Induction Immunotherapy to Promote Immunologic Priming and Enhanced Response to Neoadjuvant Pembrolizumab + Chemotherapy in Triple Negative Breast Cancer (TNBC)
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Breast Cancer
- Sponsor
- Providence Health & Services
- Enrollment
- 12
- Locations
- 2
- Primary Endpoint
- Pathological Complete Response (pCR) Rate (ypT0/Tis ypN0)
- Status
- Active, Not Recruiting
- Last Updated
- 8 days ago
Overview
Brief Summary
This is a Phase II, randomized, open-label trial to evaluate the clinical and immunologic activity of pembrolizumab plus chemotherapy when combined with various immunotherapy induction regimens as neoadjuvant therapy for triple negative breast cancer (TNBC).
Detailed Description
This is a Phase II, randomized, open-label trial to evaluate the clinical and immunologic activity of pembrolizumab plus chemotherapy when combined with various immunotherapy induction regimens as neoadjuvant therapy for triple negative breast cancer (TNBC). A commonly used standard neoadjuvant regimen for TNBC is a weekly taxane (e.g., paclitaxel 80mg/m2) for 12 weeks followed by an anthracycline (e.g., doxorubicin 60 mg/m2 plus cyclophosphamide at 600 mg/m2 \[AC\]) every 3 weeks (Q3W) for 4 cycles. The chemotherapy regimen included in this study is built upon the aforementioned regimen. Pembrolizumab in combination with this regimen will be studied as part of a multi-arm study that randomizes subjects to receive: * Control Arm: (Pembro + ACT): Pembrolizumab induction (single-dose 200mg IV), followed by pembrolizumab Q3W + paclitaxel (T) weekly x 4 cycles, followed by pembrolizumab + doxorubicin + cyclophosphamide (AC) Q3W x 4 cycles as neoadjuvant therapy prior to surgery. * Arm A: (Pembro + IRX-2 + ACT): Pembrolizumab (single-dose 200mg IV) + cyclophosphamide (single-dose 300 mg/m2 IV) + IRX-2 induction (1mL SQ x 2 daily, x 10 days), followed by pembrolizumab Q3W + paclitaxel (T) weekly x 4 cycles, followed by IRX-2 re-induction (1mL SQ x 2 daily, x 10 days), followed by pembrolizumab + doxorubicin + cyclophosphamide (AC) Q3W x 4 cycles as neoadjuvant therapy prior to surgery. * Subsequent induction therapy arms are to be included in protocol amendments. Note: 1 cycle = 21 days
Investigators
Eligibility Criteria
Inclusion Criteria
- •Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
- •Be a male or female subject greater than or equal to 18 years of age on day of signing informed consent.
- •Have locally confirmed TNBC, as defined by the most recent ASCO/CAP guidelines.
- •Have previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per the current AJCC Version 8 staging criteria for breast cancer staging criteria as assessed by the investigator based on radiological and/or clinical assessment:
- •T1c, N1-N2
- •T2, N0-N2
- •T3, N0-N2
- •T4a-d, N0-N2 Note: bilateral tumors (i.e., synchronous cancers in both breasts) and/or multi-focal (i.e., 2, separate lesions in the same quadrant)/multi-centric (i.e., 2 separate lesions in different quadrants) tumors are allowed, as well as inflammatory breast cancer, and the tumor with the most advanced T stage should be used to assess the eligibility.
- •Provide a core needle biopsy consisting of at least 1 separate tumor-bearing cores from the primary tumor at screening for translational research (archival is acceptable if sufficient tumor is available; slides are acceptable if at least 15 are available)
- •Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 14 days of treatment initiation.
Exclusion Criteria
- •Has a history of invasive malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
- •Has received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months.
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) or has previously participated in MK-3475 clinical trials.
- •Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 4 weeks of the first dose of treatment in this current trial.
- •Note: subject should be excluded if he/she received an investigational agent with anti-cancer or anti-proliferative intent within the last 12 months.
- •Has received a live vaccine within 30 days of the first dose of study treatment.
- •Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines, and are not allowed.
- •Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- •Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
Arms & Interventions
Control
Control Arm: (Pembro + ACT): Pembrolizumab induction (single-dose 200mg IV), followed by pembrolizumab Q3W + paclitaxel (T) weekly x 4 cycles, followed by pembrolizumab + doxorubicin + cyclophosphamide (AC) Q3W x 4 cycles as neoadjuvant therapy prior to surgery.
Intervention: Pembrolizumab
Arm A
• Arm A: (Pembro + IRX-2 + ACT): Pembrolizumab (single-dose 200mg IV) + cyclophosphamide (single-dose 300 mg/m2 IV) + IRX-2 induction (1mL SQ x 2 daily, x 10 days), followed by pembrolizumab Q3W + paclitaxel (T) weekly x 4 cycles, followed by IRX-2 re-induction (1mL SQ x 2 daily, x 10 days), followed by pembrolizumab + doxorubicin + cyclophosphamide (AC) Q3W x 4 cycles as neoadjuvant therapy prior to surgery.
Intervention: IRX 2
Arm A
• Arm A: (Pembro + IRX-2 + ACT): Pembrolizumab (single-dose 200mg IV) + cyclophosphamide (single-dose 300 mg/m2 IV) + IRX-2 induction (1mL SQ x 2 daily, x 10 days), followed by pembrolizumab Q3W + paclitaxel (T) weekly x 4 cycles, followed by IRX-2 re-induction (1mL SQ x 2 daily, x 10 days), followed by pembrolizumab + doxorubicin + cyclophosphamide (AC) Q3W x 4 cycles as neoadjuvant therapy prior to surgery.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Pathological Complete Response (pCR) Rate (ypT0/Tis ypN0)
Time Frame: Following definitive surgery, approximately 9 months.
Number of patients who showed pCR post surgery. pCR rate (ypT0/Tis ypN0) is defined as the proportion of subjects without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy per the current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery.
Pathological Complete Response (pCR) Rate (ypT0/Tis ypN0)
Time Frame: Following definitive surgery, approximately 9 months.
Number of patients who showed pCR post surgery. pCR rate (ypT0/Tis ypN0) is defined as the proportion of subjects without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy per the current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery.
Secondary Outcomes
- Safety and Tolerability Profile as Assessed by CTCAE v5.0(Cycle 1, Day 1 through safety follow-up visit, approximately 9 months.)
- Percent Change in Tumor Infiltrating Lymphocytes (TIL) Quantity Changes(Following definitive surgery, approximately 9 months.)