Reference Detail

Ref Type Journal Article
PMID (30037815)
Authors Alemany R, Moura DS, Redondo A, Martinez-Trufero J, Calabuig S, Saus C, Obrador-Hevia A, Ramos R, Villar VH, Valverde C, Vaz MA, Medina J, Felipe-Abrio I, Hindi N, Taron M, Martin-Broto J
Title Nilotinib as Coadjuvant Treatment with Doxorubicin in Patients with Sarcomas: A Phase I Trial of the Spanish Group for Research on Sarcoma.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 24
Issue 21
Date 2018 Nov 01
URL
Abstract Text 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 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown chondrosarcoma not applicable Doxorubicin + Nilotinib Phase I Actionable In a Phase I trial, Tasigna (nilotinib) in combination with doxorubicin resulted in 5 stable disease and 2 progressive disease in 7 patients with chondrosarcoma, with a median progression-free survival of 14 months and a median overall survival of 25 months (PMID: 30037815; NCT02587169). 30037815
Unknown unknown leiomyosarcoma not applicable Doxorubicin + Nilotinib Phase I Actionable In a Phase I trial, Tasigna (nilotinib) in combination with doxorubicin resulted in 1 short-duration stable disease and 1 progressive disease in 2 patients with leiomyosarcoma, consistent with synergistic growth inhibition in liposarcoma cells in culture and in xenograft models (PMID: 30037815; NCT02587169). 30037815
Unknown unknown liposarcoma not applicable Doxorubicin + Nilotinib Clinical Study Actionable In a Phase I trial, Tasigna (nilotinib) in combination with doxorubicin resulted in 1 partial response and 3 stable disease in 4 patients with liposarcoma, consistent with synergistic growth inhibition in liposarcoma cells in culture (PMID: 30037815; NCT02587169). 30037815
Unknown unknown sarcoma not applicable Doxorubicin + Nilotinib Phase I Actionable In a Phase I trial, Tasigna (nilotinib) in combination with doxorubicin demonstrated safety and preliminary efficacy, resulted in 1 partial response and 9 stable disease in 13 patients with sarcomas (PMID: 30037815; NCT02587169). 30037815