Alemany, ReginaMoura, David SRedondo, AndresMartinez-Trufero, JavierCalabuig, SilviaSaus, CarlosObrador-Hevia, AntoniaRamos, RafaelVillar, Victor HValverde, ClaudiaVaz, Maria AngelesMedina, JavierFelipe-Abrio, IreneHindi, NadiaTaron, MiguelMartin-Broto, Javier2023-01-252023-01-252018-07-23http://hdl.handle.net/10668/12744Purpose: 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.Patients and Methods: 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/m2 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.Results: 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. 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 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/m2Clin Cancer Res; 24(21); 5239-49. ©2018 AACR.enAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisBiomarkers, TumorCell Line, TumorCell ProliferationChemotherapy, AdjuvantDoxorubicinDrug Evaluation, PreclinicalFemaleHumansMaleMiceNeoplasm GradingNeoplasm StagingPyrimidinesSarcomaresearch article30037815open access10.1158/1078-0432.CCR-18-08511557-3265https://clincancerres.aacrjournals.org/content/clincanres/24/21/5239.full.pdf