534MO - First in human study of ONO-4578, a PGE2-receptor EP4 antagonist, in monotherapy and combination with PD-1 checkpoint inhibitor nivolumab in patients with advanced or metastatic solid tumours

Background

Prostaglandin E₂ (PGE₂) contributes to immunosuppression in the tumour microenvironment through PGE₂ receptor 4 (EP4). ONO-4578 is a novel, potent, and highly selective small-molecule antagonist of EP4. Our preclinical data showed that ONO-4578 promoted anti-tumour immunity and a combination of ONO-4578 and anti-PD-1 antibody resulted in enhanced anti-tumour effects in syngeneic mouse models compared with anti-PD-1 monotherapy. ONO-4578 in combination with Nivolumab may be useful in the treatment of cancer patients (pts).

Methods

This is a first-in-human, dose-escalation study. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of ONO-4578 monotherapy (Part A) and combination with Nivolumab (Part B) in pts with advanced or metastatic solid tumours. Patients received ONO-4578 (30-100 mg, QD, orally), or a combination of ONO-4578 (2-60 mg, QD, orally) and Nivolumab (240 mg, i.v., Q2W). We evaluated pharmacological effect on ex vivo TNF-α release and urinary tetranor-PGEM.

Results

As of 6 Feb 2020, 10 pts received ONO-4578 monotherapy (1 pt at 30 mg, 3 pts at 60 mg, 6 pts at 100 mg), and 21 pts received a combination of ONO-4578 and Nivolumab (3 pts each at 2, 5, 10, 20, 40 mg and 6 pts at 60 mg of ONO-4578). DLTs occurred in 3 pts: grade (G) 3 duodenal ulcer at 100 mg in Part A; G3 erythema multiforme at 60 mg, G3 amylase increased and G4 lipase increased at 60 mg in Part B. MTD was not reached in either parts. Treatment was discontinued due to AEs for 2 pts in Part A (2 duodenal ulcers, duodenitis and gastritis) and 2 pts in Part B (erythema multiforme, amylase increased and lipase increased). ONO-4578 exposure was dose-proportional up to 100 mg and not interactive with nivolumab. Of 10 tumour-evaluable pts in Part A, no pts had complete or partial responses, and 3 pts had stable disease (SD). Of 21 tumour-evaluable pts in Part B, 1 pt (SCLC, ONO-4578 dose, 40 mg) had partial response (PR), and 5 pts had SD including 1 pt (PDAC, 2 mg) unconfirmed PR.

Conclusions

ONO-4578, both monotherapy and in combination with Nivolumab, was well tolerated. The MTD was not reached in patients with solid tumours.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

ONO PHARMACEUTICAL CO., LTD.

Funding

ONO PHARMACEUTICAL CO., LTD. Bristol-Myers Squibb.

Disclosure

N. Yamamoto: Advisory/Consultancy, Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): Takeda; Advisory/Consultancy: Otsuka; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Advisory/Consultancy: Cimic; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Chugai; Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli Lilly; Speaker Bureau/Expert testimony, Research grant/Funding (institution): ONO; Speaker Bureau/Expert testimony: Sysmex; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Taiho; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Kyowa-Hakko Kirin; Research grant/Funding (institution): Janssen Pharma; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Merck; Research grant/Funding (institution): GSK. T. Koyama: Honoraria (self): Sysmex; Honoraria (self): Chugai. M. Nishino: Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): Boehringer Ingelheim Japan; Honoraria (self), Honoraria (institution): Chugai; Honoraria (self), Honoraria (institution): Eli Lilly; Honoraria (self): MSD; Honoraria (self): ONO; Honoraria (self): Taiho. S. Iwasa: Honoraria (self), Research grant/Funding (institution): ONO; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self): Eli Lilly; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Merck Biopharma. S. Kondo: Research grant/Funding (institution): MSD; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): AZD; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Boehringer Ingelheim. K. Yonemori: Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): Pfizer; Honoraria (self): Taiho; Advisory/Consultancy: Novartis; Advisory/Consultancy: Chugai; Advisory/Consultancy: Ono; Advisory/Consultancy: Takeda. T. Yoshida: Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Chugai; Speaker Bureau/Expert testimony: Novartis; Research grant/Funding (institution): Ono; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): MSD; Research grant/Funding (institution): AbbVie. K. Tamura: Speaker Bureau/Expert testimony, Research grant/Funding (self): Eli Lilly; Speaker Bureau/Expert testimony, Research grant/Funding (self): Chugai; Speaker Bureau/Expert testimony, Research grant/Funding (self): Pfizer; Research grant/Funding (self): Daiichi Sankyo; Research grant/Funding (self): Sanofi; Research grant/Funding (self): MSD; Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Novartis; Research grant/Funding (self): Clovis Oncology. T. Ozaki: Full/Part-time employment: Ono pharmaceutical. M. Kondo: Full/Part-time employment: Ono pharmaceutical. T. Shimizu: Advisory/Consultancy, Research grant/Funding (institution): Millenium-Takeda; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): BMS; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Symbio Pharmaceuticals; Research grant/Funding (institution): 3D-Medicine; Research grant/Funding (institution): Chordia Therapeutics; Research grant/Funding (institution): Five Prime; Research grant/Funding (institution): PharmaMar. All other authors have declared no conflicts of interest.