Nilotinib as Coadjuvant Treatment with Doxorubicin in Patients with Sarcomas: A Phase I Trial of the Spanish Group for Research on Sarcoma

• Published in: Clinical cancer research Vol. 24; no. 21; pp. 5239 - 5249
• Main Authors: Alemany, Regina, Moura, David S, Redondo, Andres, Martinez-Trufero, Javier, Calabuig, Silvia, Saus, Carlos, Obrador-Hevia, Antonia, Ramos, Rafael, Villar, Victor H, Valverde, Claudia, Vaz, Maria Angeles, Medina, Javier, Felipe-Abrio, Irene, Hindi, Nadia, Taron, Miguel, Martin-Broto, Javier
• Format: Journal Article
• Language: English
• Published: United States 01.11.2018
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy, Adjuvant; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Drug Evaluation, Preclinical; Female; Humans; Male; Mice; Neoplasm Grading; Neoplasm Staging; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Sarcoma - diagnosis; Sarcoma - drug therapy; Sarcoma - metabolism; Sarcoma - mortality
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-0851

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 coadjuvant of doxorubicin by inhibiting MRP-1/P-gp efflux activity. The phase I part of the study is presented here. Nilotinib 400 mg/12 hours 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, 65, and 75 mg/m were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma, leiomyosarcoma, and unresectable/metastatic high-grade chondrosarcoma. Thirteen patients were enrolled: 7 chondrosarcoma, 4 liposarcoma, and 2 leiomyosarcoma. 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. With regard to efficacy, 1 partial response (1 liposarcoma), 9 stable diseases (5 chondrosarcoma, 2 liposarcoma, 1 leiomyosarcoma), and 3 progressive diseases (2 chondrosarcoma and 1 leiomyosarcoma) were present. and RNA expression levels decreased by 58.47-fold and 1.47-fold, respectively, on day 5 of the cycle. Combination of MRP-1/P-gp inhibitor, nilotinib, as coadjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared with doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m .