Vandetanib With Mfolfox6 In Advanced Colorectal Adenocarcinoma: An Open-Label, Multicenter Phase I Study

4095 Background: Vandetanib (ZD6474) is a once-daily oral anticancer agent that selectively inhibits VEGFR- dependent tumor angiogenesis, and EGFR- and RET-dependent tumor cell proliferation. The primary objective of this Phase I study was to establish the safety and tolerability of the vandetanib + mFOLFOX6 combination in patients with metastatic colorectal cancer (CRC). Secondary objectives included an assessment of pharmacokinetic (PK) interactions between vandetanib and mFOLFOX6, and preliminary evaluation of efficacy (RECIST). Methods: Patients with CRC who were eligible for 1st- or 2nd-line chemotherapy received once-daily oral doses of vandetanib (100 mg) plus standard 14-day treatment cycles of mFOLFOX6 (oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 2-hr IV; 5-fluorouracil [5-FU] 400 mg/mg2 IV bolus and 5-FU 2400 mg/m2 46-hr IV). If <2 of 6 evaluable patients (ie, having completed 6 weeks of vandetanib treatment with associated mFOLFOX6 cycles) experienced a vandetanib-related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + mFOLFOX6. Results: Seventeen patients (12 male/5 female; 7 1st-line/10 2nd-line; mean age 61 years, range 48–75) received vandetanib 100 mg (n=9) or 300 mg (n=8) + mFOLFOX6; the median number of oxaliplatin cycles was 8. Two DLTs were reported: one patient receiving 100 mg vandetanib developed diarrhea (CTC grade 2), dehydration, electrolyte imbalance and QTc prolongation, and one patient receiving vandetanib 300 mg developed diarrhea (grade 3) that responded to dose reduction. Common adverse events (AEs), irrespective of grade, were diarrhea, nausea, lethargy (all n=11), neutropenia and peripheral neuropathy (both n=10); AEs =grade 3 reported in more than one patient were diarrhea (n=4, all grade 3) and neutropenia (n=5, grade 3; n=2, grade 4). There was no apparent PK interaction between vandetanib and oxaliplatin or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=3), stable disease =8 weeks (n=8), and progressive disease (n=3). Conclusions: In patients with advanced CRC, combining once-daily vandetanib (100 or 300 mg) with mFOLFOX6 was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies No significant financial relationships to disclose.