Phase I study of PS-341 (bortezomib) with 5-fluorouracil/leucovorin (5-FU/LV) in advanced solid tumors: A California Cancer Consortium study

Abstract

2057 Background: PS-341 inhibits the proteasome and the degradation of a number of proteins involved in cell cycle regulation, apoptosis and cell adhesion. PS-341 was combined with 5-FU/LV, to find the maximum tolerated dose (MTD) and investigate pharmacodynamics. Previously we reported interim results of this trial (Iqbal et al; Proc ASCO 2002). We are now reporting the final results. Methods: PS-341 was administered IV bolus in escalating doses (0.5 mg/m2, 0.7 mg/m2, 1.0 mg/m2, 1.3 mg/m2) twice weekly, with weekly 5-FU 500 mg/m2/LV 20 mg/m2 for 4 weeks, with 2 weeks rest. Two patients (pts) were entered at each dose level (DL) until moderate toxicity was observed in 2 pts or dose-limiting toxicity (DLT) was observed in 1; thereafter the standard 3+3 design was used. Results: Twenty-one pts were entered: 12 males, 9 females; median age: 58 (range 43–84) years; 15 colorectal primary; 2 unknown; and 1 esophageal, breast, pancreatic and anal. Pts received a median of 3 (range 0 –4) prior chemotherapeutic regimens for advanced disease. Two, 7, 9, and 3 pts entered dose levels 1, 2, 3, and 4, respectively. One pt at DL 2 and 3 pts at DL 3 did not complete Cycle 1 and were inevaluable for toxicity. All DLT's were Grade 3. Two pts at DL 4 experienced DLTs (Pt1: abdominal pain or cramping; Pt2: anorexia, dehydration, diarrhea). DL 3 was then expanded, at which 2 pts experienced DLTs (Pt1: abdominal pain or cramping; Pt2: dehydration, depressed level of consciousness, fatigue, hypoxia, anorexia, dyspnea, nausea). DL 2 was then also expanded, at which only 1 pt experienced DLTs (vomiting, nausea, fatigue, headache, anorexia). The MTD was determined to be DL 2. Interestingly, peripheral neuropathy was not a DLT in this trial. Pts received a median of 2 (range 1–4) cycles of chemotherapy. Nineteen pts were evaluable for response: 1 partial response (esophageal) at DL 4; 8 stable disease (7 colorectal, 1 anal) at DLs 1–4; 10 progressive disease. Conclusions: PS-341 0.7 mg/m2, when given twice weekly with once weekly 5-FU 500 mg/m2/LV 20 mg/m2 for 4 weeks, followed by 2 weeks rest is a safe regimen for Phase II testing. Grant#: U01CA62505 Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Millennium; Sanofi Millennium