Nilotinib as co-adjuvant treatment with doxorubicin in patients with sarcomas: A phase I trial of the Spanish Group for Research on Sarcoma.

Purpose: Nilotinib plus doxorubicin showed to be synergistic regarding apoptosis in several sarcoma cell lines. A phase I/II trial was thus designed to explore the feasibility of nilotinib as co-adjuvant of doxorubicin by inhibiting MRP-1/ P-gp efflux activity. The phase I part of the study is presented here. Experimental Design: Nilotinib 400 mg/12 h was administered in fixed dose from day 1 to 6, and doxorubicin on day 5 of each cycle. Three dose-escalation levels for doxorubicin at 60 mg/m2, 65 mg/m2 and 75 mg/m2 were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma (LPS), leiomyosarcoma (LMS) and unresectable/ metastatic high-grade chondrosarcoma (CHO). Results: Thirteen patients were enrolled: 7 CHO, 4 LPS and 2 LMS. In 46 cycles administered, the most relevant grade 3/4 adverse effects per patient were: neutropenia 54%, febrile neutropenia 15%, and asthenia 8%. No cardiac toxicity was observed. Only one dose-limiting toxicity (febrile neutropenia) was reported in the third dose-level. As regards efficacy, there were 1 partial response (1 LPS), 9 SD (5 CHO, 2 LPS, 1 LMS) and 3 progressive diseases (2 CHO and 1 LMS). ABCB1 and ABCC1 RNA expression levels decreased by 58.47-fold and 1.47-fold respectively on day 5 of the cycle. Conclusions: Combination of MRP-1/P-gp inhibitor, nilotinib, as co-adjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared to doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m2.

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