Phase 1 study of picoplatin (pico) in combination with 5-fluorouracil (FU) and leucovorin (LV) as initial therapy in subjects with metastatic colorectal cancer (CRC)

Abstract

14510 Background: Pico is a platinum analogue designed to overcome platinum resistance with improved safety and efficacy compared with conventional platinum agents. FOLFOX (FU, LV, oxaliplatin) has emerged as the standard of care in first and second-line therapy of advanced -stage CRC but significant neurotoxicity limits long-term use of oxaliplatin in this regimen. Pico has been well tolerated in >600 patients with rare clinically significant nephro-, oto-, or neurotoxicity (∼2% grade 3 and 0% grade 4), even in platinum pretreated patients. Pico has demonstrated synergy with FU in vitro and is thus an attractive candidate to replace oxaliplatin in the FOLFOX regimen. The objective of this Phase 1 study is to identify the maximum tolerated dose (MTD) of pico administered either every 2 wks or every 4 wks with FU and LV administered every 2 wks. Methods: Each patient receives q 2 wk FU and LV: LV, 400 mg/m2, 2-hr infusion, followed by 5- FU bolus, 400 mg/m2 and then 5-FU, 2,400 mg/m2, 46 hr continuous infusion. Subjects are randomized to pico administered either every 2 or every 4 wks. Starting dose of pico for q 2 weekly regimen was 45 mg/m2 and in subsequent cohorts pico increases by 15 mg/m2. Starting dose of pico for q 4 wk regimen was 60 mg/m2 and in subsequent cohorts pico increases by 30 mg/m2 until dose limiting toxicity (DLT) establishes the MTD. Results: 23 pts have been treated to date, the first have received 32 wks of therapy. Therapy has been well tolerated, with infrequent dose delays from non-cumulative platelet and ANC toxicity and 1 episode of mild diarrhea. No DLT has been seen through the first 3 cohorts, i.e. with picoplatin, 75 mg/m2 with every dose of FU-LV or120 mg/m2 with every other dose of FU-LV. Dose escalation continues. Response assessments for 12 patients in the first 2 cohorts (6 on each pico schedule, all below the MTD) after 16 wks show 4 partial responses, 5 stable disease and 3 progressive disease. Conclusions: Picoplatin can be safely administered with 5FU and LV. A phase 2 study of FU, LV and pico will begin as soon as the MTD is identified and a safe dose and schedule are defined. No significant financial relationships to disclose.