A phase 2, open-label, multi-center study of amuvatinib in combination with platinum etoposide chemotherapy in platinum-refractory small cell lung cancer patients

Abstract

Background: Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination with platinum-etoposide (EP) chemotherapy by objective response rate, survival, and tolerability in platinum-refractory small cell lung cancer (SCLC) patients.Methods: This study used a Simon 2-stage design requiring ≥3 centrally confirmed responses in the first 21 subjects. Subjects received EP with 300 mg amuvatinib orally three times daily in cycles of 21 days. A three-day amuvatinib run-in period before EP occurred in Cycle 1. Subjects received the same EP chemotherapy regimen given prior to progression/relapse.Results: Among 23 subjects treated, we observed four PRs (17.4%) per RECIST 1.1, only two of which were centrally confirmed (8.7%, response duration 119, 151 days). Three subjects (13%) had confirmed stable disease. c-Kit H-score was ≥100 in two subjects whose respective durations of disease control were 151 and 256 days.Conclusions: The addition of amuvatinib to EP chemotherapy in unselected, platinum-refractory SCLC did not meet the primary endpoint of ≥3 confirmed responses in stage 1. However, high c-Kit expression in two subjects with durable disease control suggests the potential for further study of amuvatinib in SCLC patients with high c-Kit expression.

A SARS-CoV-2 cytopathicity dataset generated by high-content screening of a large drug repurposing collection

“…Amuvatinib was one of the most potent compounds we identified (IC 50 = 0.02 µM). It was unsuccessful in trials for the treatment of solid tumors and small cell lung carcinoma, although it was well tolerated 49 . Amuvatinib is a promiscuous tyrosine kinase inhibitor, with activity against c-MET, c-RET and the mutant forms of c-KIT, PDGFR and FLT3.…”

Regulation and pharmacological targeting of RAD51 in cancer

“…Amuvatinib phase I clinical trials resulted in reduced RAD51 expression in many patient tumors similar to in vitro studies using human cancer cell lines ( 161 ). However, a subsequent phase II trial with amuvatinib in conjunction with cisplatin or carboplatin did not result in abatement of RAD51 expression, and therefore clinical development of this drug was suspended ( 162 ). While RAD51 inhibitors are a promising target, preclinical investigation is still needed to better understand RAD51 targeting and develop more effective compounds.…”

MET Inhibitors in Small Cell Lung Cancer: From the Bench to the Bedside

“…Finally, a phase II clinical trial [94] evaluating the efficacy of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in combination with platinum-etoposide in relapsed SCLC patients was conducted. Although the study was designed mainly because of the activity of the inhibitor in c-KIT mutant forms, it also has activity against MET.…”