Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors

3548 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented. [Table: see text]