Anti-VEGFR, PDGFR, and CSF1R tyrosine kinase inhibitor CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma: a phase 1 clinical trial

Abstract

BackgroundCM082 (X-82) is an oral multikinase inhibitor that targets VEGFR, PDGFR, and CSF1R. We aimed to investigate the safety profile of CM082 in combination with everolimus for treatment of metastatic renal cell carcinoma. MethodsWe did a phase 1 study in Chinese patients aged 18–75 years, with histologically or cytologically confirmed diagnosis of clear cell renal cell carcinoma, which had progressed on at least one VEGFR tyrosine kinase inhibitor therapy in Peking University Cancer Hospital, Beijing, China. 3+3 dose escalation was done from 100 mg to 200 mg to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of oral CM082 daily in combination with oral everolimus 5 mg daily. We further assessed the safety and efficacy of this combination regimen in an expansion cohort. FindingsBetween Sept 11, 2015, and July 12, 2016, we enrolled 22 patients with clear cell renal cell carcinoma. At the cutoff date (Aug 16, 2017), 15 patients had completed treatment, four patients had discontinued treatment, and three patients were still on treatment. 21 patients (95%) had received at least one VEGFR tyrosine kinase inhibitor therapy. DLT was observed in one (17%) of six patients: grade 4 thrombocytopenia at 200 mg. CM082 200 mg plus everolimus 5 mg did not exceed MTD, and was chosen as the optimal biological dose regimen. CM082 was well tolerated by most patients at a daily dose of 200 mg or less; grade 3–4 adverse events and adverse reactions were reported in 14 (64%) patients. The most common grade 3–4 adverse event (10%) and adverse reaction (14%) were hypertension. 20 patients (91%) were evaluable for tumour response per Response Evaluation Criteria In Solid Tumors version 1.1. Promising antitumour activity of CM082 and everolimus 5 mg in patients with metastatic renal cell carcinoma has been shown. No complete remission was seen. Partial response was observed in six (30%) of 20 patients, and stable disease was achieved in 14 (70%) of 20 patients. The objective response was achieved in 30% and disease control in 100%. At CM082 200 mg plus everolimus 5 mg, five (36%) of 14 patients had partial response and nine (64%) of 14 patients had stable disease with 100% disease control. The median progression-free survival was 7·9 months (95% CI 4·5–17·0). InterpretationCM082 in combination with everolimus 5 mg was well tolerated in patients with advanced renal cell carcinoma who received at least one previous VEGFR tyrosine kinase inhibitor. MTD was not reached at up to CM082 200 mg plus everolimus 5 mg. This dose regimen was chosen as the recommended phase 2 dose for Chinese patients with renal cell carcinoma. FundingAnewPharma.