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

purposeDoxorubicin 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

methodsDoxorubicin-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.

resultsOf 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.

conclusionsThe recommended phase II dose is ribociclib 400 mg followed by doxorubicin 60 mg/m2, which demonstrated an acceptable toxicity profile.