Abstract A128: Design of a Phase 2 basket trial to assess mifomelatide (TCMCB07) in GI cancer cachexia: A focus on pancreatic ductal adenocarcinoma (PDAC)

Abstract

Background: Cachexia is common in gastrointestinal (GI) cancers in general and pancreatic ductal adenocarcinoma (PDAC) in particular. PDAC has one of the highest prevalences and earliest onsets of cancer cachexia, affecting up to 90% of patients. Furthermore, the extent of weight lost among patients with PDAC exceeds that observed in most other tumor types. Cachexia-induced muscle mass and energy store depletion reduces chemotherapy tolerance, often leading to dose reductions, treatment delays/discontinuation, and poorer survival outcomes. Therefore, body weight preservation during chemotherapy may improve treatment effectiveness and outcomes for patients with PDAC. The central melanocortin (MC) system, including MC3 and MC4 receptors, plays an essential role in regulating appetite, body mass, and energy homeostasis and is a logical therapeutic target to prevent and treat cachexia. Mifomelatide is a novel peptide MC3R/MC4R dual antagonist that is being studied for cancer and chemotherapy-associated weight loss. Our previously published work showed that mifomelatide is safe and ameliorates cancer- and chemotherapy-associated cachexia in preclinical animal studies with mice, rats, and pet dogs. In a Phase 1 trial with healthy volunteers, mifomelatide was well tolerated; the only adverse events were low-grade injection-site reactions. In addition, while the trial was not powered for efficacy, mifomelatide treatment was associated with a modest increase in body weight and hunger compared with placebo, warranting further clinical development. Methods: The randomized, double-blind, placebo-controlled Phase 2 basket trial of mifomelatide (NCT06937177) is enrolling participants initiating first-line chemotherapy for newly diagnosed, unresectable PDAC and cachexia or newly diagnosed, unresectable colorectal cancer (CRC) and < 10% body weight loss in the past 6 months. Participants, grouped into 2 cohorts by tumor type, are randomly assigned to receive subcutaneous mifomelatide (12.5, 25, or 50 mg) or placebo daily for 12 weeks. Following double-blind treatment, eligible participants may enroll in an open-label extension phase and receive mifomelatide 25 mg daily for up to an additional 26 weeks. Primary endpoints are change from baseline in body weight at 12 weeks and safety. Secondary endpoints are focused on changes in anorexia/cachexia-related PROs and BMI. This Phase 2 basket trial will generate robust insights into the benefit–risk profile of MC3R/MC4R dual antagonism with mifomelatide to treat cachexia across GI cancers and inform optimal dose selection, endpoints, sample size, and other key design elements for a planned pivotal trial in PDAC.