Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: an open-label, multicenter Phase I study

Abstract

4085 Background: Vandetanib (ZD6474) is a once-daily oral agent in Phase III development that selectively targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinases. Methods: Patients with metastatic colorectal adenocarcinoma who were eligible for 1st- or 2nd-line chemotherapy received once-daily oral doses of vandetanib (100 mg) in combination with standard 14-day treatment cycles of FOLFIRI (irinotecan 180 mg/m2 1.5-hr and leucovorin 400 mg/m2 2-hr i.v. infusions, followed by 5-fluorouracil [5-FU] 400 mg/mg2 i.v. bolus and 5-FU 2400 mg/m2 46–48-hr i.v. infusion). If <2 of 6 evaluable patients (i.e., having completed 6 weeks of treatment) experienced a vandetanib- related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + FOLFIRI. The primary objective of the study was to establish the safety and tolerability of vandetanib + FOLFIRI. Secondary objectives included an assessment of any pharmacokinetic (PK) interaction between vandetanib, irinotecan (SN-38) and 5-FU, and preliminary evaluation of efficacy (RECIST). Results: Twenty- one patients (12 male/9 female; mean age 53 years, range 33–72) received vandetanib 100 mg (n=11) or 300 mg (n=10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort, with one DLT of hypertension (CTC grade 3) with QTc prolongation in the 300 mg cohort. The most common adverse events (AEs; all grade 1/2) were diarrhea (n=20), nausea (n=12), fatigue (n=10) and alopecia (n=9); AEs =grade 3 reported in more than one patient were neutropenia (n=4, all grade 3), hypertension (n=3, all grade 3), catheter-related complication (n=2, both grade 3) and pulmonary embolism (n=2, both grade 4). There was no apparent PK interaction between vandetanib and irintotecan (SN-38) or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=2), stable disease =8 weeks (n=9), and progressive disease (n=3). Conclusions: In patients with advanced colorectal adenocarcinoma, combining once-daily vandetanib (100 or 300 mg) with a standard FOLFIRI regimen was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies. No significant financial relationships to disclose.