SAR-096: Phase II clinical trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL), and leiomyosarcoma (LMS)

Purpose: DDL and LMS are two common subtypes of soft tissue sarcoma, a rare group of diseases for which new treatments are needed. Chemotherapy remains the standard option for advanced disease. Targeting CDK4/6 in DDL and mTOR in LMS is of biologic interest. When combined, the CDK4 inhibitor ribociclib and the mTOR inhibitor everolimus, have shown synergistic growth inhibition in multiple tumor models, suggesting that this combination could be beneficial in patients.Methods: This was a single arm, open label, multi-center phase II study of the combination of ribociclib and everolimus. Patients were enrolled into one of two cohorts: DDL or LMS with intact Rb. The primary endpoint was progression free rate (PFR) at 16 weeks. Secondary endpoints included progression free (PFS) and overall survival, safety and biomarker analyses. Results: In the DDL cohort, 33.3% (95% CI 15.6%-55.3%) of patients were progression free at 16 weeks. Median PFS in this cohort was 15.4 weeks (95% CI, 8-36 weeks) with 2 partial responses. In the LMS cohort the PFR at 16 weeks was 29.2% (95% CI 12.6%-51.1%). Median PFS in this cohort was 15.7 weeks (95% CI 7.7-NA). Most common toxicities included fatigue (66.7%), anorexia (43.8%) and hyperglycemia (43.8%). Concordance between Rb testing methodologies was poor.Conclusions: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (≥16 weeks) meeting the primary endpoint. Notably partial responses were observed. The primary endpoint was not reached in the LMS cohort. The combination was well tolerated with expected side effects. We have collected total RNAs of sarcoma patient samples which are either responders or non-responders. We want to study the gene expression changes between the two groups.