Phase 1 pilot study of RRx-001 + nivolumab in patients with advanced metastatic cancer (PRIMETIME)
| Autor: | Reid, Tony, Oronsky, Bryan, Caroen, Scott, Quinn, Mary, Williams, Jeannie, Cabrales, Pedro, Abrouk, Nacer |
|---|---|
| Rok vydání: | 2023 |
| Předmět: |
nivolumab
cold tumors Clinical Trials and Supportive Activities Immunology Evaluation of treatments and therapeutic interventions Pilot Projects bromonitrozidine tumor associated macrophage NLRP3 inflammasome inhibitor Second Primary Clinical Research Medical Microbiology Neoplasms 6.1 Pharmaceuticals Humans Azetidines Immunology and Allergy CD-47 RRx-001 6.2 Cellular and gene therapies vascular normalization Cancer |
| Zdroj: | Frontiers in Immunology. 14 |
| ISSN: | 1664-3224 |
| Popis: | BackgroundBromonitrozidine (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.MethodsThis 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.ResultsTwelve 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.ConclusionsThe 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 registrationClinicalTrials.gov identifier, NCT02518958. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|