Ribociclib in Sequential Combination with Doxorubicin in Anthracycline-Naïve Advanced Soft-Tissue Sarcomas: Results of a Dose-Finding Phase Ib Study

Abstract Purpose: Doxorubicin is the first-line treatment for metastatic soft-tissue sarcomas. Ribociclib, a cyclin-dependent kinase 4/6 intargets the retinoblastoma pathway to induce cell-cycle arrest at the G1–S cell-cycle checkpoint. We hypothesized that administering ribociclib prior to doxorubicin to synchronize cell-cycle progression among tumor cells may enhance the efficacy of doxorubicin. Patients and Methods: Doxorubicin-naïve patients with metastatic soft-tissue sarcoma were enrolled in this phase Ib study. Every 21 days, subjects received ribociclib daily for 7 days followed by 3 days of no treatment before administration of doxorubicin. The primary objective was to establish the recommended phase II dose of the sequenced drug combination. Secondary objectives included progression-free survival and objective response rate. Exploratory correlative studies assessed pharmacokinetic and pharmacodynamic measures. Results: Of 38 screened patients, 16 were enrolled and 15 were evaluable for dose determination. The most common reason for exclusion was lack of normal retinoblastoma protein expression. At dose level 0 (ribociclib 400 mg and doxorubicin 75 mg/m2), four of seven patients experienced febrile neutropenia as a dose-limiting toxicity. Of the eight patients treated at dose level −1 (ribociclib 400 mg and doxorubicin 60 mg/m2), one had a dose-limiting toxicity of grade 4 anemia. Three patients achieved partial response (objective response rate, 20.0%). Ribociclib pharmacokinetic levels were lower than predicted. Levels of phosphorylated retinoblastoma protein in on-treatment tumor biopsy tissue were variable and did not correlate with ribociclib plasma levels. Conclusions: The recommended phase II dose is ribociclib 400 mg followed by doxorubicin 60 mg/m2, which demonstrated an acceptable toxicity profile.