A Phase I, Open-Label, Multi-Center, Dose-Escalation Study of Codrituzumab, an Anti-Glypican-3 Monoclonal Antibody, in Combination with Atezolizumab in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma

Background: Codrituzumab (Cod) is a recombinant humanized monoclonal antibody against Glypican-3 (GPC3). GPC3 is over-expressed in hepatocellular carcinoma (HCC). Cod elicits antibody-dependent cellular cytotoxicity against human HCC cell lines and shows more potent anti-tumor activity when combined with anti-PD-L1 antibody in syngeneic mouse model. This is a phase I dose-escalation study to evaluate safety/tolerability and pharmacokinetics in combination with the anti-PD-L1 antibody, atezolizumab (Atezo) in advanced HCC patients. Methods: This study is composed of a 3 + 3 dose-escalation part and an expansion part. Patients with advanced or metastatic HCC who had failed prior systemic therapy, GPC3 high expression, ECOG PS 0-1, Child-Pugh A-B7 were eligible. Cod given intravenously 800 or 1600 mg on Day 1, 4, then weekly from Day 8 combined with 1200 mg every 3 weeks dosing of Atezo until disease progression/toxicity. The objectives were to determine MTD of Cod and Atezo combination primarily, to assess safety, antitumor effect (RECIST 1.1) and pharmacokinetics secondarily, and to assess biomarkers exploratory. Results: Ten patients each were enrolled in dose-escalation and expansion parts, respectively. There were 16 men/4 women, median age 58, all Asian, HBV/HCV/neither 11/4/5, ECOG 0/1 15/5. No dose limiting toxicities were observed in dose-escalation part. The most frequently observed adverse events (AEs) were pyrexia (80%), fatigue (50%), decreased appetite (30%), aspartate aminotransferase increased, lymphocyte count decreased (25%), constipation, cough, nasopharyngitis (20%). Grade 3 or higher AEs (≥ 2 patients) were aspartate aminotransferase increased, lymphocyte count decreased (20%), anemia (15%), and ascites (10%). There was 1 confirmed PR, 10 SD (including 1 unconfirmed PR) among 18 evaluable patients and 6 of them had SD for more than 6 months before progression. Conclusions: Cod + Atezo combination was well-tolerated and showed antitumor activity in this advanced, previously treated and GPC3 highly expressed HCC patients. Clinical trial identification: JapicCTI-163325 Registered date: 22/07/2016. Legal entity responsible for the study: Chugai Pharmaceutical Co., Ltd. Funding: Chugai Pharmaceutical Co., Ltd. Disclosure: T. Okusaka: Advisory board: Dainippon Sumitomo Pharma, Taiho Pharmaceutical, Zeria Pharmaceutical, Daiichi Sankyo; Research funding: Eli Lilly Japan K.K. Eisai, Novartis Pharma K.K. Yakult Honsha, Taiho Pharmaceutical, Kowa Company, Kyowa Hakko Kirin, Ono Pharmaceutical, Bayer Yakuhin, Pfizer Japan Inc. AstraZeneca K.K., Dainippon Sumitomo Pharma, Nano Carrier, Baxter Chugai Pharmaceutical, M. Ikeda: Advisory board: Bayer, Yakuhin, Eisai, Novartis Pharma, Shire, MSD; Research funding: Bayer Yakuhin, Kyowa Hakko Kirin, Yakult, Eli Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Baxalta Japan Limited, Chugai Pharmaceutical, Bristol Myers Sqiibb, Merck Serono, Nano Carrier, Aslan Pharmaceuticals, Novartis Pharma, Takara Bio. C-H. Hsu: Advisory board: BMS, ONO, MSD, Merck/Sorono, Novartis, Research funding: MSD. C. Morizane: Advisory board: Yakult Honsha, Novartis, Taiho Pharmaceutical; Research funding: Pfizer, Nobelpharma, Eisai, Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical; Honoraria: Pfizer, Novartis, Yakult Honsha, Lilly, Nobelpharma, Fujifilm, Teijin Pharma, Taiho Pharmaceutical. Y. Hashimoto: Advisory board: Medicos Hirata. T. Ohtomo: Employee: Chugai Pharmaceutical. T. Tanaka: Stock ownership, Employee: Chugai pharmaceutical. M. Kudo: Advisory board: Eisai, Bayer, MSD, Ono, BMS; Research funding: Ono, MSD, Eisai. All other authors have declared no conflicts of interest.