGC). Ramucirumab (Ram) is a human IgG1 monoclonal VEGFR-2 antagonist antibody. Ram as monotherapy or in combination with paclitaxel, prolonged survival in AGC. Blocking VEGFR-2 relieves T cell exhaustion by reverting the expression of inhibitory molecules, and improves T cell infiltration into tumors. Based on synergistic anti-tumor effect induced by simultaneous blockades of PD-1 and VEGFR-2 in preclinical studies, this phase I/II study is designed to investigate the safety and tolerability of Nivo plus Ram in the 2nd line chemotherapy for with AGC. This study is conducted at 5 sites in Japan and started in January 2017.
AGC pts with measurable lesions, aged ≥ 20 years, after disease progression on 1st line chemotherapy (platinum plus fluoropryimidine) will be enrolled in this study. Eligible pts will receive Ram and Nivo every two weeks until unacceptable toxicity or disease progression. In the phase I part, the doses of Ram/Nivo will set at 8/3 mg/kg (level 1) and 8/1 (level 0), and the recommended dose (RD) of Ram and Nivo will be determined based on the safety of 6 patients. In the phase II part, the primary endpoint is a 6-months progression-free survival (PFS) rate. The planned sample size is 44 with one-sided alpha of 0.05 and power of 80% based on the expected and threshold 6-months PFS ratios as 36% and 18% (using the Kaplan–Meier estimator). Secondary endpoints include overall response rate, disease control rate, overall survival, and safety. Exploratory endpoints include anti-tumor immune response using immune gene expression, PD-L1 and mismatch repair protein expression in tumor tissue, immune cell subset in peripheral blood, serum drug concentration measurements, serum microRNA expression, and genomic profiling of CTCs using next-generation sequencing, etc. Clinical trial information: NCT02999295
Clinical trial identification
Legal entity responsible for the study
H. Miyamoto: Leadership: Fiverings (CRO Company), stock ownership: Fiverings (CRO company), ONO Pharmaceutical. H. Hara: Honoraria; Chugai Pharma, Taiho Pharmaceutical, Merck Serono, Yakult Honsha, Lilly Counsulting or Advisory Role; Ono Pharmaceutical, Chugai Pharma. D. Takahari: Honoraria; Taiho, Eli lilly, Chugai, Yakult Consulting or advisory role; Taiho, Eli Lilly. Research Funding; Taiho. N. Machida: Honoraria; Taiho, Chugai, Lilly, Yakult. Research Funding; MSD, Taiho, Ono, Lilly, Daiichi-Sankyo. T. Esaki: Honoraria; Chugai, Eli lilly, Taiho, Merck Serono, Ono, Nihon Kayaku, Eisai. Research Funding; Eli lilly, Taiho, Novartis, Daiich-Sankyo, DS pharma, AstraZeneca, Merck Serono, Ono, MSD. N. Boku, K. Kato: Consulting or Advisory role; Ono. Research Funding; Ono, MSD, Merck Serono. All other authors have declared no conflicts of interest.