A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study.

Abstract

Background The effectiveness of reintroducing oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a phase II study (RE-OPEN). We conducted a phase I study to determine the maximum tolerated dose of oxaliplatin plus trifluridine/tipiracil (FTD/TPI) in patients with refractory mCRC. Patients and Methods Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m2) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m2 twice daily (bid) on days 1-5 and 15-19 every 4 weeks were investigated in patients with refractory mCRC using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study. Results Twelve patients were enrolled in the study. Three of six patients in the oxaliplatin 85 mg/m2 cohort had dose-limiting toxicities (DLTs) with treatment delays during the second cycle at ≥8 days due to grade ≥ 2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. Grade ≥ 3 AEs were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1), and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin or severe peripheral sensory neuropathy. Conclusions A combination of FTD/TPI 35 mg/m2 bid on days 1-5 and 15-19 and oxaliplatin 85 mg/m2 on days 1 and 15 every 4 weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC.

• Authors: Mitsukuni Suenaga, Takeru Wakatsuki, Tetsuo Mashima, Mariko Ogura, Takashi Ichimura, Eiji Shinozaki, Izuma Nakayama, Hiroki Osumi, Yumiko Ota, Daisuke Takahari, Keisho Chin, Hiroyuki Seimiya, Kensei Yamaguchi
• Journal: Investigational new drugs (Invest New Drugs) Vol. 38 Issue 1 Pg. 111-119 (02 2020) ISSN: 1573-0646 [Electronic] United States
• PMID: 30838483 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrrolidines
• Oxaliplatin
• tipiracil
• Thymine
• Trifluridine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Colorectal Neoplasms (drug therapy, pathology)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Follow-Up Studies
• Humans
• Liver Neoplasms (drug therapy, secondary)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy, pathology)
• Oxaliplatin (administration & dosage)
• Prognosis
• Prospective Studies
• Pyrrolidines (administration & dosage)
• Salvage Therapy
• Thymine (administration & dosage)
• Tissue Distribution
• Trifluridine (administration & dosage)
• Young Adult