Activity observed in a phase I dose escalation trial of the hypoxia-activated, NO prodrug, RRx001.

Abstract

Listen

Translate article

241 Background: RRx-001, the first member of a new class of anticancer compounds sourced from the defense industry, is a hypoxia-selective, nitrite reductase-activated prodrug of nitric oxide (NO). The active metabolites selectively enhance oxidative and nitrosative stress in cancer cells through glutathione depletion, ROS formation, and the generation of high local concentrations of NO. The objectives of this Phase 1 dose-escalation trial were to investigate safety, dose-limiting toxicities (DLTs), pharmacodynamics and pharmacokinetics (PK) of RRx-001. Methods: 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) over 2-3 hours once weekly for 8 weeks to patients with advanced cancer in successive dose-escalating cohorts. PK was collected on days 1 and 50, and tumor blood flow, assessed by CEUS or DCE/DWI-MRI, was performed on days 1 and 8. Tumor response was determined every 8 weeks. Results: To date 12 patients have been dosed across 3 successive cohorts (10, 16.7, and 24.6 mg/m2). Tumor types included pancreas (3), colorectal (5), head and neck (2), melanoma (1), and cholangiocarcinoma (1). No DLTs or treatment-associated SAEs were observed. Transient infusion site pain was reported in 10/12 patients, grade 1 (9/10) or grade 2 (1/10), generally managed by lengthening the infusion duration and using peripheral venous access. No relevant treatment-related changes in laboratory values were observed. Seven patients were evaluable for response, with 1 partial response (parotid tumor). Three patients had stable disease ≥ 2 months (2 pancreas, 1 colorectal with treatment duration 10+ months, exceeding the response to his previous chemo regimen). One pancreas patient with an increase in tumor size due to treatment-related central necrosis was diagnosed with pseudoprogression and remained on study for 4 months. Conclusions: RRx-001, an anticancer agent with a novel structure and mechanism of action, is well tolerated with mild infusion-site pain. PK and PD data will be presented. Escalation is ongoing, but preliminary evidence of anti-tumor activity is promising. Clinical trial information: NCT01359982.