Preliminary results from a phase II study of ARQ 197 in patients with microphthalmia transcription factor family (MiT)-associated tumors

Abstract

10502 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. The drug has demonstrated a favorable safety profile and preliminary anti-cancer activity in three phase 1 studies. MiT tumors include clear cell sarcoma (CCS), alveolar soft part sarcoma (ASPS), and translocation-associated renal cell carcinoma (TLA RCC) and are linked biologically by a shared activated transcriptional mechanism which directly upregulates c-Met. Tumors with this type of chromosomal abnormality are generally resistant to all approved therapies and, in the absence of complete surgical resection, prove invariably fatal. Methods: This is a multi-center, single arm, two-stage phase 2 trial in patients (pts) 13 years of age or older with MiT tumors. Initially pts received 120 mg ARQ 197 orally twice daily (bid). The protocol was amended in August 2008 to increase the dose to 360 mg bid. If either a complete response (CR) or a partial response (PR) were to be observed in the 23 pts in stage 1, the study would be advanced to stage 2 where 16 additional patients will be enrolled. Tumor responses are measured in 8-week intervals per RECIST criteria. Results: To date, 28 pts (19 females, 9 males; median age = 21; 7 CCS, 17 ASPS, 4 RCC) have been treated. One pt with CCS demonstrated a confirmed PR, 15 pts (10 ASPS, 2 CCS, 3 RCC) demonstrated stable disease (SD) for durations up to 29+ weeks, and 4 pts progressed. An overall response rate of 5% and a disease control rate (CR+PR+SD) of 80% were demonstrated among 20 pts who were evaluable for efficacy. The most common drug-related adverse events (AEs) have been fatigue (35.7%), nausea (35.7%), vomiting (21.4%), decreased hemoglobin (10.7%). and cough (10.7%). To date, only 3 drug-related Grade 3 or 4 AEs have been reported including anemia (2) and decreased neutrophil count (1). No drug-related serious AEs or deaths have been reported. Conclusions: To date, ARQ 197 has demonstrated an extremely favorable safety profile and preliminary evidence of anti-cancer activity in these young pts. The criterion for advancing the study from stage 1 to stage 2 has been met. Stage 2 enrollment is ongoing. Updated data on both dose levels will be presented. [Table: see text]