ASPEN-09-03: A Study of Evorpacept in Combination With Trastuzumab and Chemotherapy in Metastatic HER2-Positive Breast Cancer

Inclusion Criteria: * Histologically confirmed invasive HER2+ breast cancer based on an evaluable tumor tissue biopsy obtained after cessation of T-DXd (ENHERTU) treatment and no more than 6 months prior to C1D1. * Received no more than 4 prior lines of HER2-directed therapy including at least one prior line of T-DXd (ENHERTU) for locally advanced/metastatic HER2+ breast cancer. Prior neoadjuvant therapy which resulted in relapse within 6 months of completion of T-DXd will be considered a line of treatment for metastatic disease. Participants who discontinue T-DXd due to intolerance are considered eligible. * Progressed on or following the most recent line of therapy. * Eligible to receive one of the following chemotherapy options (capecitabine, eribulin, gemcitabine, paclitaxel or vinorelbine). * Measurable disease as defined by RECIST v1.1. * LVEF ≥50%. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be 0 to 1. * Life expectancy of at least 3 months. * Adequate renal function (estimated creatinine clearance ≥30 mL/min as calculated using the Cockcroft-Gault equation or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. * Adequate liver function: * Total bilirubin ≤1.5 x upper limit of normal (ULN) (≤3.0 x ULN if the participant has documented Gilbert syndrome); * Aspartate and alanine transaminase (AST and ALT) ≤3 x ULN (≤5.0 x ULN if liver involved by metastatic disease). * Participants must have recovered from all AEs due to previous therapies, procedures, and surgeries to baseline severity or ≤Grade 1 per NCI CTCAE v5.0 except for AEs not deemed reversible and which do not constitute a safety risk by Investigator judgment. Exclusion Criteria: * Untreated CNS metastases. * Prior exposure to any anti-CD47 or anti-SIRPα agent. * Any condition that would be contraindicated to receiving trastuzumab * Has a diagnosis of complete dihydropyrimidine dehydrogenase (DPD) deficiency or significant toxicity with prior flurouracil (5FU) based regimen * Following anti-cancer therapy with insufficient washout before start of treatment: 1. chemotherapy, hormonal therapy, radiation therapy or small molecule anti-cancer therapy within 14 days or 5 half-lives (whichever is shorter) of start of treatment. 2. Immune therapy or other biologic therapy (e.g., monoclonal antibodies, antibody-drug conjugates) for the treatment of cancer for: 28 days or 5 half-lives (whichever is shorter) of start of treatment). * History of autoimmune hemolytic anemia, autoimmune thrombocytopenia, or hemolytic transfusion reaction. * Had an allogeneic tissue/solid organ transplant. * Any active, unstable cardiovascular disease. * Intolerance to or who have had a severe allergic or anaphylactic reaction to antibodies or infused therapeutic proteins or participants who have had a severe allergic or anaphylactic reaction to any of the substances included in the study drug (including excipients). * Has an active autoimmune disease that has required systemic treatment in past 2 years. * Other primary malignancy within 2 years.