Phase II trial of subcutaneous methylnaltrexone in the treatment of severe opioid-induced constipation in cancer patients.

Abstract

TPS236 Background: Opioid-induced constipation (OIC) is mainly caused by binding of opioids to mu-opioid receptors in the gastrointestinal system, which affects gastrointestinal motility, secretion, fluid absorption and blood flow, and causes delayed colonic transit and inhibited defecation. Methylnaltrexone bromide is a peripherally-acting antagonist of the mu-opioid receptor. It has recently been approved by the U.S. Food and Drug Administration for treatment of OIC in patients with advanced disease receiving palliative care. However, its clinical utility has not been documented in cancer patients at earlier stages of disease. Methods: The objective of this prospective, single-arm, phase II trial is to evaluate the efficacy of methylnaltrexone in relieving OIC in cancer patients at earlier stages of disease. The primary endpoint is a rescue-free laxation ≤ 4 hours after the dose. Eligible for enrollment are cancer patients at earlier stages of disease with life expectancy ≥ 6 months and OIC with < 3 laxations during the preceding week and no clinically meaningful laxation (as determined by the investigators) ≤ 24 hours before the study entry. A single dose of methylnaltrexone will be administered subcutaneously to eligible patients. The efficacy and adverse events will be evaluated for 48 hours. Patients will complete questionnaires on laxation (frequency, consistency and difficulty), constipation (severity and distress), pain score, symptoms of opioid withdrawal, and satisfaction with the response at 4, 24 and 48 hours following the dose. 17 subjects are required assuming a baseline response rate of 15% against an alternative value of 50% using an exact binomial test with a two-tailed Type I error level of 10% and a power level of 90%. To date 5 patients have been enrolled. Obstacles to enrollment have included the multi-factorial nature of constipation in cancer patients which makes the detection of OIC difficult, initiation of various empirical treatments for OIC in patients who would otherwise be eligible, and lack of timely referral of potentially eligible patients because of poor awareness of supportive care trials. (NCT01004393)