Combination Immunotherapy Treatment for Locally Advanced Unresectable or Metastatic, PD-L1 Negative (CPS<10), gBRCA Negative, Triple Negative Breast Cancer Including BreakVax ImmunoTreatment (Designed and Manufactured Per Patient), Chemotherapy and Anti PD-1 Therapy

Study Design OverviewPatient Timeline: ‐ Patients will start first‐line therapy with ADC (not yet enrolled on this study) ‐ Patients provide tumor tissue (frozen in AllProtect) to BreakBio for analysis in thefirst 10 weeks of ADC therapy (patients sign 1st consent to share tumor tissue withBreakBio). Biopsy can be from primary site or metastatic site. BreakBio will providedetailed reports from DNA and RNA analysis to treating physician (not yet enrolledon this study) ‐ Patients who progress on first‐line ADC therapy are pre‐screened for this study (notyet enrolled on this study) ‐ Patients who pass the pre‐screening for this study start 2 cycles of inductionchemotherapy of physician's choice. Treating physician informs BreakBio to beginmanufacturing BreakVax (not yet enrolled on this study) ‐ After 2 cycles of induction chemotherapy, patients are screened for eligibility forthis study. If BreakVax manufacturing is delayed, patients should complete a 3rdcycle of induction chemotherapy before screening. Patients are only eligible if theydo not experience progression during these induction chemotherapy cycles (not yetenrolled on this study) ‐ Patients who pass screening will sign 2nd consent to enroll in study (enrolled instudy) ‐ The first 3 patients, who are enrolled on Substudy A or B or a combination of both,will comprise the Safety Lead‐in Cohort (no randomization, as detailed below)(enrolled in study) ‐ After the Safety Lead‐in Cohort is complete, further patients will be randomized toeither the BreakVax Arm or the Delayed BreakVax Arm as detailed below (enrolled instudy)Safety Lead‐in Cohort The first three patients, who are enrolled on Substudy A or B or acombination of both, will comprise a Safety Lead‐in Cohort to characterize dose‐limitingtoxicities (DLTs) and early safety. For Substudy A, the treatment cycle is 21 days,however, the DLT evaluation period will be 28 days. These patients will receive 2 cyclesof induction chemotherapy (Cycles ‐1 and ‐2), followed by a 28 day DLT evaluation period(21 days of Cycle 1 and 7 days of Cycle 2). ‐ Treatment: In the first 21 days (Cycle 1) formulated BreakVax and low‐dosesubcutaneous ipilimumab (administered locally at the injection site as a localdendritic cell adjuvant to enhance T‐cell priming) will be administered withoutchemotherapy or other combination drugs. Then, patients will proceed to Cycle 2 ofthe BreakVax Arm, where they will receive BreakVax and all combination drugs. ‐ Monitoring: Patients will be monitored over 28 days (21 days with BreakVax andlow‐dose ipilimumab alone, and then the first 7 days of Cycle 2 of the BreakVax Arm,where they will receive BreakVax and all combination drugs) for DLTs. ‐ Following completion of the DLT evaluation period (28‐days), patients will continuewith Cycle 2 of the BreakVax Arm. After the three patients in the Safety Lead‐inCohort have completed the DLT evaluation period (either as part of Substudy A or Bor a combination of both), the randomized phase of the study will begin.If ≥2 DLTs are observed among the initial 3 patients, an additional 3 patients, who willbe enrolled on Substudy A or B or a combination of both, will be enrolled in the SafetyLead‐in Cohort. If ≥3 DLTs are observed among the 6 patients, continuation of the studywill be reviewed by the Safety Monitoring Committee (SMC), which may recommend studytermination based on safety findings.Randomized Combination Therapy CohortFollowing completion of the Safety Lead‐in Cohort, 10 patients will be randomized in a1:1 ratio to one of the following arms: ‐ BreakVax Arm: BreakVax formulated with adjuvants and low‐dose subcutaneousipilimumab (as a local dendritic cell adjuvant) in combination with pembrolizumab,losartan, aspirin, and SOC chemotherapy of physician's choice. ‐ Delayed BreakVax Arm: SOC chemotherapy of physician's choice until diseaseprogression per iRECIST. Upon progression, patients will cross over to receive thestudy combination regimen, including BreakVax formulated with adjuvants, low‐dosesubcutaneous ipilimumab (as a local dendritic cell adjuvant), pembrolizumab,losartan, aspirin, and chemotherapy of physician's choice.Treatment Schedule:A treatment cycle is defined as 21 days. BreakVax Arm BreakVax, in combination with itsadjuvants and low‐dose subcutaneous ipilimumab (as a local dendritic cell adjuvant) willbe administered on Day 1 of Cycles 1, 2, and 3. Thereafter, BreakVax will be administeredon Day 1 of every even cycle (i.e. cycles 4, 6, 8, etc.) until disease progression periRECIST or other discontinuation criteria.In addition to BreakVax: ‐ Losartan will be administered orally once daily throughout treatment. ‐ Chemotherapy of physician's choice will be administered per the selected regimenwithin each 21‐day cycle. Steroid‐containing premedications are not permitted (seeDisallowed Concomitant Medications listed below). ‐ Aspirin will be administered orally once daily, except on Days 1, 2, and 3 of cyclesin which BreakVax is administered. ‐ Pembrolizumab will be initiated on Day 10 of Cycle 4 and will thereafter beadministered on Day 10 of every even‐numbered cycle (i.e., Cycles 4, 6, 8, etc.)until disease progression or discontinuation.Delayed BreakVax Arm Patients randomized to the Delayed BreakVax Arm will receivechemotherapy of physician's choice in each 21‐day cycle until disease progression periRECIST.Upon documented disease progression, patients will cross over to receive the fullcombination regimen, including BreakVax with adjuvants, low‐dose subcutaneous ipilimumab(as a local dendritic cell adjuvant), pembrolizumab, losartan, aspirin, and chemotherapyof physician's choice, according to the BreakVax Arm schedule.