Abstract Background: Cancer cachexia is a complex metabolic syndrome characterized by involuntary weight loss, muscle wasting and weakness leading to resistance to therapy and high mortality. Elevated levels of circulating GDF-15, an inflammatory cytokine involved in stress response and body weight regulation, are common in cancer pts with cachexia. Furthermore, GDF-15 expression increases in proportion to disease severity, and preclinical models have shown that elevated levels of circulating GDF-15 elicit cachexia. AV-380 is an antibody that binds with high affinity to GDF-15 resulting in its elimination from circulation. It has been shown to reverse weight loss and increase recovery of muscle in animal cancer models and was well tolerated without serious AEs in a phase 1 study in healthy subjects. The current study is designed to determine if adding AV-380 to standard-of-care (SoC) chemotherapy will confer additional clinically meaningful benefits in metastatic cancer pts with cachexia. Methods: This is an open-label, dose escalation, multicenter phase 1b study to assess the safety, PK, and PD of AV-380. Eligible pts must be ≥18 years of age, have confirmed metastatic colorectal or pancreatic cancer, actively receiving 1st-line SoC chemotherapy (>2 cycles of FOLFOX/FOLFOXIRI±bevacizumab for colorectal, FOLFOX/FOLFIRINOX for pancreatic), have cachexia defined by Fearon criteria (weight loss >5% over past 6 months w/o simple starvation, or BMI <20 kg/m2 or sarcopenia plus any degree of weight loss >2%), life expectancy ≥3 months, GDF-15 >1200 pg/mL, and ECOG PS 0/1. Those with brain metastases (unless treated and stable for ≥2 weeks prior to study treatment), significant cardiovascular disease, corrected QT interval >460 ms, uncontrolled pleural or pericardial effusion, parenteral nutrition, or non-cancer related cachexia are excluded. Primary endpoints are AE characterization, serum PK parameters, and serum levels of GDF-15; secondary endpoints include assessments of weight/BMI, cachexia measures, and anti-AV-380 antibodies; and exploratory endpoints include best objective response and biomarkers. Five escalating dose cohorts of AV-380 are planned (50, 100, 200, 400, 800 mg IV) with 4-6 pts in each and following a standard 3+3 design. Dose de-escalation will be performed if the lowest dose cohort is successful. The study is structured into 28-day courses with Course 1 being the single-dose phase of AV-380 and Course 2 starting the multiple-dose phase where AV-380 is administered every 14 days. Pts will remain enrolled until they start 2nd-line systemic anticancer therapy, have unacceptable toxicity related to AV-380, complete 4 courses of AV-380, withdraw consent, or sponsor terminates study. Statistical analyses will be done by cohort and summarized descriptively. Clinicaltrials.gov: NCT05865535 Encore abstract. Originially accepted at the annual Cancer Cachexia Society meeting, 28-30 September 2023, Edinburgh Scotland. Citation Format: Arvind Chaudhry, RIchard Zuniga, J. Eva Selfridge, Bruno Bastos, Vipin Lohiya, Martin Birkhofer. A phase 1b dose escalation study of AV-380 in combination with standard of care chemotherapy in metastatic cancer patients (pts) with cachexia and elevated GDF-15 levels [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C02.