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.
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.
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.
Parallel
BreakVax
DrugBreakVax (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
Ipilimumab 2.5 mg
DrugA local dendritic cell adjuvant injected adjacent to the BreakVax site to promote antigen presentation and T-cell priming
Pembrolizumab
DrugTo mitigate PD-1-mediated T-cell exhaustion and sustain effector function
Standard-of-care chemotherapy
DrugMay promote immunogenic cell death, increase antigen release and modulate the tumor microenvironment
Losartan and aspirin
DrugHave been associated in preclinical and translational studies with modulation of stromal architecture, vascular normalization, and reduction of tumor-associated immunosuppressive signaling
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.
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.
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.
Adverse events
Number and percentage of participants experiencing treatment-emergent adverse events
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).
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).
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).
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).
T-cell priming
Rate and magnitude of antigen-specific T-cell responses induced by BreakVax in peripheral blood
Tumor T-cell infiltration
On-treatment tumor biopsy intratumoral and stromal T-cell infiltration
Tumor microenvironment modulation
Change in tumor-associated immune cell populations, including macrophage polarization (e.g., M1/M2 markers), and other immunosuppressive or activation signatures
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BreakBio Corp
Lead sponsor
Miami Cancer Institute
Collaborator
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