A phase I clinical trial of CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma.

Abstract

4575 Background: CM082 is an oral multikinase inhibitor targeting VEGFR, PDGFR and CSF1R with a shorter half-life and limited tissue accumulation, designed to lower toxicity and enable combination with other therapies. This is a phase I study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of CM082 in combination with everolimus in patients with metastatic renal cell carcinoma. Methods: A 3+3 dose escalation design with expansion cohort was utilized to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of CM082 plus everolimus at 5 mg PO daily for patients with metastatic clear cell renal cell carcinoma. Eligibility include PS 0-1, age ≥18 y, measurable disease, adequate organ function. Results: 22 patients (M/F: 16/6; median age: 55 y [range 32-69]; 21/22 pts [95.5%] had received prior anti-VEGF treatment (tx); 2/22 pts [9.1%] had also received prior mTOR-targeted tx) were treated at 3 dose levels of CM082 (100 mg [n = 4]; 150 mg [n = 3]; 200 mg [n = 15]) in combination with everolimus 5 mg. One patient in cohort 1 was not evaluable for DLT due to consent withdrawal. DLT were observed in one patient: G4 thrombocytopenia at 200 mg. CM082 200 mg plus everolimus 5 mg did not exceed MTD, but was chosen as the optimal biological dose regimen. Median duration of tx was 24 wk (range 1-57, 7/22 [32%] pts ongoing. The most common tx-related adverse events (AEs), all grades, were proteinuria 96% (G3, 5%); leukopenia 77% (G3, 9%); neutropenia 59%, hypercholesterolemia 64%, anemia 50% (G3, 9%), hypertension 46% (G3, 14%), raised aspartate aminotransferase 41%, fatigue 45%, diarrhea 32%, hypertriglyceridemia 32% (G3, 5%) and thrombocytopenia 20% (G4, 5%). At 200mg, partial response (PR) was observed in 5/14 (36%) patients, durable stable disease (SD) (≥24 week) or PR were achieved in 10/14 (71%) patients. Median PFS was 170 days (5.7 months) at this cohort. Conclusions: CM082 200mg in combination with everolimus 5 mg appeared to be well tolerated when administered to pretreated patients with advanced RCC in this Ph1 study. The preliminary efficacy warrant further evaluationand and the follow-up Ph 2/3 study is underway. Clinical trial information: NCT02577458.