Phase I study of fixed-dose rate (FDR) gemcitabine with capecitabine in advanced solid malignancies

Abstract

13509 Background: Combining FDR gemcitabine and capecitabine has potential advantages of non-overlapping mechanisms/toxicity and higher, more efficacious extracellular concentrations of gemcitabine. Methods: Eligible patients (age ≥ 18; biopsy-proven, measurable advanced solid tumor; ECOG performance status (PS) ≤ 2; no brain metastasis; prior chemotherapies ≤ 3; and adequate major organ function) received capecitabine 500 mg/m2 PO BID days 1–14 of 21 with varying concentrations of FDR gemcitabine (400 to 1000 mg/m2 IV escalating by 200 mg/m2 increments) on days 1 & 8 using a 3 by 3 cohort design. The primary endpoint was to find dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Secondary endpoints were tolerability and response. Results: Twenty-seven patients (12 women/15 men; median age 59 years (range, 35 to 80 years); median PS 1; cancers: six kidney; four esophageal; two each: bladder, cholangiocarcinoma, soft tissue sarcoma, pancreas and head & neck; and one each: anal, non-small cell lung cancer, ovarian, uterine, rectal, hepatoma and salivary gland) were enrolled between 3/04 and 10/07. Accrual: 400 mg/m2 of gemcitabine, nine patients; 600 mg/m2, six; 800 mg/m2, four; and 1000 mg/m2, eight. Predominant grade ≥ 3 toxicities (123 cycles) were neutropenia (grade 3, nine patients; grade 4, six patients), thrombocytopenia (grade 3, two patients; grade 4, one patient) and rash (grade 3, two patients). DLTs: 400 mg/m2 of gemcitabine, grade 3 rash (one patient) and grade 3 neutropenia (one patient); 600 mg/m2, grade 4 neutropenia (one patient); and at 1000 mg/m2, one patient had grade 4 neutropenia and thrombocytopenia. The MTD and recommended phase II dose is capecitabine 500 mg/m2 PO BID days 1–14 of 21 with FDR gemcitabine 800 mg/m2 IV days 1 & 8. One patient died on treatment from progressive disease. Twenty-five were evaluable for response. There were no complete responses. Three had a confirmed partial response (12.0%; kidney, bladder and esophageal, 95% CI: 4–30%) and 10 (40.0%, 95% CI: 23–59%) had stable disease as a best response. Conclusions: This regimen was moderately tolerated with neutropenia as the primary toxicity. The recommended phase II dose is capecitabine 500 mg/m2 PO BID days 1–14 of 21 with 800 mg/m2 IV FDR gemcitabine days 1 & 8. No significant financial relationships to disclose.