G1t28, A Cyclin Dependent Kinase 4/6 Inhibitor, In Combination With Etoposide And Carboplatin For Extensive Stage Small Cell Lung Cancer (Es-Sclc): Preliminary Results

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LABackground: Chemotherapy-induced toxicity to the bone marrow and immune system is a significant acute and long-term issue of cancer therapy. G1T28 is a highly potent and selective CDK4/6 inhibitor (CDK4/6i) in development to reduce chemotherapy-induced myelosuppression and preserve immune system function in patients (pts) with CDK4/6-independent cancers such as SCLC. Hematopoietic stem and progenitor cells (HSPC) are dependent upon CDK4/6 for proliferation, and preclinical models demonstrated that transient G1T28-induced G1 cell cycle arrest renders them resistant to chemotherapy cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term function, and enhancement of chemotherapy anti-tumor activity. Methods: Objectives of this ongoing multicenter Phase 1b/2a study are to assess the dose limiting toxicities (DLTs), safety and tolerability, hematological profile, PK, and anti-tumor activity of G1T28 in combination with etoposide and carboplatin (EP; [NCT02499770][1]). Part 1 is open-label, dose-finding, in up to 24 pts, and Part 2 is randomized (1:1), double-blind, in 70 pts. Eligible pts had histologically or cytologically confirmed diagnosis of ES-SCLC, adequate organ function, ECOG performance status (PS) 0-2, no prior chemotherapy, and no symptomatic brain metastases. G1T28 200 mg/m2 (derived from Phase 1a healthy volunteer study [G1T28-1-01] and expected to maintain HSPC G1 arrest beyond EP exposure) was administered IV prior to EP on days 1-3 every 21-days. Results: The first cohort enrolled 6 pts: median age 72 years; 5 females, 1 male; 2, 3, and 1 with ECOG PS of 0, 1, and 2, respectively. G1T28 + EP was well tolerated. Two asymptomatic DLTs occurred in cycle 1 in two pts: absolute neutrophil count (ANC) u003c 1,500 prior to cycle 2 day 1 (ANC = 1,200), and grade 4 thrombocytopenia (24,000 platelets). No febrile neutropenia occurred. All pts had a tumor response. Two had disappearance of all target lesions after 4 cycles, one with a confirmed complete response (CR) at cycle 6 and one with a confirmed partial response (PR) after cycle 4 (non-target lesions still present). Three pts had robust confirmed PRs after cycle 4 and one pt had a robust PR after cycle 2. G1T28 AUC was slightly lower than expected; etoposide and carboplatin PK were consistent with historical data. Conclusions: G1T28, a novel CDK4/6i, is being investigated in combination with EP for pts with ES-SCLC. In the first 6 pts, the combination was well tolerated, without any episodes of febrile neutropenia. Early efficacy results are promising with all 6 enrolled pts responding to therapy (CR or PR). This novel approach allowing the administration of chemotherapy with preservation of hematopoietic function and cellular immunity could improve treatment outcomes of pts with CDK4/6-independent tumors. Enrollment is ongoing and updated data will be presented.Citation Format: Caio Max S. Rocha Lima, Patrick J. Roberts, Victor M. Priego, Stephen G. Divers, Melanie Thomas, Ralph Boccia, R. Timothy Webb, Katie Stabler, Karenann M. Makhuli, Rajesh Malik, Raid Aljumaily. G1T28, a cyclin dependent kinase 4/6 inhibitor, in combination with etoposide and carboplatin for extensive stage small cell lung cancer (ES-SCLC): preliminary results. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT151. [1]: /lookup/external-ref?link_type=CLINTRIALGOVu0026access_num=NCT02499770u0026atom=%2Fcanres%2F76%2F14_Supplement%2FCT151.atom