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 Overview

Patient 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 the first 10 weeks of ADC therapy (patients sign 1st consent to share tumor tissue with BreakBio). Biopsy can be from primary site or metastatic site. BreakBio will provide detailed reports from DNA and RNA analysis to treating physician (not yet enrolled on this study)
• Patients who progress on first-line ADC therapy are pre-screened for this study (not yet enrolled on this study)
• Patients who pass the pre-screening for this study start 2 cycles of induction chemotherapy of physician's choice. Treating physician informs BreakBio to begin manufacturing BreakVax (not yet enrolled on this study)
• After 2 cycles of induction chemotherapy, patients are screened for eligibility for this study. If BreakVax manufacturing is delayed, patients should complete a 3rd cycle of induction chemotherapy before screening. Patients are only eligible if they do not experience progression during these induction chemotherapy cycles (not yet enrolled on this study)
• Patients who pass screening will sign 2nd consent to enroll in study (enrolled in study)
• 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 to either the BreakVax Arm or the Delayed BreakVax Arm as detailed below (enrolled in study)

Safety Lead-in Cohort The first three patients, who are enrolled on Substudy A or B or a combination of both, will comprise a Safety Lead-in Cohort to characterize dose-limiting toxicities (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 cycles of 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-dose subcutaneous ipilimumab (administered locally at the injection site as a local dendritic cell adjuvant to enhance T-cell priming) will be administered without chemotherapy or other combination drugs. Then, patients will proceed to Cycle 2 of the BreakVax Arm, where they will receive BreakVax and all combination drugs.
• Monitoring: Patients will be monitored over 28 days (21 days with BreakVax and low-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 continue with Cycle 2 of the BreakVax Arm. After the three patients in the Safety Lead-in Cohort have completed the DLT evaluation period (either as part of Substudy A or B or 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 will be enrolled on Substudy A or B or a combination of both, will be enrolled in the Safety Lead-in Cohort. If ≥3 DLTs are observed among the 6 patients, continuation of the study will be reviewed by the Safety Monitoring Committee (SMC), which may recommend study termination based on safety findings.

Randomized Combination Therapy Cohort

Following completion of the Safety Lead-in Cohort, 10 patients will be randomized in a 1:1 ratio to one of the following arms:

• BreakVax Arm: BreakVax formulated with adjuvants and low-dose subcutaneous ipilimumab (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 disease progression per iRECIST. Upon progression, patients will cross over to receive the study combination regimen, including BreakVax formulated with adjuvants, low-dose subcutaneous 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 its adjuvants and low-dose subcutaneous ipilimumab (as a local dendritic cell adjuvant) will be administered on Day 1 of Cycles 1, 2, and 3. Thereafter, BreakVax will be administered on Day 1 of every even cycle (i.e. cycles 4, 6, 8, etc.) until disease progression per iRECIST 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 regimen within each 21-day cycle. Steroid-containing premedications are not permitted (see Disallowed Concomitant Medications listed below).
• Aspirin will be administered orally once daily, except on Days 1, 2, and 3 of cycles in which BreakVax is administered.
• Pembrolizumab will be initiated on Day 10 of Cycle 4 and will thereafter be administered 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 receive chemotherapy of physician's choice in each 21-day cycle until disease progression per iRECIST.

Upon documented disease progression, patients will cross over to receive the full combination regimen, including BreakVax with adjuvants, low-dose subcutaneous ipilimumab (as a local dendritic cell adjuvant), pembrolizumab, losartan, aspirin, and chemotherapy of physician's choice, according to the BreakVax Arm schedule.

Inclusion criteria

• Age ≥ 18 years and < 72
• Patients with histologically confirmed locally advanced unresectable or metastatic, PD-L1 negative (CPS <10), gBRCA-negative TNBC who received first-line ADC treatment and experienced disease progression and have sent 200mg (approximately) of tumor tissue (fresh tissue immersed in AllProtect then frozen) to BreakBio for analysis.
• Must have measurable disease per RECIST v1.1 (at least one non-nodal lesion ≥10 mm in longest diameter and/or pathologic lymph node(s) ≥15 mm in short axis on CT/MRI) on imaging obtained within 21 days of first dose of treatment combination.
• Must not have experienced progression during the induction chemotherapy cycles.
• Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1 on day of first dose
• Patient has adequate organ function on day one of the trial as defined by:

• Neutrophil to Lymphocyte Ratio (NLR)1 at a healthy adult's normal level: ≤ 3.5
• Absolute Neutrophil Count (ANC) at the normal level: ≤ 7,000/mm3
• Absolute Lymphocyte Count in normal level: ≥ 1,000/mm3
• Monocytes at normal level: < 700/mm3
• Platelet count: ≥ 100 x 109/L (without transfusion support in the last two weeks)
• Hemoglobin: > 10.0 g/dL (without transfusion support in the last two weeks)
• AST and ALT: ≤ 3 X institutional upper limit of normal (ULN) in the absence of liver mets; AST and/or ALT may be ≤ 5 x ULN in the setting of liver metastases
• Total Bilirubin: ≤ 1.2mg/dL
• Serum creatinine: ≤ 1.5 x institution's ULN
• Albumin: ≥ 3.4 g/dL
• Serum Magnesium: ≥ 1.7 mg/dL
• Pulse oximetry ≥ 95% on room air
• Provision of consent for on-treatment biopsy (compulsory) and post-treatment biopsy (optional).
• Both male and female patients enrolled in this trial must agree to use effective contraception during the course of the trial and for at least 3 months after discontinuing study treatment. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.
• Negative pregnancy test ≤ 7 days prior to day one of cycle 1, for women of childbearing potential only.
• Life expectancy > 6 months
• Willing and able to provide informed consent

Exclusion criteria

• Prior exposure to anti PD- 1/PD-L1 agents.
• Prior exposure to immunosuppressive therapy within the last 12 months prior to enrollment
• Receiving or previously receiving oral or IV steroids within 6 weeks of starting study treatment. Currently using or previously used topical steroids within 6 weeks of starting study treatment. Expected to require steroid-containing pre-meds before chemotherapy doses.
• Patients with deficient mismatch repair (dMMR) or microsatellite instability (MSI-H) phenotype.
• Any liver metastasis greater than 2 cm or greater than 5 liver metastases. Patients who have liver metastasis removed by surgery, and therefore meet this criterion at first dose, may enroll.
• Patients not recovered from all clinically significant toxic effects of previous therapies to ≤Grade 1 or baseline with the exception of peripheral neuropathy and alopecia.
• Patients not recovered adequately from the toxicity and/or complications from any major surgery prior to starting study treatment.
• Known or suspected hypersensitivity to any of the study drugs
• Received an investigational agent within 28 days prior to the first dose of study drug.
• History of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), as well as unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction within the past 6 months. Note: Prior to trial entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• LVEF <50%
• Active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids.
• Untreated, symptomatic, or progressing brain/CNS metastases; leptomeningeal disease; or prior whole-brain radiation. CNS metastases are allowed only if treated and stable on MRI for ≥8 weeks, the patient has recovered from CNS therapy, and has been off steroids for ≥12 weeks.
• Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. (Individuals who are hepatitis C antibody positive may be enrolled if negative viral load confirmed).
• History of autoimmune disease including: inflammatory bowel disease (including ulcerative colitis and Crohn's Disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis (e.g. Wegener's granulomatosis); central nervous system or motor neuropathy considered of autoimmune origin (e.g. Guillain-Barré syndrome, myasthenia gravis, multiple sclerosis). Individuals with vitiligo, Sjogren's Syndrome, interstitial cystitis, Graves' or Hashimoto's Disease, celiac disease, DM1, hypothyroidism stable on hormone replacement, or any autoimmune disease without symptoms and not requiring active therapy for at least 2 years will be allowed with Study Medical Monitor's approval.
• A serious local infection (e.g. cellulitis, abscess) or systemic infection (e.g. pneumonia, septicemia) which requires systemic antibiotic treatment within 4 weeks prior to the first dose of study medication.
• Receiving coumarin-derived anticoagulants.
• Unable or unwilling to withhold or discontinue any prohibited or restricted medications/ procedures for the specified windows during the study.
• Inability or refusal to comply with the protocol or with the clinical trial procedures
• If female, pregnant or breastfeeding. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
• Chronic intake of drugs that lead to known interference with metabolism through strong Cytochrome P450 3A4 (CYP3A4) interaction: e.g. Rifampicin, Rifabutin, Clarithromycin, Telithromycin, Ketoconazole, Itraconazole, Fluconazole, Hypericum perforatum (St. John's Wort /Johanniskraut) or any strong CYP3A4 inducing or inhibiting drug (Note: participants in this study should avoid consuming grapefruit or grapefruit-containing products during the duration of the study, including the screening phase, treatment period, and follow-up period.)
• Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
• Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months before the start of study medication. Active pulmonary emboli or deep vein thrombosis that are significant or not adequately controlled on anticoagulation regimen
• Any hemorrhage or bleeding event ≥ National Cancer Institute - Common terminology criteria for adverse events (NCI-CTCAE) Grade 3 within 28 days prior to the start of study medication
• History of other invasive cancer within 2 years prior to enrollment, except for treated non-melanoma skin cancer
• Known DNA Polymerase Epsilon (POLE) mutations