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Phase 1 pilot study of RRx-001 + nivolumab in patients with advanced metastatic cancer (PRIMETIME)
Tony Reid1, Bryan Oronsky2, Scott Caroen2
1Department of Bioengineering, University of California at San Diego, San Diego, CA, United States.
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.
Clinical Trial Registration:
ClinicalTrials.gov identifier, NCT02518958.
Insights
This pilot study found the combination of Bromonitrozidine (RRx-001) and nivolumab to be safe and well-tolerated in advanced cancer patients. Preliminary anti-cancer activity was observed, warranting further clinical trials for this novel cancer therapy.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Bromonitrozidine (RRx-001) is an NLRP3 inhibitor with potential immunomodulatory effects, including CD47 downregulation and tumor microenvironment normalization.
- RRx-001 exhibits minimal toxicity and has shown promise in experimental systems for repolarizing tumor-associated macrophages (TAMs) and normalizing tumor perfusion.
Purpose of the Study:
- To assess the safety and feasibility of combining RRx-001 with nivolumab in patients with advanced cancer lacking standard treatment options.
- To establish the safety profile of the RRx-001 and nivolumab combination through a dose-escalation Phase 1 study.
Main Methods:
- A single-arm, open-label pilot study (NCT02518958) involving 12 patients with advanced malignancies.
- A 3+3 trial design was employed to determine the maximum tolerated dose, with RRx-001 administered weekly and nivolumab every two weeks.
- Adverse events were characterized using CTCAE v4.03, and efficacy was assessed by RECIST v1.1.
Main Results:
- The RRx-001 and nivolumab combination was safe and well-tolerated, with no dose-limiting toxicities observed.
- The most frequent treatment-related adverse event for RRx-001 was infusion reaction (33.3%), and for the combination, pseudoprogression (25%).
- An objective response rate of 25% and a disease control rate of 67% were observed at 12 weeks.
Conclusions:
- The combination of RRx-001 and nivolumab demonstrates a favorable safety profile and preliminary anti-cancer activity in advanced cancer patients.
- Further clinical investigation of RRx-001 in combination with nivolumab is warranted to explore its therapeutic potential.
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