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

Phase 1/2 Trial of a Combination Immunotherapy Treatment for Solid Tumors Including BreakVax ImmunoTreatment (Designed and Manufactured Per Patient), Chemotherapy and Anti PD-1 Therapy

The objective of this study is to evaluate the safety, feasibility, and preliminary antitumor activity of this multi-component immunotherapy strategy in patients with advanced solid tumors. The study is designed to assess whether coordinated enhancement of antigen-specific T-cell priming and tumor microenvironment modulation can improve immune-mediated tumor control.

In this study, BreakVax with adjuvants (Montanide and Poly-ICLC) is administered in combination with:

1. Low-dose subcutaneous ipilimumab at the injection site as a dendritic cell adjuvant to enhance local dendritic cell-mediated T-cell priming;
2. Pembrolizumab to mitigate PD-1-mediated T-cell exhaustion and sustain effector function;
3. Standard-of-care chemotherapy, which may promote immunogenic cell death, increase antigen release and modulate the tumor microenvironment; and
4. Losartan and aspirin, which have been associated in preclinical and translational studies with modulation of stromal architecture, vascular normalization, and reduction of tumor-associated immunosuppressive signaling.

The study consists of two components: a Safety Lead-in Cohort and a randomized combination therapy cohort. The Safety Lead-in Cohort is designed to evaluate safety and tolerability of the study combination and to characterize dose-limiting toxicities (DLTs). The randomized combination therapy cohort portion is designed to evaluate the antitumor activity of the study combination compared with standard-of-care (SOC) chemotherapy of physician's choice, as measured by objective response rate (ORR), and to evaluate disease control rate (DCR) in patients who receive the study combination following progression on SOC chemotherapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Triple-Negative Breast Cancer (TNBC)
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Losartan and aspirin; Drug: BreakVax; Drug: Ipilimumab 2.5 mg; Drug: Standard-of-care chemotherapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33176
      • Miami Herbert Wertheim Cancer Institute
      • Principal Investigator: Reshma L Mahtani, DO
      • Principal Investigator: Manmeet Ahluwalia, MD, MBA, FASCO

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years and < 72
2. 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.
3. 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.
4. Must not have experienced progression during the induction chemotherapy cycles.
5. Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1 on day of first dose

6. 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
7. Provision of consent for on-treatment biopsy (compulsory) and post-treatment biopsy (optional).
8. 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.
9. Negative pregnancy test ≤ 7 days prior to day one of cycle 1, for women of childbearing potential only.
10. Life expectancy > 6 months
11. Willing and able to provide informed consent

Exclusion Criteria:

1. Prior exposure to anti PD- 1/PD-L1 agents.
2. Prior exposure to immunosuppressive therapy within the last 12 months prior to enrollment
3. 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.
4. Patients with deficient mismatch repair (dMMR) or microsatellite instability (MSI-H) phenotype.
5. 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.
6. 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.
7. Patients not recovered adequately from the toxicity and/or complications from any major surgery prior to starting study treatment.
8. Known or suspected hypersensitivity to any of the study drugs
9. Received an investigational agent within 28 days prior to the first dose of study drug.
10. 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.
11. LVEF <50%
12. Active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids.
13. 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.
14. 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).
15. 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.
16. 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.
17. Receiving coumarin-derived anticoagulants.
18. Unable or unwilling to withhold or discontinue any prohibited or restricted medications/ procedures for the specified windows during the study.
19. Inability or refusal to comply with the protocol or with the clinical trial procedures
20. If female, pregnant or breastfeeding. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
21. 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.)
22. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
23. 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
24. 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
25. History of other invasive cancer within 2 years prior to enrollment, except for treated non-melanoma skin cancer
26. Known DNA Polymerase Epsilon (POLE) mutations

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BreakVax Arm; 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 cycle.; 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	Drug: Pembrolizumab; To mitigate PD-1-mediated T-cell exhaustion and sustain effector function; Drug: Losartan and aspirin; Have been associated in preclinical and translational studies with modulation of stromal architecture, vascular normalization, and reduction of tumor-associated immunosuppressive signaling; Drug: BreakVax; BreakVax (BB-101) is an investigational, personalized peptide-based cancer immunotherapy designed to stimulate patient-specific antitumor T-cell responses. For each patient, tumor tissue undergoes integrated genomic, transcriptomic, and proteomic analysis to identify tumor-associated antigens (TAAs) and tumor-specific neoantigens (TSAs). A proprietary selection algorithm prioritizes peptides predicted to be presented by the patient's HLA molecules and selectively expressed or overexpressed in tumor tissue. The resulting individualized peptide pools are manufactured, formulated with adjuvants (Montanide ISA 51 and Poly-ICLC), and administered subcutaneously; Drug: Ipilimumab 2.5 mg; A local dendritic cell adjuvant injected adjacent to the BreakVax site to promote antigen presentation and T-cell priming; Drug: Standard-of-care chemotherapy; May promote immunogenic cell death, increase antigen release and modulate the tumor microenvironment
Active Comparator: 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	Drug: Standard-of-care chemotherapy; May promote immunogenic cell death, increase antigen release and modulate the tumor microenvironment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune-related Objective Response Rate (irORR) per iRECIST Assessed by Independent Review Committee	Percentage of treated participants who achieve a confirmed immune complete response (iCR) or immune partial response (iPR) according to iRECIST, as assessed by a central independent review committee (IRC). For participants randomized to the Delayed BreakVax Arm, only responses occurring before initiation of BreakVax following progression on chemotherapy will be included in the primary irORR analysis.	From start of assigned treatment through disease progression; for the Delayed BreakVax Arm, through progression on chemotherapy before crossover to BreakVax, up to 2 years
Disease Control Rate (DCR) Following Crossover to BreakVax Combination Treatment	Percentage of participants in the Delayed BreakVax Arm who experience disease progression while receiving standard-of-care chemotherapy and subsequently achieve disease control after crossover to the BreakVax combination treatment. Disease control is defined as complete response, partial response, or stable disease according to iRECIST.	From initiation of BreakVax combination treatment after crossover through subsequent disease progression, up to 2 years
Percentage of patients for whom BreakVax is successfully manufactured	Percentage of enrolled participants for whom a patient-specific BreakVax drug product is successfully manufactured and available for administration according to protocol-defined manufacturing requirements.	up to 24 Months
Adverse events	Number and percentage of participants experiencing treatment-emergent adverse events	up to 24 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Tumor T-cell Infiltration Between Pre-treatment and On-treatment Biopsies	Tumor T-cell infiltration will be compared between the pre-treatment tumor biopsy and the on-treatment tumor biopsy obtained at approximately Cycle 3 (after imaging).	Baseline to approximately Cycle 3 after imaging
Progression-Free Survival (PFS) per RECIST v1.1	Progression-free survival is defined as the time from the start of study treatment to disease progression according to RECIST v1.1 or death, whichever occurs first, as assessed by a central independent review committee (IRC).	From start of study treatment to disease progression or death, up to 2 years
Duration of Response (DoR) per RECIST v1.1	Duration of response is defined for participants who achieve a complete response (CR) or partial response (PR) as the time from the first assessment at which criteria for CR or PR are met until the first objectively documented disease progression according to RECIST v1.1, as assessed by a central independent review committee (IRC).	From first documented CR or PR to disease progression, up to 2 years
Clinical Benefit Rate (CBR) per RECIST v1.1	Percentage of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) lasting at least 12 weeks according to RECIST v1.1, as assessed by a central independent review committee (IRC).	From start of study treatment through disease progression, up to 2 years
Objective Response Rate (ORR) per RECIST v1.1	Percentage of participants with measurable disease who achieve a complete response (CR) or partial response (PR) according to RECIST v1.1, as assessed by a central independent review committee (IRC).	From start of study treatment through disease progression, up to 2 years
Immune-related Progression-Free Survival (irPFS) per iRECIST	Immune-related progression-free survival is defined as the time from the start of study treatment to confirmed progressive disease according to iRECIST or death, whichever occurs first. Unconfirmed progression does not constitute a progression event until progression is confirmed according to iRECIST.	From start of study treatment to confirmed disease progression or death, up to 2 years
Incidence of Pseudoprogression per iRECIST	Percentage of participants who experience pseudoprogression according to iRECIST, defined as an apparent increase in tumor burden or appearance of new lesions that is not subsequently confirmed as true disease progression on follow-up assessment.	From start of study treatment through disease progression, up to 2 years
Stable Disease for at Least 12 Weeks per iRECIST	Percentage of participants who have stable disease according to iRECIST lasting at least 12 weeks, using the protocol-specified assessment window of 12 weeks ±1 week.	From start of study treatment through disease progression, up to 2 years
Overall Survival (OS)	Overall survival is defined as the time from randomization to death from any cause. Overall survival will be analyzed descriptively because of the crossover design.	From randomization to death, up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
T-cell priming	Rate and magnitude of antigen-specific T-cell responses induced by BreakVax in peripheral blood	24 Months
Tumor T-cell infiltration	On-treatment tumor biopsy intratumoral and stromal T-cell infiltration	24 Months
Tumor microenvironment modulation	Change in tumor-associated immune cell populations, including macrophage polarization (e.g., M1/M2 markers), and other immunosuppressive or activation signatures	24 Months

Collaborators and Investigators

• Sponsor: BreakBio Corp
• Collaborators: Miami Cancer Institute

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2030
• Study Completion (Estimated): September 1, 2030

Study Registration Dates

• First Submitted: August 7, 2026
• First Submitted That Met QC Criteria: August 11, 2026
• First Posted (Actual): August 13, 2026

Study Record Updates

• Last Update Posted (Actual): August 19, 2026
• Last Update Submitted That Met QC Criteria: August 18, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Metastatic; Unresectable; Locally Advanced; Triple Negative Breast Cancer; PD-L1 negative; gBRCA negative
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplastic Processes; Skin Diseases; Breast Diseases; Breast Neoplasms; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Neoplasm Metastasis; Triple Negative Breast Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Imidazoles; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Phenols; Benzene Derivatives; Salicylates; Hydroxybenzoates; Tetrazoles; Biphenyl Compounds; Ipilimumab; Aspirin; Losartan; pembrolizumab
• Other Study ID Numbers: BreakBio-3 Substudy A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No