Chemotherapy (chemo)-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. T is an iv CDK4/6i in development to preserve HSPC and immune system function during chemo (myelopreservation). Preclinically, transient T-induced G1 arrest renders HSPCs resistant to chemo cytotoxicity, leading to faster hematopoietic recovery and enhanced anti-tumor immunity.
This Phase 2, randomized, placebo (P)-controlled, double-blind study dosed 75 chemo-naïve ES-SCLC pts with adequate organ function, ECOG 0-2, and no symptomatic brain metastases (NCT02499770). Pts received T or P iv prior to etoposide/carboplatin (EP) on days 1 to 3 of each cycle. Growth factors were prohibited in cycle 1; otherwise supportive care was allowed as needed. Lineage-specific endpoints were prespecified to assess the effect of T on myelosuppression. Tumor response was assessed using RECIST v1.1.
Key results are in the table. T + EP was well tolerated with fewer ≥ G3 AEs in T (50%) vs P (83.8%), primarily due to less hematological (heme) toxicity. No T-related ≥ G3 AEs occurred. Improvements were seen with T in neutrophil, RBC and lymphocyte measures in all pt subgroups. There was an increase in activated CD8+ T-cells and a decrease in regulatory T-cells in the peripheral blood (PB) with T. Tumor assessment showed: objective response rate (T 66.7%, P 62.2%); DOR (median T 5.7m, P 4.3m); and PFS (median T 6.2m, P 5.0m; HR 0.6, p = 0.06).Table: 1666PD
|Parameter, n||EP + P N = 37||EP + T N = 38||P-value (1)|
|RBC transfusion ≥ 5 weeks on study||8||2||0.0781|
|Dose reductions due to heme toxicity||12||2||0.0029|
|Lymphocyte count at end of 6 cycles(2)||1.608 x 109/L||1.935 x 109/L||0.0499|
Significance testing at 2-sided α = 0.2 P, n = 22; T, n = 20
Trilaciclib demonstrated (1) myelopreservation across three hematopoietic lineages with fewer supportive care interventions and dose reductions, (2) encouraging DOR and PFS, and (3) changes in peripheral blood T-cell subsets indicating a more robust immune response. These data demonstrate strong proof-of-concept for the myelopreservation benefits of T.
Clinical trial identification
NCT02499770; EudraCT: 2016-001583-11.
Legal entity responsible for the study
G1 Therapeutics, Inc.
G1 Therapeutics, Inc.
Z. Yang, P.J. Roberts, J.M. Antal, R.K. Malik, S.R. Morris: Employee: G1 Therapeutics. J.M. Weiss: Financial support to institution: AstraZeneca, Celgene, Merck; Advisory board: AstraZeneca, Celgene, Boston Biomedical. All other authors have declared no conflicts of interest.