In patients (n=32) with advanced solid tumours, continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 g/m2 for 3 days or 6 g/m2 for 5 days, administered every 3 weeks. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed. Ifosfamide produced decreased sunitinib blood levels due to CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this is true for anti-tumour activity needs to be further explored.
Decreased exposure to sunitinib due to concomitant administration of ifosfamide: results of a phase I and pharmacokinetic study on the combination of sunitinib and ifosfamide in patients with advanced solid malignancies. Hamberg P, Steeghs N, Loos WJ et al. Br J Cancer. 2010 Jun 8;102(12):1699-706.