First-in-human study with ARQ 621, a novel inhibitor of Eg5: Final results from the solid tumors cohort.

Developmental Therapeutics - Experimental Therapeutics
Session Type and Session Title: 
General Poster Session, Developmental Therapeutics - Experimental Therapeutics
Abstract Number: 


J Clin Oncol 29: 2011 (suppl; abstr 3076)
L. C. Chen, L. S. Rosen, T. Iyengar, J. W. Goldman, R. Savage, J. Kazakin, T. C. K. Chan, B. E. Schwartz, G. Abbadessa, D. D. Von Hoff; Nevada Cancer Institute, Las Vegas, NV; Premiere Oncology, Santa Monica, CA; Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ; ArQule, Inc., Woburn, MA

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Abstract Disclosures


Background: ARQ 621 is an allosteric, potent and selective inhibitor of Eg5, a microtubule-based ATPase motor protein involved in cell division. Over-expression of Eg5 causes genomic instability and tumor formation in mice; therefore, Eg5 is a potential anti-cancer target. Preclinical data shows anti-tumor activity of ARQ 621 across a wide range of cell lines from human solid and hematological malignancies. We present here safety, pharmacokinetics (PK), and preliminary activity of ARQ 621 in patients with solid tumors. Methods: Patients (pts) were enrolled into this multi-cohort phase I trial at the initial intravenous dose of 10 mg/m2/week. Drug was administered over 1-2 hours weekly. Cohorts of 3 or 6 patients were based on a 3+3 dose escalation schedule. Dose was increased according to a modified Fibonacci scheme. Treatment continued until disease progression or unacceptable toxicity. Results: The bone marrow toxicity and DNA damage seen with other Eg5 inhibitors were not evident with ARQ 621. As of January 20, 2011, 48 pts (22 male; median age 60.5 yrs, ECOG PS 0 [N=11], PS 1 [N=36], PS 2 [N=1]) with solid tumors were enrolled. The most common tumors in enrolled pts were colorectal (N=11), pancreatic (N=5) and breast (N=4). Treatment-emergent adverse events (TEAEs) were reported in 47 (95.9%) pts. The most common (> 10%) include fatigue 17 (34.7%), nausea 12 (24.5%), anemia 11 (22.4%), and vomiting 10 (20.4 %). Sixteen pts experienced 27 serious AEs (including anemia, sepsis, pneumonia, pleural effusion, DVT). SAEs considered at least possibly drug related were fatigue, acute intravascular hemolysis, abdominal pain (at 400 mg/m2/wk) and DVT (at 140 mg/m2/wk). Two cases of transient neutropenia were reported at 400mg/m2/wk. The next lower dose of 280mg/m2/wk was deemed to be the recommended phase 2 dose. Six pts (cholangiosarcoma, liposarcoma, leiomyosarcoma, cervical, carcinoid, colorectal carcinoma) remained stable for > 4 months. Conclusions: ARQ 621 appears well tolerated at the weekly dose of 280mg/m2. The dose and frequency are higher than those reported with other Eg5 inhibitors.