Background: Amuvatinib is an oral multi-targeted TKI of c-Kit and PDGFRα and modulates DNA repair by down regulation of Rad51. Rad51 is a key protein in the homologous recombination repair pathway for DNA double strand breaks which can mediate resistance to DNA-damaging agents. Amuvatinib has demonstrated synergistic activity preclinically with DNA damaging chemotherapy agents including etoposide and doxorubicin. Amuvatinib in combination with DNA damaging agents resulted in clinical responses in SCLC patients, induced Rad51 suppression, and increased DNA damage (53BP1 foci) in skin punch biopsies. These results provided the justification for a Phase 2, OL study of amuvatinib in combination with platinum and etoposide (PE) chemotherapy in SCLC patients who have not responded to or relapsed after standard treatment (ESCAPE; TrEatment of Small Cell lung cancer with Amuvatinib in combination with Platinum Etoposide).

Methods: Patients ≥ 18 years, ECOG PS 0-2, with confirmed SCLC who met one of the following major eligibility criteria were enrolled based on prior PE response: 1) disease progression during PE, 2) relapse ≤ 90 days, 3) SD as best response after at least 2 cycles. Patients who received second-line therapy were eligible if they met any one of these 3 conditions and all other study eligibility criteria. An optimal Simon 2-stage design was employed (α=10%, β=10%, p0=10%, p1=25%). In Stage 1, 21 patients were to be enrolled and ≥ 3 confirmed responses (CR or PR) were required in order to proceed to Stage 2, where an additional 29 patients were to be enrolled. Amuvatinib was administered PO 300 mg TID.

Results: Twenty-three patients, median age of 62 years (range, 44-80); 11 M/12 F; ECOG PS 0 (n=3), 1 (n=12), 2 (n=6), were enrolled in Stage 1 and received a median of two 21-day cycles (range, 1-10). At study entry, 9 (39%), 11 (48%), and 3 (13%) patients presented with disease progression, relapse ≤ 90 days, and SD after at least 2 cycles of PE, respectively. Per PI's assessment, 4 PRs and 7 SDs were observed as best response. Per RECIST 1.1, 2 PRs and 3 SDs were confirmed by follow-up scan ≥ 4 weeks apart for an overall clinical benefit rate (CBR) of 5/23 (22%). No CRs were observed. Grade 3/4 suspected amuvatinib related AEs were neutropenia, thrombocytopenia, atrial fibrillation, diarrhea, esophagitis, and hypercalcemia (1 patient each; 4%); hypokalemia and leukopenia, (2 patients each; 9%). By IHC, baseline expression of RAD51, ERCC1, Chk2, ATM, cKit, and RB will be evaluated and correlated with response.

Conclusions: Amuvatinib demonstrated an overall CBR of 22% in refractory SCLC. While clinical activity was observed, the response rate in Stage 1 did not meet pre-specified study primary endpoint. The safety profile of amuvatinib is consistent with previous published reports of manageable toxicity with non-overlapping toxicities with PE chemotherapy.

Citation Format: Lauren Byers, Leora Horn, Jitendra Gandhi, Goetz Kloecker, Taofeek K. Owonikoko, Saiama Waqar, Maciej J. Krzakowski, Gavin Choy, Nancy Cecchettini, Pietro Taverna, Amarpal Sahai, Mojtaba Noursalehi, Mohammad Azab, D. Ross Camidge. A phase 2 study of Amuvatinib (MP-470), the first RAD51 inhibitor in combination with platinum-etoposide (PE) in refractory or relapsed small cell lung cancer (ESCAPE). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2095. doi:10.1158/1538-7445.AM2013-2095