2279 - FRONTiER: A Feasibility Trial of Nivolumab With Neoadjuvant CF or DCF Therapy for Locally Advanced Esophageal Carcinoma

Background

The standard neoadjuvant chemotherapy (NAC) in Japan for locally advanced esophageal squamous cell cancer (ESCC) is chemotherapy with CDDP + 5-FU (CF). Docetaxel (DTX) + CF (DCF) is considered a promising regimen, which has been evaluated in a phase III study, JCOG1109. Nivolumab (Nivo) has shown promising efficacy in unresectable ESCC. In a preclinical study immune-checkpoint inhibitors (ICI) have shown efficacy as NAC and may work better than when used as adjuvants. Nivo monotherapy showed a major pathologic response in 43% of lung cancer patients (pts), but it was not shown whether ICI also work with chemotherapy that can lead to myelosuppression. The operative mortality and morbidity after use of ICI as NAC in ESCC are unknown.

Trial design

This multi-cohort phase I study is designed to evaluate the safety and efficacy of ICI combined with NAC in ESCC. Histologically proven ESCC pts with cT1N1-3M0 or cT2-3N0-3M0 (8th-UICC TNM classification), 20-75 years old, PS ≤ 1, no prior therapy against any cancer are eligible. The primary endpoint is the incidence of dose-limiting toxicities (DLT) from the initial dose to the 30th postoperative day. This study contains 4 experimental cohorts; cohort A: 2 courses of CDDP at 80 mg/m2, Nivo at 360mg/body on day 1 and 5-FU at 800 mg/m2 on days 1–5, q3wks; cohort B: one prior administration of Nivo at 240mg/body and otherwise the same regimen as cohort A; cohort C: 3 courses of DTX at 70 mg/m2, CDDP at 70 mg/m2, Nivo at 360mg/body on day 1, and 5-FU at 750 mg/m2 on days 1–5, q3wks; cohort D: one prior administration of Nivo at 240mg/body and otherwise the same regimen as cohort C. DLT was defined as follows: Nivo related, grade 4 neutropenia lasting 5 days or longer, >38 degree fever or grade 4 neutropenia lasting 3 days or longer, grade 4 thrombocytopenia lasting 3 days or longer, non-hematological toxicities of grade 3 or higher, grade 4 post-operative adverse events or grade 3 post-operative adverse events excluding hematological toxicity, anastomotic leak, pleural effusion and lung infection. 6 pts are planned to enroll to each cohort and less than one DLT was determined as safety among 6 pts. After this evaluation, we will add 12 pts as an expanded cohort.

Clinical trial identification

NCT03914443.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Ono Pharmaceutical Co.,Ltd.

Disclosure

K. Kato: Research grant / Funding (self), Research grant / Funding (institution): ONO Pharmaceuticals; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Eli Lilly; Research grant / Funding (institution): Beigene. T. Kojima: Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Oncolys BioPharma; Research grant / Funding (institution): Astellas Amgen BioPharma; Research grant / Funding (institution): Chugaiseiyaku; Research grant / Funding (institution): Parexel; Research grant / Funding (institution): Shionogi. H. Hara: Research grant / Funding (self): Japan Agency for Medical Research and Development (AMED); Honoraria (self), Research grant / Funding (self): ONO; Honoraria (self), Research grant / Funding (self): BMS; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Dainippon Sumitomo Pharma; Honoraria (self): Lilly; Research grant / Funding (self): Merck Serono; Honoraria (self), Research grant / Funding (self): MSD; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self), Research grant / Funding (self): Chugai; Research grant / Funding (self): Eisai; Research grant / Funding (self): LSK BioPharma; Research grant / Funding (self): Incyte; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Boehringer-ingelheim; Research grant / Funding (self): Beigene; Honoraria (self): Yakult Honsha; Honoraria (self): Sanofi; Honoraria (self): Takeda. Y. Kitagawa: Research grant / Funding (self): Taiho Pharmaceutical Co., Ltd; Research grant / Funding (self): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (self): Yakult Honsha Co. Ltd.; Research grant / Funding (self): Daiichi Sankyo Company, Limited; Research grant / Funding (self): Merck Serono Co., Ltd.; Research grant / Funding (self): AsahiKASEI Co., Ltd.; Research grant / Funding (self): EA Pharma Co., Ltd.; Research grant / Funding (self): Otsuka Pharmaceutical Co., Ltd.; Research grant / Funding (self): Takeda Pharmaceutical Co., Ltd.; Research grant / Funding (self): Otsuka Pharmaceutical Factory Inc.; Research grant / Funding (self): Shionogi & Co., Ltd.; Research grant / Funding (self): Kaken Pharmaceutical Co., Ltd.; Research grant / Funding (self): Kowa Pharmaceutical Co., Ltd.; Research grant / Funding (self): Astellas Pharma Inc.; Research grant / Funding (self): Medicon Inc.; Research grant / Funding (self): Dainippon Sumitomo Pharma Co., Ltd.; Research grant / Funding (self): Taisho Toyama Pharmaceutical Co., Ltd.; Research grant / Funding (self): Kyouwa Hakkou Kirin Co., Ltd.; Research grant / Funding (self): Pfizer Japan Inc.; Research grant / Funding (self): Ono Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.