Abstract 2750: ARQ 621, a novel potent and selective inhibitor of Eg5: Preclinical data and early results from a clinical phase 1 study

Background: ARQ 621 is an allosteric, potent and selective inhibitor of Eg5, a microtubule-based ATPase motor protein involved in cell division. Eg5 inhibition is recognized as a potential therapeutic strategy in cancer supported by the observation that over-expression of Eg5 causes genomic instability and tumor formation in mice. In this clinical trial we sought to evaluate the safety and pharmacokinetics of ARQ 621 in patients with solid tumors.

Methods: Patients (pts) are being enrolled into this multi-cohort phase 1 trial at the initial i.v. dose of 10 mg/m2/week. Drug is administered weekly intravenously over 1-2 hours. Cohorts of 3 or 6 patients are based on a 3+3 dose escalation schedule and dose is increased according to a modified Fibonacci scheme. Treatment continues until disease progression or unacceptable toxicity.

Results: Recently expanded preclinical data with ARQ 621 shows anti-tumor activity with potencies in the low nanomolar range across a much wider range of human cancer cell types than previously reported, including colon, NSCLC, gastric, and hematologic cancer cell lines. Furthermore, no evidence of bone marrow toxicity and DNA damage is evident with ARQ 621 as we have seen with a leading Eg5 inhibitor. As of November 19, 2009, 18 pts (60% male; median age 60 yrs, ECOG PS 0 (N=3), PS 1 (N=13), PS 2 (N=2) were enrolled. The most common tumors treated with ARQ 621 were colorectal (N=6) and breast (N=2). Treatment-emergent adverse events (TEAEs) were reported in 13 pts. The most common (> 10%) include fatigue (27%), redness at infusion site 3 (16%), and anemia 3 (16%). Three pts experienced serious AEs (1 each of anemia, sepsis, pneumonia) reported as not drug related. Three pts (cholangiosarcoma, liposarcoma and colorectal carcinoma) remained stable for > 4 months.

Conclusions: Preclinical studies continue to elucidate the potential indications for Eg5 inhibition as well as the combinability of ARQ 621 with other molecularly targeted therapeutics. To date, therapy with ARQ 621 appears well tolerated, with no dose-limiting toxicity observed at doses and frequencies much higher than those achieved with the leading Eg5 inhibitors of comparable potencies. Dose-limiting toxicity has not been reached, and recruitment continues to identify the maximum tolerated dose and a recommended Phase 2 dose. Additional safety, pharmacokinetic, and preliminary efficacy data will be available for presentation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2750.