Background <p>Maintaining quality of life (QoL) for older cancer patients (≥ 70 years) undergoing systemic treatment is challenging. Melatonin supplementation could be a potential strategy.</p> Aims <p>The MEQAPAG trial investigated the effects of melatonin supplementation on this specific population’s quality of life.</p> Methods <p>A multi-centre, double-blind, randomized placebo-controlled trial was implemented. Patients in the interventional arm received a daily dose of melatonin (2&#xa0;mg/j for 90 days, 1–2&#xa0;h before bedtime and after a meal) for the first three months of a new systemic treatment line. The primary endpoint was QoL assessment using the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) before and after supplementation. Among the secondary objectives, we evaluated the impact of supplementation on sleep and on urinary melatonin concentrations. We also studied safety and survival.</p> Results <p>One hundred and twenty-three patients were included in the study between July 2015 and January 2021. The trial was prematurely terminated due to futility. Only 61% (<i>n</i> = 59) of the patients were assessable and considered as compliant (i.e., at least two months of supplementation), 30 and 29 were allocated to the experimental and control groups respectively. Median age was 76 years (range [70, 88]). No difference in the QLQ-C30 questionnaire global score was shown. After the supplementation, the aMT6s concentration is 8,4 ng/mg creatinine (range [0.15, 201], IQI [0.99, 105]) in the experimental group.</p> Conclusion <p>In an older cancer population, supplementation with 2&#xa0;mg melatonin was safe but did not lead to any significant improvement in the global quality of life score on the QLQ-C30 for compliant patients. MEQAPAG trial provides novelty data on urinary aMT6s concentration for older cancer patients.</p> Trial registration number <p>NCT02454855, register on 05/12/2015.</p>