Phase I trial to determine the safety and tolerability of GW572016 in combination with oxaliplatin (OX)/5-fluorouracil (5-FU)/leucovorin (LV) [FOLFOX4] in patients with solid tumors

Abstract

2044 Background: EGFR and erbB2 receptor expression in tumors predicts a poor outcome. GW572016 (GW) is a potent EGFR/erbB2 RTK inhibitor. The FOLFOX4 is an effective therapy in colorectal cancer. It is hypothesized that inhibition of kinase activation by GW will contribute to the cytotoxicity of FOLFOX4. This phase I trial aimed to determine the safety and optimally tolerated regimen (OTR) of FOLFOX4 with daily oral GW in patients (pts) with solid tumors. Methods: Pts were sequentially enrolled into 3 cohorts: cohort 1 - GW 1250 mg/day + FOLFOX4 at –20% of the standard dose; cohort 2 –GW 1250 mg/day + FOLFOX4 at standard dose; cohort 3 –GW 1500 mg/day + FOLFOX4 at standard dose. OTR was the dose level at which ≤ 1/6 pts experiences a DLT. DLT was based on hematological and non-hematological toxicity in cycle 1. Assessments of anti-tumor activity and left ventricular ejection fraction (LVEF) were performed every 4 cycles. Results: 13 pts were treated (cohort 1 - 3; cohort 2 - 3; cohort 3 - 7). Median age was 57 years (39–70). Histology: 2 colon, 1 ovary, 3 rectum, 2 cholangio, 2 cervix, 2 pancreas, and 1 esophagus. Total of 57 cycles were delivered: median 4 (2–9). Main toxicities are summarized in the table. 2 Pts had grade ≥ 3 hematological toxicities, which resolved after delay of the next cycle. No DLTs have been reported. LVEF values were relatively unchanged compared to pre-study values. 7 pts are evaluable for response. 2 PR, 2 SD and 3 PD. Conclusion: Standard dose FOLFOX4 in combination with GW 1500 mg/day is well tolerated. Enrollment continues at this dose level including pharmacokinetic assessments. No significant financial relationships to disclose.