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

Abstract

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 .

Erdafitinib Resensitizes ABCB1-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

“…In contrast, recent studies have demonstrated that several FDA-approved therapeutic agents such as osimertinib and midostaurin exhibited an inhibitory effect on ABCB1-mediated drug efflux, thus resensitizing ABCB1-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer agents [29,[44][45][46]. Moreover, the advantage of using combination therapy against multidrug-resistant cancers was demonstrated in a recent phase I study of concomitant administration of doxorubicin with nilotinib as a co-adjuvant treatment in sarcoma patients [47]. Similarly, studies have reported that a combination-therapy of lapatinib and capecitabine was superior to capecitabine alone in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer [48,49], whereas erlotinib significantly improved the survival of patients with advanced pancreatic cancer receiving gemcitabine [50,51].…”

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs

“…Moreover, Geyer et al and Cetin et al, reported that the efficacy of capecitabine was significantly improved by lapatinib in HER2-positive metastatic breast cancer patients who have previously failed conventional anticancer therapies [63,64]. More recently, encouraging results were reported in a phase I study using nilotinib as co-adjuvant treatment with doxorubicin in patients with sarcomas [65]. Collectively, these studies have shown that, in principle, a combination therapy of a cytotoxic anticancer agent and a molecularly targeted agent with a drug transporter modulating activity is a feasible therapeutic strategy against multidrug-resistant cancers.…”

Cancer Stem Cells in Soft-Tissue Sarcomas

“…Phase I results showed that the combination is feasible and it does not add substantial toxicity in comparison with doxorubicin alone. Of note, it was reported a decreased expression of both MRP-1 and P-gp after 5 days of Nilotinib treatment [85]. The results of the phase II part are expected to be published soon.…”