Phase 1 pilot study of RRx-001 + nivolumab in patients with advanced metastatic cancer (PRIMETIME)

by Selleckchem | Aug 01 2023

Background: Bromonitrozidine (RRx-001) is a minimally toxic, NLRP3 inhibitor that has been observed, in experimental systems, to also downregulate CD47, repolarize tumor associated macrophages (TAMs) and normalize aberrant tumor perfusion. This phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced cancer and no standard options.

Methods: This single arm, single site, open-label pilot study (NCT02518958) called PRIMETIME was designed to evaluate the safety profile of RRx-001 and nivolumab in patients with advanced malignancies and no other standard therapeutic options. A 3 + 3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. The RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, twelve patients received treatment for only 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 16 weeks of the first dose of RRx-001 and nivolumab were characterized according to CTCAE v4.03.

Results: Twelve patients received ≥1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no DLTs. The main adverse event related to RRx-001 was infusion reaction (33.3%). The main adverse event related to the combination was pseudoprogression manifested by larger tumors in patients that were symptomatically improved (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). The objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of ≥SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination.

Conclusions: The combination of RRx-001 and nivolumab was safe and well-tolerated with preliminary evidence of anti-cancer activity. Further clinical trials with RRx-001 and nivolumab are warranted.

Comments:

The study you described is a phase 1 pilot study called PRIMETIME (NCT02518958), which aimed to investigate the safety and feasibility of combining RRx-001, a minimally toxic NLRP3 inhibitor, with nivolumab in patients with advanced cancer who had no other standard treatment options available.

The study utilized a single-arm, single-site, open-label design. The safety profile of the combination was evaluated using a 3 + 3 trial design, which involved escalating the dose of RRx-001 while administering nivolumab at a fixed dose of 3 mg/kg once every two weeks. The initial dose of RRx-001 was 2 mg IV weekly, with four dose level escalations up to 16 mg IV weekly.

Twelve patients participated in the study and received at least one dose of RRx-001 and nivolumab. The treatment duration was limited to four cycles (12 weeks) for all patients due to the unavailability of nivolumab supplied to the Sponsor during the study period.

The results of the study showed that the combination of RRx-001 and nivolumab was generally well-tolerated. There were no dose-limiting toxicities (DLTs) observed. The main adverse event related to RRx-001 was infusion reaction, which occurred in 33.3% of patients. Pseudoprogression, characterized by an increase in tumor size in patients who showed symptomatic improvement, was the main adverse event related to the combination, observed in 25% of patients. Immune-related treatment-emergent adverse events included pneumonitis (8.3%) and hypothyroidism (8.3%).

The objective response rate at 12 weeks was 25%, indicating a partial response in a subset of patients, and the disease control rate (DCR), which includes stable disease or better, was 67% based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. However, 25% of the patients experienced disease progression while on the combination therapy.

Based on the findings of this pilot study, the combination of RRx-001 and nivolumab demonstrated a favorable safety profile and preliminary evidence of anti-cancer activity. The results suggest the need for further clinical trials to evaluate the efficacy and safety of RRx-001 and nivolumab in a larger cohort of patients.