Abstract 330P
Background
Acidosis is known to promote proliferation and metabasis in tumor microenvironment including pancreatic cancer (PC). Focusing on the ability to exert antitumor effects by alkalizing the cancer microenvironment under acidic conditions, we have developed an alkalizing agent, DFP-17729 (potassium citrate and sodium citrate hydrate combination tablets). We aimed to examine the safety and efficacy of DFP-17729 with chemotherapy in patients with metastatic PC.
Methods
The study was a multi-center, open-label phase I/II study investigating the combination of DFP-17729 plus gemcitabine (Gem) or S-1 after first-line treatment in patients with metastatic PC. The primary objective of phase I portion was to confirm the tolerability with high dose of DFP-17729 (3 g four times every day) in combination with Gem (1000 mg/m2 on days 1, 8 and 15 of 4-week cycle) or S-1 (80 mg/m2 for 28-day of 6-week cycle). The primary objective of phase II portion was to evaluate the efficacy based on overall survival.
Results
From November 2020 to May 2022, 39 patients were enrolled at 6 centers in Japan, and 33 patients were randomized (2:1 ratio). The median age was 65 years (range, 49-77), 5 patients (13%) were second-line treatment, 34 patients (87%) were third-line or later treatment, 8 patients (21%) were treated with Gem and 31 patients (79%) with S-1. No serious adverse event was observed in the phase I portion, and the combination of DFP-17729 with chemotherapy was well tolerated. Median survival time (MST) was 5.3 months for experimental arm versus 6.3 months for control arm with no significant difference in the phase II portion. According to subgroup analysis of combined two portions, MST was 8.9 months for experimental group versus 5.4 months for control group in patients with third-line or later, when combined with S-1 for 6 or more weeks of treatment. Causal mediation analysis showed a significant difference in urine pH between treatment with DFP-17729 and overall survival. No grade 4 or 5 adverse events were observed.
Conclusions
Although the primary endpoint was not met in this study, alkalization of DFP-17729 combined with S-1 shows good potential with survival benefit as third/fourth-line treatment for metastatic PC.
Clinical trial identification
UMIN000042064.
Legal entity responsible for the study
Delta-Fly Pharma, Inc.
Funding
Delta-Fly Pharma, Inc.
Disclosure
M. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Eli Lilly Japan, Eisai, Nihon Servier, Novartis, MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Chugai, Eli Lilly Japan, Eisai, NIHON Servier, Novartis, Taiho, Yakult, Teijin Pharma, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, Incyte Biosciences Japan, Takeda, Ono, MSD, Taisho Pharmaceutical, Nippon Kayaku, Guardant Health Japan, Chugai, Nihon Servier, Takeda, Novartis, Eisai, Rakuten Medical; Financial Interests, Institutional, Invited Speaker: Bayer, Bristol Myers Squibb, Eisai, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, MSD, Ono, Novartis, J-Pharma, Pfizer, Chiome Bioscience, Nihon Servier, Delta-Fly Pharma, Syneos Health, Merus. N.V., Merck biopharma, Boehringer Ingelheim, Invitae. M. Ueno: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Incyte, MSD, Nihon Servier, Ono Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical; Financial Interests, Personal, Advisory Board: Nippon Boehringer Ingelheim, Novartis; Financial Interests, Institutional, Invited Speaker: Astellas Pharma, AstraZeneca, Chugai Pharmaceutical, DFP, Daiichi Sankyo, Eisai, Incyte, MSD, Merck Biopharma, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis. M. Ozaka: Financial Interests, Personal, Invited Speaker: Taiho, Yakult, MSD, Incyte, Ono, Bayer, Servier. J. Furuse: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical, Bayer, Eisai, Eli Lilly Japan, MSD, Yakult Honsha, Chugai Pharma, Novartis Pharma, AstraZeneca, Pfizer, Takeda, Taiho Pharmaceutical, Sanofi, Mylan EPD, EA Pharma, Kyowa Hakko Kirin, Daiichi Sankyo, Teijin pharma, Servier Japan, Incy, Merck Bio, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Astellas, AstraZeneca, Incyte Japan; Financial Interests, Personal, Advisory Board: Fuji film, Mudi Pharma, Onco Therapy Science, Merck Bio, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Chugai Pharma, Astellas, AstraZeneca, Takara Bio, Delta-Fly-Pharma, Incyte Japan; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical, MSD, Merck Bio, J-Pharma, Taiho Pharmaceutical, Takeda, Chugai Pharma, AstraZeneca, Yakult Honsha, Eisai, Daiichi Sankyo, Mochida, Sanofi, Sumitomo Dainippon Bayer, Astellas, Incyte Japan. All other authors have declared no conflicts of interest.