A phase II trial of the proteosome inhibitor PS-341 in patients with metastatic colorectal cancer

Abstract

3109 Background: The ubiquitinin-proteosome proteolytic pathway regulates the metabolism of critical proteins involved in the cell cycle, apoptosis and metastasis such as p53, p21, p27 and NFκB. PS341(Bortezomib; Velcade) is a specific and selective inhibitor of the 26S proteosome. PS341 results in significant regression in a human colon cancer xenograft model. Methods: This phase II study aimed to assess the activity of PS341 in patients with metastatic colorectal cancer who had received no more than 1 prior line of chemotherapy with irinotecan (or oxaliplatin)/5 fluorouracil for metastatic disease. Primary endpoints were objective response or disease stabilization; with a multinomial stopping rule and secondary endpoints included assessment of molecular changes with therapy, survival and tolerability. PS 341 at a dose of 1.3mg/m2/day was administered as an intravenous bolus days 1,4,8 and 11 of a 21 day cycle. Tumor response was assessed by RECIST criteria every 2 cycles. Tumor biopsies were performed prior to treatment and on day 9 of the first treatment cycle. Results: 19 patients (9M:10F), median age 62 (range 46–81) years received 41 (range 1–4) cycles of treatment. 3 patients had stable disease (SD), 14 had progressive disease (PD) and 2 were non- evaluable . Of the 2 patients with SD at cycle 2, two patients discontinued treatment during cycle 4 due to grade 3 abdominal pain and grade 3 peripheral neuropathy. One patient had SD after 3 cycles but was withdrawn due to a cerebrovascular accident (CVA). The most common adverse events (AEs), any grade, were lymphopenia (80% of cycles), fatigue (77%), anemia (66%), constipation (61%), nausea(51%) and headache (42%). Discontinuation of treatment occurred due to the following AEs: grade 3 peripheral neuropathy (2 patients), CVA and grade 3 abdominal pain, myalgia and rash. Paired tumor biopsies were obtained from 9 patients and examined for transcription factors NFkβ and HIF-1α, p53, p27, and p21 by immunohistochemistry. Data will be presented at the meeting. Conclusions: PS341 has insufficient activity in colorectal cancer and the study has closed to accrual. No significant financial relationships to disclose.