Feasibility IB trial of paclitaxel/carboplatin + Galunisertib. (a small molecule inhibitor of the kinase domain of type 1 TGF-B receptor) in patients with newly diagnosed, persistent or recurrent carcinosarcoma of the uterus or ovary.

OBJECTIVE: Carcinosarcoma (CS) is a rare, aggressive malignancy characterized by high rates of extrauterine spread, frequent recurrences, and poor prognosis. Until recently, the standard of care treatment included surgery and chemotherapy given in an adjuvant or metastatic setting. This study assessed safety and tolerability of combining carboplatin(C) and paclitaxel(T) with the TGFb-R1 inhibitor galunisertib (GB). METHODS: In this IRB approved (NCT03206177) feasibility study, eligible patients (pts) included those diagnosed with uterine or ovarian CS for whom treatment with CT is planned. A safety lead of CT plus GB 80 mg days 4-17 on a 28-day cycle, and if no dose-limiting toxicities (DLTs), the full dose of GB 150 mg BID would be used. The primary endpoint was completing 4 cycles of combination therapy without DLT. RESULTS: 3 patients were enrolled in the safety lead and 21 pts. were treated with CT and GB 150 mg po BID combination for a total of 24 patients. Among them, 81 % had stage III/IV and 54.2 % had measurable disease (MD). No DLTs were reported in the safety lead in. Among the 21 pts. treated at 150 mg po BID 1/21 had a DLT that compromised completion of 4 cycles. Therefore, the combination was deemed feasible. Among the 13 pts. with MD, 31 % had a partial response and 15 % had stable disease. The median progression-free survival (PFS) was 6.6 months (95 % CI: 5.4-10.8 months), and the median overall survival (OS) was 18.9 months (95 % CI: 10.81 -NR). 75 % had ≥ grade 3 treatment-emerged adverse events, the most common was neutropenia (41.7 %). CONCLUSIONS: GB with CT was well-tolerated with 1 DLT noted. The study was prematurely stopped when the development of GB was discontinued, but targeting TGFb downstream signaling remains of interest.