Abstract CT151: 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

Background: 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). 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) < 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