A randomized, double-blind, placebo-controlled Phase 2 study of mifomelatide (TCMCB07) in patients with newly diagnosed metastatic colorectal cancer undergoing chemotherapy: The Paradox Trial

Background: Cachexia is a complex metabolic disorder characterized by involuntary weight loss, anorexia, and fatigue. It affects many patients with cancer and is associated with reduced chemotherapy tolerance, diminished quality of life, and reduced overall survival (OS). While obesity is a risk factor for developing many tumor types, higher BMI is protective in most cancers in terms of OS (Renfro et al. J Clin Oncol . 2015;34:144). Moreover, the ability to maintain body weight during treatment, even among patients with obesity at diagnosis, correlates with an OS benefit in metastatic colorectal cancer (mCRC; Franko et al. Eur J Cancer . 2022;174:142). Therefore, body weight preservation during cancer treatment may improve survival outcomes. The central melanocortin (MC) system, comprised of MC3 and MC4 receptors, plays essential roles in regulating appetite, body mass, and energy homeostasis. While MC3R mediates adaptation to fasting and nutrient use, MC4R is involved in feeding behavior, adaptive thermogenesis, and glucose homeostasis. As such, the MC system is a logical therapeutic target for cancer and chemotherapy-associated weight loss. Mifomelatide, a synthetic peptide MC3R/MC4R antagonist, is being tested as a novel treatment for cancer cachexia. In preclinical studies, mifomelatide safely and effectively ameliorated cancer cachexia in rats and dogs, and a Phase 1 trial in healthy volunteers showed mifomelatide was well tolerated and not associated with abnormal vital signs, abnormal ECGs, or drug-related SAEs. Although the Phase 1 trial was not designed to study efficacy, participants treated with mifomelatide experienced a modest increase in body weight and hunger compared with placebo (Qi et al. J Clin Oncol. 2023;41:e15195). These findings warranted further study of mifomelatide in the randomized, double-blind, placebo-controlled Phase 2 Paradox Trial (NCT06937177) for body weight optimization in patients undergoing chemotherapy for newly diagnosed mCRC. Methods: Adults (≥18 years old) with newly diagnosed mCRC and a BMI ≤ 29 kg/m 2 are randomized to receive a daily subcutaneous injection with placebo or 12.5, 25, or 50 mg mifomelatide for 12 weeks starting with the second chemotherapy round. Primary endpoints are change from baseline in body weight, incidence and severity of AEs, and incidence of lab or vital sign abnormalities. Secondary endpoints include change from baseline in FAACT-5IASS score, BMI, and EORTC QLQ-C30 score. Results: Paradox is currently enrolling, with a planned enrollment of 120 participants in the US and Canada. Conclusion: The Paradox Trial will be the first study to assess the ability of MC3R/MC4R antagonism to safely and proactively optimize body weight in participants with newly diagnosed mCRC undergoing chemotherapy.