Phase I study to evaluate the safety and efficacy of sunitinib in combination with FOLFIRI in treatment-naïve metastatic colorectal cancer (mCRC)

Abstract

3563 Background: Sunitinib malate (SU) is an oral, multitargeted inhibitor of VEGFR, PDGFR, KIT, RET and FLT3, approved in advanced RCC and imatinib-resistant/-intolerant GIST. VEGF and VEGFRs are expressed in CRC and correlate with increased angiogenesis. Angiogenesis inhibition by SU may augment antitumor activity when combined with chemotherapy regimens, e.g. FOLFIRI. Methods: Successive cohorts of 3–6 treatment-naïve mCRC patients (pts) received FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 and 5-FU 400 mg/m2 on day 1, followed by 5-FU 2,400 mg/m2 46-hr infusion) every 2 wks with SU 37.5 or 50 mg/d on a 4/2 schedule (4 wks on, 2 wks off) or SU 37.5 or 25 mg/d on a continuous dosing schedule. The primary endpoint was the MTD, the dose at which ≤1 in 6 pts had DLTs, and overall safety of FOLFIRI + SU. PK and antitumor activity (RECIST) were also assessed. Results: By Dec 2007, 27 pts on the SU 4/2 schedule (21 at 37.5; 6 at 50 mg/d) were safety- evaluable. No DLTs were seen in the first 6 pts at 37.5 mg/d; 2 DLTs were seen in the expansion cohort (n=15) (both febrile neutropenia, one with suspected line infection). 2 pts at 50 mg/d had DLTs (febrile neutropenia and gr 4 neutropenia). 8 pts receiving SU continuously (3 at 37.5; 5 at 25 mg/d) were safety-evaluable. 2 pts at each dose had a DLT (37.5 mg/d, gr 4 neutropenia and DVT; 25 mg/d, both gr 4 neutropenia). The MTD for SU on the 4/2 schedule with FOLFIRI was 37.5mg/d. The 25 mg/d continuous dosing regimen + FOLFIRI was not tolerable. Dose delays (mainly for hematologic recovery) of ≥1 week were most common in the SU 50 mg/d 4/2 group (21% of all FOLFIRI cycles). Updated tolerability data will be presented. There were no clinically significant changes in PK parameters. Initial efficacy data are shown (Table). Conclusions: The MTD of SU combined with FOLFIRI is 37.5mg/d on a 4/2 schedule. This regimen is tolerable and has promising antitumour activity in treatment-naïve mCRC pts. A phase III study is enrolling pts to further evaluate this regimen in mCRC. mg/d 4/2 Continuous 37.5 n=21 50 n=6 37.5 n=3 25 n=7 Confirmed PR 8 0 0 2 SD 10 6 3 2 PD 1 0 0 0 Unevaluable 2 - - 3 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Merck, Pfizer, Roche, sanofi-aventis Merck, Pfizer, Roche, sanofi-aventis Pfizer Pfizer