Phase I safety and pharmacokinetic (PK) study of sunitinib (S) in combination with ifosfamide (I) in patients (pts) with advanced solid tumors (STs)

Abstract

e13520 Background: S is a tyrosine kinase inhibitor (TKI) of PDGFR, VEGFR and KIT. As combinations of VEGFR-TKI with cytotoxic therapy are promising, this phase I study aimed to determine the recommended phase II dose (RP2D) of S in combination with 2 different I schedules. Methods: Pts with progressive STs, good PS, organ function, and no standard therapy available, were eligible. I (3 g/m2/day, 72h CIV (I*3), every 3 wks) was combined with continuous S. S was started at 12.5 mg/day and to be escalated in serial cohorts of 3–6 pts. RP2D was exceeded if ≥ 1/3 pts experienced dose-limiting toxicity (DLT) within the 1st cycle. After establishing the RP2D of S with I*3, feasibility of this S dose with I at 1.2 g/m2/day for 5 days CIV (I*5) every 3 wks was assessed without further scheduled dose-escalation. At RP2D, additional patients were enrolled to assess PK. Circulating endothelial cells (CECs) were measured prior to the 1st, 3rd and 6th cycle. Results: 26 pts (36–68 yrs) were accrued. 12.5 mg S was not feasible with I*3 due to neutropenia > 7 days in 2/6 pts. After protocol amendment, pegfilgrastim 6 mg (P) was given to all subsequent patients after each I-cycle. Using P, the RP2D was I*3 plus 12.5 mg S (in 1/9 pts DLT: febrile neutropenia), while I*3 plus 25 mg S was not feasible due to febrile neutropenia in 2/5 pts and hypertension & cardiac chest pain in 1/5 pts. 12.5 mg S was also feasible using I*5 as 1/6 pts had a DLT: encephalopathy. Most frequent drug related adverse events (all grades/grade 3–4) were: neutropenia (77%/62%), thrombocytopenia (73%/31%), elevated transaminases (65%/0%), renal (42%/4%), nausea (77%/0%), vomiting (58%/0%) and alopecia (62%/0%). 4/22 pts evaluable for response had PR: 1 CUP, 1 small cell carcinoma (SCC) and 2 sarcoma pts. 7 pts had SD for ≥ 3 months: 1 CUP, 1 uveal melanoma, 1 SCC, and 4 sarcoma pts. The AUC ratio of I and its metabolites in cycles I*3 without versus with S ranged from 0.72 to 1.36. No consistent change in the number of CECs during treatment was observed. Conclusions: S at 12.5 mg/day with I*3 or I*5 every 3 weeks supported by P is tolerable in pts with advanced STs. S does not affect I-PK. Antitumor activity was observed in pts with diverse tumor entities including sarcoma. No significant financial relationships to disclose.