First-line phase Ib and II studies of picoplatin in combination with 5-fluorouracil and leucovorin (FOLPI) as a potential neuropathy-sparing therapy for colorectal cancer (CRC)

Abstract

4100 Background: Picoplatin (Pico) is a therapy designed to overcome platinum resistance with improved safety and efficacy compared with other platinum agents. FOLFOX (FU, LV, oxaliplatin) treatment for advanced CRC has significant neurotoxicity due to oxaliplatin. The incidence of grade 3–4 neurotoxicity with Pico in previous studies was <2% suggesting that Pico may provide a neuropathy-sparing alternative to oxaliplatin. The present studies were designed to determine the maximum tolerated dose (MTD) of Pico when administered q2w or q4w with FU and LV (FOLPI) and to evaluate the efficacy and safety of FOLPI at the MTD. Methods: Each patient (pt) received LV and infusional FU per FOLFOX6 q2w. Pts received Pico either every 2 or every 4 wks. Starting dose of Pico q2w was 45 mg/m2 and increased by 15 mg/m2 in subsequent cohorts. Starting dose of Pico q4w schedule was 60 mg/m2 and increased by 30 mg/m2 in subsequent cohorts. The 100 pt Phase II study is a randomized study comparing 50 pts treated with FOLPI using the q4w schedule at the MTD dose of 150 mg/m2 with 50 pts treated with q2w modified FOLFOX6 (85 mg/m2 oxaliplatin). Tumor response is assessed by RECIST using CT scans. Neuropathy is assessed using the FACT- Neurotoxicity questionnaire and by a blinded neurologist. Results: 59 pts have been treated in phase I FOLPI CRC studies to date. In the q4w schedule, 18 pts were studied and DLT, febrile neutropenia and thrombocytopenia, was observed at 180 mg/m2 in 2 of 6 pts. In the q2w schedule, 41 pts have been treated up to 120 mg/m2 and DLT has not been observed to date. Pts have received up to 24 cycles of Pico. 15 pts received a total Pico exposure of >600 mg/m2 and 7 have received >800 mg/m2. Mild neuropathy occurred in 9 pts, but no grade 3 or higher neuropathy was observed. Adverse events were primarily neutropenia, thrombocytopenia, nausea, asthenia and anorexia. The randomized Phase II study has enrolled 16/100 pts to date. Conclusions: The Phase I FOLPI study identified the MTD at 150 mg/m2 when Pico was infused every 4 wks with FU and LV. The DLT of Pico was hematological with no Grade 3 or 4 neuropathy. The Phase I FOLPI q2w study is ongoing with doses up to 120 mg/m2. Additional data is expected from the Phase I and ongoing Phase II studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Poniard Pharmaceuticals Poniard Pharmaceuticals