WINSHIP 4468-18: Phase II evaluation of the effect of 2- versus 6-hour oxaliplatin infusions on neuropathy and pharmacokinetics in patients with gastrointestinal cancers.

Abstract

TPS12174 Background: Oxaliplatin, a third-generation platinum agent, improves outcomes in gastrointestinal (GI) cancers when combined with fluoropyrimidines. However, it is also associated with clinically significant acute and chronic neurotoxicity. Approximately 33% of patients develop grade 3–4 sensory neuropathy, and up to 11% discontinue therapy due to neuropathy. Acute neurotoxicity is linked to the maximum plasma concentration (Cmax) of platinum ultrafiltrate, and greater acute sensory neuropathic symptoms predict later chronic neuropathy. Prior data suggest that extending infusion duration from 2 hours to 4–6 hours lowers Cmax by ~32–50% and reduces recurrence of acute neuropathic symptoms. We hypothesize that a 6-hour oxaliplatin infusion will reduce platinum ultrafiltrate Cmax and decrease the incidence and severity of chronic sensory neuropathy. Methods: WINSHIP 4468-18 is a randomized, open-label phase II trial enrolling a real-world population of patients with gastrointestinal (GI) cancers for whom oxaliplatin-containing combination therapy is indicated. All participants receive IV infusion of oxaliplatin 85 mg/m² every 2 weeks as part of a standard combination regimen. Sixty patients will be randomized 2:1 to 6-hour (n = 40) versus 2-hour (n = 20) oxaliplatin infusion duration. Eligibility includes confirmed GI malignancy, ECOG 0–2, and adequate organ function. Key exclusion criteria are baseline grade ≥2 neuropathy and prior hypersensitivity/intolerance to oxaliplatin. The primary endpoint is the between-arm difference in EORTC Chemotherapy Induced Peipheral Neuropathy (CIPN)20 sensory scores from baseline to cycle 4. Secondary endpoints include comparison of pharmacokinetic parameters, particularly Cmax of platinum ultrafiltrate. With an assumed 10-point between-group difference in CIPN20 sensory score at cycle 4, 60 patients provide 80% power (two-sided α = 0.05). The study is open and accruing (NCT03800693). Clinical trial information: NCT03800693 .