Abstract CT110: CDK4 inhibition prior to doxorubicin for advanced sarcomas: A Phase IB trial
Authors: Lara E. Davis, Kevin Nusser, Janet Pittsenbarger, Sierra Bertolone-Smith, Phil Norr, Chris W. Ryan
Journal: Cancer Research (2019)

Abstract Background The majority of high-grade sarcomas exploit pathologic hyperphosphorylation of Rb protein (pRb) as a mechanism to evade the G1/S cell cycle checkpoint. CDK4/6 inhibitors such as ribociclib block phosphorylation of pRb, but have minimal efficacy as single agents beyond breast cancer and liposarcoma. Combinations of chemotherapy with concurrent CDK4/6 inhibition may decrease the efficacy of cytotoxic agents by reducing the number of tumor cells actively progressing through the cell cycle. We hypothesized that an alternative dosing strategy could be employed to increase the efficacy of sarcoma chemotherapy, namely CDK4 inhibition-induced cell cycle synchronization. To test this in vitro, we briefly treated pRb-intact sarcoma cells lines with a CDK4/6 inhibitor, then allowed a period of washout prior to exposure to cytotoxic chemotherapy. This approach results in an increased proportion of actively cycling cells at time of chemotherapy treatment as determined by immunoblotting, flow cytometry and BrdU incorporation, as well as increased sensitivity to doxorubicin in MTS assays. In vivo experiments in a xenograft model showed modest efficacy of CDK4/6 monotherapy. Further, compared to chemotherapy alone, the addition of ribociclib for three days prior to chemotherapy resulted in significant survival prolongation (21.5 vs 40.5 days, p=0.008). We therefore designed, “A Phase 1B Study of Ribociclib in Combination with Doxorubicin in Advanced Soft Tissue Sarcomas” (NCT03009201). Methods This is a single-institution, single-arm, dose-finding study. Eligible subjects are ≥12yo with metastatic or advanced soft tissue sarcoma (STS) and archival tumor tissue that is IHC-positive for pRb, since intact pRb is necessary for effective CDK4/6 inhibition. Prior systemic therapy with anthracycline is exclusionary. Each 21-day cycle includes 1 week of ribociclib PO daily followed by 3 days of rest prior to doxorubicin dose. Subjects without disease progression after 6 cycles are allowed to continue ribociclib maintenance monotherapy. Subjects receive treatment at one of three dosing levels per a modified toxicity probability interval (mTPI) design: ribociclib 400 mg / doxorubicin 75 mg/m2 (starting dose), ribociclib 600 mg / doxorubicin 75 mg/m2 (dose level +1), or ribociclib 400 mg / doxorubicin 60 mg/m2 (dose level -1). A fresh tumor biopsy is performed on Day 7 of ribociclib during Cycle 1. Correlative studies to investigate potential predictive biomarkers include comparison of archival and biopsy tissue by immunoblotting and multiplex IHC as well as cell cycle analysis of peripheral blood mononuclear cells by flow cytometry at baseline, C1D7 and C1D10. Enrollment is continuing as planned, with 47% of subjects enrolled as of December 2018. Note: This abstract was not presented at the meeting. Citation Format: Lara E. Davis, Kevin Nusser, Janet Pittsenbarger, Sierra Bertolone-Smith, Phil Norr, Chris W. Ryan. CDK4 inhibition prior to doxorubicin for advanced sarcomas: A Phase IB trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT110.