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Purpose: This randomized, double-blind, placebo-controlled, parallel-group, phase II trial assessed the efficacy and safety of adagloxad simolenin (OBI-822; a Globo H epitope covalently linked to keyhole limpet hemocyanin (KLH)) with adjuvant OBI-821 in metastatic breast cancer (MBC)., Methods: At 40 sites in Taiwan, USA, Korea, India, and Hong Kong, patients with MBC of any molecular subtype and ≤2 prior progressive disease events with stable/responding disease after the last anticancer regimen were randomized (2:1) to adagloxad simolenin (AS/OBI-821) or placebo, subcutaneously for nine doses with low-dose cyclophosphamide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, correlation of clinical outcome with humoral immune response and Globo H expression, and safety., Results: Of 349 patients randomized, 348 received study drug. Patients with the following breast cancer subtypes were included: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (70.4%), triple negative (12.9%), and HER2+ (16.7%), similarly distributed between treatment arms. Median PFS was 7.6 months (95% CI: 6.5-10.9) with AS/OBI-821 (n=224) and 9.2 months (95% CI: 7.3-11.3) with placebo (n=124) (HR=0.96; 95% CI: 0.74-1.25; p=0.77), with no difference by breast cancer subtype. AS/OBI-821 recipients with anti-Globo H IgG titer ≥1:160 had significantly longer median PFS (11.1 months (95% CI: 9.3-17.6)) versus those with titers <1:160 (5.5 months (95% CI: 3.7-5.6); HR=0.52; p<0.0001) and placebo recipients (HR=0.71; p=0.03). Anti-KLH immune responses were similar at week 40 between AS/OBI-821 recipients with anti-Globo IgG titer ≥1:160 and those with anti-Globo IgG titer <1:160. The most common adverse events with AS/OBI-821 were grade 1 or 2 injection site reactions (56.7%; placebo, 8.9%) and fever (20.1%; placebo, 6.5%)., Conclusion: AS/OBI-821 did not improve PFS in patients with previously treated MBC. However, humoral immune response to Globo H correlated with improved PFS in AS/OBI-821 recipients, leading the way to further marker-driven studies. Treatment was well tolerated.NCT01516307., Competing Interests: Competing interests: C-SH: Consulting fees from Amgen, AstraZeneca, Pfizer, and Roche. Contracted Research with Amgen, AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, and Roche. ALY: Member of a scientific advisory board for OBI Pharma and member of the Board of Directors for OPKO Health Corporation; has received funding for sponsored research from United Therapeutics Corporation and Cancer Prevention Pharmaceuticals. SAH: Has received grants/support from Ambrx, Amgen, Bayer, Biomarin, BI Pharma, Cascadian, Daiichi Sankyo, Dignitana, Genentech, GSK, Eli Lilly, MacroGenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Pieris, PUMA Biotechnology, Roche, and Seattle Genetics. Travel support from Eli Lilly, Novartis, and OBI Pharma. RBS: Owns stock in Samumed; expert witness for PUMA Biotechnology. H-KC: Research grants from Merck, Ono, and Roche. S-BK: Institutional funding from Dongkook Pharmaceutical Co, Genzyme, Kyowa Kirin, and Novartis. S-HL: Employee of OBI Pharma. C-CC: Previously employed by OBI Pharma. Consultant to Amwise Diagnostics, MiCareo Diagnostics, and SynCore Pharmaceuticals. Independent board member of Anxo Pharmaceuticals. HR: Receives research support for clinical trials through the University of California at San Francisco from: Eisai, Daiichi Sankyo, Genentech/Roche, Eli Lilly, MacroGenics, Merck, Novartis, OBI Pharma, Odonate, Pfizer, and Plexxikon. Has received travel support for clinical trials from Amgen, Eli Lilly, Merck, Mylan, Pfizer, and PUMA Biotechnology., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)