This phase I/II trial is trying to understand how safe and tolerable the combination of a targeted therapy and chemotherapy is for the treatment of patients with previously treated HER2-positive breast cancer that is locally advanced or has spread to other parts of the bodyA Phase lb/ll, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Venetoclax in Combination With Trastuzumab Emtansine in Patients With Previously Treated HER2-Positive Locally Advanced or Metastatic Breast Cancer

Exclusion

• Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1
• Radiation therapy within 2 weeks prior to Cycle 1, Day 1
• History of exposure to the following cumulative doses of anthracyclines as specified: Doxorubicin >500 mg/m2; Liposomal doxorubicin >500 mg/m2; Epirubucin >720 mg/m2; Mitoxantrone >120 mg/m2; Idarubicin >90 mg/m2. If another anthracycline or more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.
• History of other malignancy within the previous 5 years
• Cardiopulmonary dysfunction
• Current severe, uncontrolled systemic disease
• Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1
• Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, autoimmune hepatic disorders, sclerosis cholangitis, or active infection with HBV or HCV)
• Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
• Known HIV infection or human T-cell leukemia virus 1 infection
• Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization
• Known central nervous system (CNS) disease
• Leptomeningeal disease
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
• Current Grade >/= 3 peripheral neuropathy
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion proteins
• Prior allogeneic stem cell or solid organ transplantation
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 30 days after the last dose of venetoclax or 7 months after the last dose of trastuzumab emtansine after the final dose of study treatment, whichever is later
• Consumption of grapefruit, grapefruit products, Seville oranges, or starfruit within 3 days before anticipated first dose of study drug until the last dose of study drug
• Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study
• Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment
• Malabsorption syndrome or other condition that would interfere with enteral absorption
• History of active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) requiring specific medication in the 12 months prior to randomization, or active and uncontrolled bowel inflammation (e.g., diverticulitis) at time of randomization
• Inability or unwillingness to swallow a large number of tablets
• Known hypersensitivity to venetoclax or trastuzumab emtansine or to any of their excipients
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
• Other medical or psychiatric conditions that, in the opinion of the investigator, may interfere with the patient's participation in the study
• Blood transfusions if performed within 2 weeks prior to screening

Exclusion Criteria for Randomized Phase II Stage

In addition to the general exclusion criteria, participants in the randomized Phase II stage who meet the following criteria will be excluded:

• Prior treatment with trastuzumab emtansine in any setting (neoadjuvant/adjuvant or advanced/metastatic setting)
• Prior treatment with venetoclax in any setting
• Prior treatment with anti-HER2 antibody drug conjugates (e.g. trastuzumab deruxtecan [DS-8201a]), margetuximab, pyrotinib, or tucatinib)