A phase 1b dose escalation study of AV-380 (anti-GDF15 monoclonal antibody) in combination with standard-of-care therapy in cancer patients with cachexia.

TPS12142 Background: Cachexia is a complex and common cancer comorbidity associated with a high risk of death. Despite its significant impact, no FDA-approved therapies exist to treat cancer cachexia, and current off-label treatments are limited and increase the risk of side effects. Circulating GDF-15, an inflammatory cytokine involved in the stress response and body weight regulation, has emerged as a main modulator implicated in the pathogenesis of cachexia. Further, preclinical models have shown that elevated levels of circulating GDF-15 elicit cachexia, and GDF-15 expression increases in proportion to disease severity. AV-380 is a high-affinity anti-GDF-15 IgG1 monoclonal antibody resulting in circulating GDF-15 elimination. AV-380 has been shown to reverse weight loss and increase muscle recovery in animal cancer models. In a phase 1 healthy volunteer study (in-house data), AV-380 was well-tolerated without serious AEs. Methods: This is an open-label, dose-escalation, multicenter phase 1b study to assess the safety, tolerability, PK, and PD of AV-380. Eligible patients must be ≥18 years of age, have cancer with cachexia (per international consensus criteria), receive standard-of-care antineoplastic therapy, have a prognosis of ≥3 months, and have an ECOG PS ≤2. Patients with known brain metastases (unless treated and stable for ≥2 weeks), myocardial infarction or grade 3/4 heart failure (≤3 months), uncontrolled third-spacing of fluids (pleural effusion, pericardial effusion, and/or ascites), or non-cancer-related cachexia, are excluded. Primary endpoints will evaluate the safety and tolerability per dose-limiting toxicities, adverse events (NCI CTCAE v5), and laboratory test results. Secondary endpoints include PK analysis, and exploratory endpoints include anti-drug antibodies, weight changes, patient-reported outcomes (Functional Assessment of Anorexia Cachexia Therapy, Patient Global Impression of Severity, Patient’s Global Impression of Change, Patient-Reported Outcomes Measurement Information System) physical function (by digital measures), and body composition (Lumbar 3 Skeletal Muscle Index). Escalating dose cohorts of AV-380 consist of 3-6 patients each, following a standard 3+3 design. The treatment is structured into 28-day courses for each cohort. AV-380 will be administered by IV infusion. Patients will remain on AV-380 until they have unacceptable toxicity, complete 4 courses, withdraw consent, or the sponsor terminates the study. Statistical analyses will be completed by cohort and summarized descriptively. Clinical trial information: NCT05865535 .