13525 Background: The combination of G and CPT-11 was reported as a promising regimen for CUP in the 2nd line setting (Hainsworth, Cancer 2005). We sought to determine the activity and toxicity of weekly G and CPT-11 as first-line therapy for CUP, and to assess the relationship between UGT1A1*28 genotype and toxicity. Methods: Pts with untreated metastatic ca, ECOG PS 0–2, and good organ function were eligible. Sufficient tumor tissue was required for central review to exclude lung, melanoma, hematologic, and neuroendocrine ca. Additionally, the following pts were ineligible: women with ca restricted to axillary lymph nodes (LN) or with ca limited to peritoneum; men with mediastinal or retroperitoneal tumors and positive tumor or serum germ cell markers; men with blastic bony metastases or elevated PSA; pts with ca involving only one site; and pts with squamous ca limited to LN. Treatment was G 1,000 mg/m2 and CPT- 11 75 mg/m2 weekly×four (6 week cycle, Cohort I) with an interim analysis to assess toxicity and the role of UGT1A1*28 genotype on toxicity. Following the observation of excessive Cohort I toxicity, the schedule was modified: G 750 mg/m2 and CPT- 11 75 mg/m2 weekly x3 of a 4 week cycle for Cohort II. Results: 31 pts were enrolled with a median age of 63 (range: 38 –94). A median of 2 cycles was administered (range: 1–14). Toxicity and efficacy are listed in Table 1. Cohort I pts experienced substantial hematologic (H) and non-H adverse events (AE), unrelated to UGT1A1*28 genotype (p=0.74 and 0.92, respectively). Cohort II pts had significantly less toxicity (Table 1). Both cohorts demonstrated lack of sufficient activity for continuation to the 2nd stage. Conclusions: The combination of G and CPT-11 is not active in CUP. A multidisciplinary clinical and pathologic approach to diagnose CUP identifies patients with inherent resistance to combination chemotherapy and a poor prognosis. New therapeutic approaches are needed. Trial was supported by Cancer Center grant CA15083 and NCCTG grant CA25224. Efficacy and Cycle 1 AE summary Cohort Dose (mg/m2/day) Grade 4+ AE* Grade 3+ Heme AE** TTP (95% CI) TTF (range) RR I CPT-11 75, Gem 1,000 29% 50% 3.7 (2.8 –7.8) 2.3 (0.2 –19.7) 1/11 (9%) II CPT-11 75, Gem 750 6% 6% 3.6 (1.9 –13.8) 1.8 (0.9 –7.7) 2/15 (13%) AE, adverse events; TTP, median time to progression in months; TTF, median time to treatment failure in months; RR, confirmed response rate (all PR’s), *p =0.15; **p=0.01. No significant financial relationships to disclose.