A phase 2 randomized, double-blind, placebo-controlled study to evaluate LY3537021 for the treatment of chemotherapy-induced nausea and vomiting in patients with malignant disease.

TPS855 Background: Chemotherapy-induced nausea and vomiting (CINV) remains an important concern for patients (pts) receiving highly emetogenic regimens such as anthracycline, cyclophosphamide (AC) and cisplatin. These agents are commonly used in treating a range of cancers, including thoracic, breast, gastrointestinal, and head and neck malignancies. CINV may become an increasing symptomatic toxicity in pts as novel antibody-drug conjugates are utilized more broadly. Standard management typically combines 5-HT3 receptor antagonists, NK1 receptor antagonists, and corticosteroids, yet significant unmet needs persist, particularly in the delayed phase of CINV. Emerging evidence suggests that GIP signaling moderates nausea and vomiting induced by broad stimuli and may represent a novel treatment approach to control CINV. LY3537021 is a potent, and selective glucose-dependent insulinotropic polypeptide receptor (GIPR) monoagonist with a half-life of 12 days being evaluated to prevent CINV. Methods: This is a randomized, double-blind, global phase 2 trial that will enroll chemotherapy-naïve pts (>18 years) scheduled to receive a chemotherapy regimen with AC or cisplatin (≥70 mg/m2, single infusion day 1 per cycle). Pts must have histologically or cytologically confirmed malignancy, be scheduled for AC or cisplatin chemotherapy, and have a life expectancy >6 months. ECOG performance status 0–2 and adequate organ function are required. Pts will be enrolled equally to AC and cisplatin therapy. Approximately 204 pts will be randomized 1:1:1:1 to receive placebo or 3 different single doses of LY3537021 in combination with a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and dexamethasone, administered prior to chemotherapy. The primary objective will be to compare the efficacy of LY3537021 to placebo in combination with other antiemetic treatments. Endpoints will be assessed during cycle 1 and will focus on the percentage of pts achieving complete response during the delayed phase (defined as no vomiting and no rescue therapies 24-120 hrs after chemotherapy). Interim safety analysis will be overseen by an independent Data Monitoring Committee (DMC). Other inclusion criteria are adequate hematologic, hepatic, renal, and pancreatic function, and agreement to contraception requirements. Exclusion criteria include the presence of symptomatic or untreated CNS metastases, hypersensitivity to antiemetics, uncontrolled diabetes (HbA1c ≥8%), significant cardiac disorders, QTcF prolongation, thyroid abnormalities, active HBV, HCV, HIV, or CMV infection, alternative causes for nausea/vomiting, or prior systemic anticancer therapy. Clinical trial information: NCT07169851 .