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|Ref Type||Journal Article|
|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|
|Date||2018 Nov 01|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||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||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||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||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|