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
brief summary
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.
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.
official title
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