Phase I trial of ARQ 501, an Activated Checkpoint Therapy (ACT) agent, in patients with advanced solid tumors

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Abstract
3042 Background: ARQ 501 (β-Lapachone) is a novel anticancer agent that exhibits selective antitumor activity in a broad range of in vitro and in vivo preclinical models. It induces apoptosis in cancer cells by modulating the expression of E2F-1, which in turn activates the G1/S-phase checkpoint. This novel mechanism of action stimulated interest in the clinical development of ARQ 501 as an antitumor agent. Methods: A phase I clinical trial was initiated to define the maximum tolerated dose (MTD) and characterize the pharmacokinetic behavior of ARQ 501 administered as a weekly 1-hour intravenous infusion. A modified Simon accelerated titration scheme was used for dose escalation. Results: Eighteen patients have received a total of 41 monthly courses of ARQ 501 at doses ranging from 10–550 mg/m2. Patient characteristics: 11M/7F; median age 58.5 years (range 33–73). Tumor types include: lung (2), sarcoma (5), colorectal (3), pancreatic (2), and others (6). All patients had received prior chemotherapy. Up to the 390 mg/m2 dose, ARQ 501 exhibited apparent linear pharmacokinetics, characterized by a mean (±SD) total body clearance that was of 114 ± 29 l/h/m2 (∼2-times > hepatic blood flow) and a steady-state volume of distribution of 490 ± 304 l/m2 (>10-times total body weight). There was no evidence of drug accumulation or change in disposition upon repeated weekly dosing. At the 390 mg/m2 dose level, the plasma concentration of ARQ 501 was 2434 ± 346 ng/ml at the end of the 1 h infusion and 6.9 ± 1.1 ng/ml at 24 h. A partial response has been observed in a patient with uterine leiomyosarcoma who remains on study after 56 weeks of therapy. Two patients achieved stable disease (16 and 32 weeks). Adverse events have been mild, including anemia and fatigue. Conclusions: Initial dose escalation of ARQ 501 has been achieved without evidence of dose limiting toxicity. Early signs of clinical activity have been demonstrated by partial response and stable disease cases.

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