A phase I study of ARQ 197 in combination with temsirolimus in patients (Pts) with advanced solid tumors.

Abstract

2555 Background: Disregulated c-Met activity is implicated in tumor progression and metastasis. Phosporylation of c-Met leads to activation of the PI3K/AKT/mTOR pathway. Preclinical studies demonstrate that combined inhibition of c-Met and mTOR is effective. ARQ 197 (tivantinib) is an inhibitor of c-Met and Temsirolimus selectively inhibits mTOR. This study is designed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), adverse events (AEs), clinical activity, and pharmacokinetic (PK) parameters of this combination. Methods: This open label phase I study utilizes a 3+3 dose escalation of ARQ 197 (120mg-480mg bid) and Temsirolimus (20-25mg IV weekly) followed by dose expansion at MTD. ARQ 197 is primarily metabolized by CYP2C19. Separate cohorts for dose escalation are incorporated for poor and extensive metabolizers. Cycles are 28 days, except cycle 1 which is 35 days, to evaluate PK interactions. Results: 14 pts (median age 60.5 [range 29-71]; 8 male:6 female) were enrolled. The most common malignancies were colorectal (4 pts), ovarian (2 pts) and renal cell carcinoma (2 pts). 3 pts were unevaluable per protocol. 11 evaluable patients were on study a median of 55.5 days (range 15-296). After 3 evaluable subjects there was no DLT at dose level (DL) 1. At DL2, there were 2 DLTs. 1 pt received <75% of drug due to grade (gr) 3 hypophosphatemia and gr 3 diarrhea but had baseline diarrhea. A 2ndpt had gr 4 neutropenia and gr 3 mucositis. DL 1 was expanded with 3 additional pts without DLT. An amendment with stricter eligibility criteria was approved by CTEP and dose was re-escalated to DL2. 2 additional pts have been treated without DLT. Dose escalation will continue if 1 additional pt at DL2 does not have DLT. The most common AEs at least possibly related to therapy included: fatigue (gr 1-2 in 9 pts), anemia (gr 2 in 7 pts, gr 3 in 1 pt), nausea (grade 1-2 in 8 pts) and diarrhea (gr 1-2 in 6 pts, and gr 3 in 1 pt). 1 pt with ovarian cancer had a confirmed partial response, a decline in CA 125 and remained on study for > 9 months. Conclusions: ARQ 197 in combination with Temsirolimus appears to be well-tolerated at biologically active doses. Dose escalation and PK analysis is ongoing. MTD expansion is planned. Clinical trial information: 9145.