A phase 1 dose-escalation study of RiMO-301 with palliative radiation in advanced tumors.

2527 Background: Nanoscale metal−organic frameworks (MOFs) are a new class of organic−inorganic hybrid nanomaterials constructed from metal centers and organic ligands. Preclinical studies have shown that nanoscale MOFs can enhance the antitumor effects of ionizing radiation via a unique radiotherapy-radiodynamic therapy mode of action, and MOFs plus radiation can enhance the immunotherapeutic effects of immune checkpoint inhibitors. RiMO-301 is a hafnium-based MOF which enhances radiotherapy and checkpoint blockade immunotherapy without showing systemic toxicity in preclinical models. RiMO-301 is the first MOF to enter clinical trials on human patients. Methods: This is a multicenter, open-label, first-in-human dose-escalation phase I trial of RiMO-301 NCT03444714. The primary objective is to determine the maximum tolerated dose (MTD) of locally injected RiMO-301 with or without the PD-1 inhibitor pembrolizumab in patients treated with concurrent palliative doses of radiation (20 Gy in 5 fractions or 30 Gy in 10 fractions) using a 3+3 design. The MTD is defined as the dose associated with dose-limiting toxicity (DLT) in less than 33% of patients. The secondary objective is to evaluate antitumor response (objective response rate, ORR) using RECIST and itRECIST criteria. Results: A total of 25 patients were enrolled and treated with escalating doses of RiMO-301 (relative to tumor volumes). No protocol defined DLT was reported. The observed possibly treatment related adverse events included mild dermatitis radiation, mild dysgeusia, diarrhea, mild hypotension (30 days post treatment) and mild dizziness (30 days post treatment). One patient each experienced a Grade 2 alanine aminotransferase increase 45 days post treatment, a Grade 2 dry mouth, and a Grade 3 pain at the injection site. Nineteen patients were evaluable, with 13 and 6 patients, respectively, for RiMO-301 without and with pembrolizumab treatments. By itRECIST criteria, RiMO-301 without pembrolizumab demonstrated 38.5% (5/13) ORR (1 complete response and 4 partial responses) with 2 additional patients experiencing 20-30% tumor size reduction. RiMO-301 with pembrolizumab exhibited 66.7% (4/6) ORR with the 2 remaining patients showing 15-20% tumor size reduction. Preliminary pharmacokinetic analysis indicated that the hafnium concentrations in the systemic circulation were either below or barely above the level of detection. Conclusions: RiMO-301 with or without pembrolizumab was well tolerated and demonstrated promising signs of efficacy in patients with advanced tumors when treated with concurrent palliative radiotherapy. The results support the use of RiMO-301 as a potential radio-enhancer and will prompt further phase 2 studies in the development of RiMO-301 for patients undergoing radiotherapy. Clinical trial information: NCT03444714 .