3158 Background: Bcl-2 overexpression occurs in 30–94% of human colorectal cancer (CRC) specimens, appears to be an early event in CRC tumorigenesis & correlates with a negative prognosis in Dukes C disease. In addition, bcl-2 overexpression confers a multi-drug resistant phenotype to tumor cells, including resistance to platinum. Oblimersen is an antisense oligonucleotide directed to the bcl-2 mRNA, & has demonstrated bcl-2 protein inhibition in vitro & in vivo. The objectives of this phase I trial were to: 1) determine the maximum tolerated dose; 2) characterize the main toxicities; 3) assess plasma pharmacokinetics (PKs); 4) determine relevant predictive biomarkers, & 5) document antitumor activity in CRC patients treated with escalating doses of oblimersen, in combination with fixed doses of 5-FU, oxaliplatin and leucovorin (FOLFOX4 regimen). Methods: Oblimersen was given as a continuous IV infusion (CIV) on days 1–7 and 15–21, and the FOLFOX4 regimen was administered on days 6–7 and 20–21 of a 28-day cycle. The protocol was subsequently amended to shorten the duration of oblimersen CIV to 5 days (days 1–5 and 15–20), while maintaining the same duration of FOLFOX4. Results: A total of 16 patients [7 male/9 female), median age 52 (range 37–76)] have received 34 cycles of the combination over 3 dose levels of oblimersen: 5 mg/kg/day x 7 days, 7 mg/kg/day x 7days, and 7 mg/kg/day x 5 days. Prolonged neutropenia resulting in dose delay > 14 days in cycle 1 was dose limiting in four patients, one each at dose levels one & two, & two at dose level three, respectively. Additionally, one patient treated at dose level 2 experienced treatment-related grade 3 fatigue Other toxicities were mild to moderate (grade 1–2) & included vomiting (3 patients), diarrhea (5 patients), oral mucositis (4 patients) & proteinuria (5 patients). One patient experienced a complete response after cycle 2, & 2 patients had partial responses in 13 evaluable patients. Mean [±SD] Oxaliplatin AUC, t1/2, and Cl were 3.7 [1.4] μg/mL*h, 14.9 [4.4] h, 220 [102] mL/min/m2, respectively. Conclusions: Although active, enhanced hematologic toxicity made FOLFOX 4 in combination with oblimersen not feasible at 7 mg/kg/day x 5 days. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genta, Sanofi Aventis, Genta