Abstract LB-86: Preliminary results from an ongoing phase I trial of RRx-001, a tumor selective cytotoxic agent.
Authors: Reid Tony , Infante Jeffrey R. , Paul Asit , Burris Howard A. , Oronsky Bryan , Scribner Curtis , Knox Susan , Stephens Janet , Santini John , Scicinski Jan 
Published: August 2014

Background and objectives: RRx-001, is the first member of a new class of anticancer compounds that binds to hemoglobin and drives heme and iron-catalyzed redox reactions under hypoxic conditions thereby enhancing oxidative and nitrosative stress in cancer cells through glutathione depletion and the generation of high local concentrations of nitric oxide. The objectives of this Phase 1 dose-escalation trial were to investigate safety, dose-limiting toxicities (DLTs), pharmacodynamics and pharmacokinetics (PK) of RRx-001.

Methodology: Eligible patients had advanced solid tumor malignancies; ECOG PS 0-2; adequate bone marrow function. In a 3+3 escalation design, RRx-001 was administered intravenously (IV) for up to 6 hours weekly for 8 weeks to patients with advanced cancer in successive dose-escalating cohorts. PK samples were collected. Tumor response (CT, PET-CT, biopsy) was determined every 4 or 8 weeks.

Preliminary Data: 19 pts have been dosed over 5 successive cohorts (10, 16.7, 24.6, 33 and 55 mg/m2). Tumor types included pancreas (3), colorectal (9), head and neck (2), melanoma (1), cholangiocarcinoma (1), uterine (1), lung (1) and HCC (1). RRx-001 has been extremely well tolerated with no DLTs or treatment-associated SAEs observed. The only drug-related adverse event (AEs) across all cohorts was acute and transient injection-site vasodilation and pain on infusion, moderate in severity and generally managed with lengthening of the infusion time, using peripheral venous access and prior administration of corticosteroids. No RRx-001-induced systemic toxicities have been observed to date.

14 patients were evaluable for response, 1 with partial response (parotid tumor). Eight patients had stable disease (3 pancreas, 3 with colorectal cancer, 1 uterine, 1 HCC). Two of these pts (salivary and CRC) have remained stable for 6 and 10 months, respectively, and another 2 pts (uterine and HCC) are continuing stably on trial for &gt;3 months. The pt. with CRC who progressed after 10 months on trial responded to previously failed chemotherapy as evidenced by marked decrease in CEA (511 to 311) and re-stabilization of disease for &gt;3 months. Two patients with pancreatic and CRC had an increase in tumor size with extensive central necrosis suggestive of pseudoprogression.

Conclusions: In the ongoing nearly completed Phase 1 trial, RRx-001, an anticancer agent with a novel structure and mechanism of action, is well tolerated with infusion-site pain the only observed AE. Toxicities normally associated with anticancer agents were absent. Single agent activity with a high response rate (64-79%) among patients with advanced, refractory cancer was observed including a renewed response to a previously failed chemotherapy regimen. Phase 2 planning in colorectal cancer and HCC is underway.

Citation Format: Tony Reid, Jeffrey R. Infante, Asit Paul, Howard A. Burris, Bryan Oronsky, Curtis Scribner, Susan Knox, Janet Stephens, John Santini, Jan Scicinski. Preliminary results from an ongoing phase I trial of RRx-001, a tumor selective cytotoxic agent. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-86. doi:10.1158/1538-7445.AM2013-LB-86