Randomized Phase 2 Clinical Trial of Nab-Paclitaxel + Durvalumab (MEDI4736) + Tremelimumab + Neoantigen Vaccine Vs. Nab-Paclitaxel + Durvalumab (MEDI4736) + Tremelimumab in Patients With Metastatic Triple Negative Breast Cancer
Overview
- Phase
- Phase 2
- Intervention
- Sacituzumab Govitecan
- Conditions
- Anatomic Stage IV Breast Cancer AJCC v8
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 70
- Locations
- 54
- Primary Endpoint
- Progression-free survival (PFS)
- Status
- Recruiting
- Last Updated
- 15 days ago
Overview
Brief Summary
This phase II trial studies how well nab-paclitaxel, durvalumab, and tremelimumab with or without personalized synthetic long peptide vaccine (neoantigen vaccine) works in treating patients with triple negative breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Chemotherapy drugs, such as nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. It is not yet known whether giving nab-paclitaxel, durvalumab, and tremelimumab with or without neoantigen vaccine will work better in treating patients with triple negative breast cancer.
Detailed Description
PRIMARY OBJECTIVE: I. Evaluate the clinical response to nab-paclitaxel + durvalumab (MEDI4736) + tremelimumab + neoantigen vaccine (Arm 1) versus (vs.) nab-paclitaxel + durvalumab (MEDI4736) + tremelimumab (Arm 2) in patients with metastatic triple negative breast cancer (TNBC). SECONDARY OBJECTIVE: I. Evaluate the safety of nab-paclitaxel + durvalumab (MEDI4736) + tremelimumab + neoantigen vaccine vs. nab-paclitaxel + durvalumab (MEDI4736) + tremelimumab in patients with metastatic TNBC. EXPLORATORY OBJECTIVES: I. Assess the immune response induced by nab-paclitaxel + durvalumab (MEDI4736) + tremelimumab + neoantigen vaccine vs. nab-paclitaxel + durvalumab (MEDI4736) + tremelimumab in patients with metastatic TNBC. II. Biomarkers of response to therapy will be assessed based on the research biopsies performed at baseline, following the chemotherapy run-in (Part A) and following nab-paclitaxel + durvalumab (MEDI4736) + tremelimumab +/- neoantigen vaccine (Part B). OUTLINE: PART A: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes and carboplatin IV over 30 minutes on days 1 and 8 of each cycle. Treatment repeats every 21 days for up to 18 weeks (6 cycles) in the absence of disease progression or unacceptable toxicity. Patients who experience progression of disease or who are intolerant of treatment may switch and receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 of each remaining cycle or sacituzumab govitecan-hziy IV over 1-3 hours on days 1 and 8 of each remaining cycle. Treatment with nab-paclitaxel repeats every 28 days for up to 2 cycles (for patients with progressive disease) or until a total of 18 weeks of treatment have been completed (for patients who are intolerant of treatment) at the discretion of the treating physician. Treatment with sacituzumab govitecan-hziyl repeats every 21 days for up to 2 cycles (for patients with progressive disease) or until a total of 18 weeks of treatment have been completed (for patients who are intolerant of treatment) at the discretion of the treating physician. PART B: Patients are randomized to 1 of 2 arms. ARM I: Patients receive personalized synthetic long peptide vaccine and poly-ICLC subcutaneously (SC) on days 1, 4, 8, 15, 22, 50, and 78 in the absence of disease progression or unacceptable toxicity. Patients also receive tremelimumab IV over 60 minutes on day 1 of cycles 1-4, durvalumab IV over 60 minutes on day 1 of each cycle and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive tremelimumab IV over 60 minutes on day 1 of cycles 1-4, durvalumab IV over 60 minutes on day 1 of each cycle and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, blood and urine sample collection, computed tomography (CT) scan and magnetic resonance imaging (MRI) on study. After completion of study treatment, patients are followed up every 3 months for 1 year, then annually thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have a histologically confirmed diagnosis of metastatic invasive triple negative breast cancer. Patients with clinical and/or radiologic suspicion of metastatic TNBC can be consented prior to this confirmation.
- •Estrogen receptor (ER) and progesterone receptor (PR) less than Allred score of 3 OR less than 1% positive staining cells in the invasive component of the tumor.
- •HER2 negative by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) staining 0 or 1+.
- •PD-L1 negative by a Clinical Laboratory Improvement Act (CLIA) approved laboratory using compatible assays appropriate for treatment decisions.
- •Patients may have measurable or evaluable disease.
- •Patients must be willing to undergo biopsy and have accessible lesions for a new biopsy, or they must have sufficient tissue available from a biopsy performed for standard of care (specifications below). If patient does not have enough archived tissue available, a new biopsy is required. A tumor specimen obtained from relapsed primary, metastatic, or locally advanced sites of disease (if applicable) must be submitted. Acceptable samples include core needle biopsies for deep tumor tissue (minimum 4 cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Formalin-fixed, paraffin-embedded (FFPE) tumor specimens in paraffin blocks are preferred; FFPE tumor tissue sections on slides may be provided if sufficient material (15 x 10μ, unstained) is available. Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable.
- •No prior therapy for metastatic TNBC. Patients who have received taxane-based adjuvant therapy are required to have a disease-free interval of at least 12 months after completion of taxane therapy.
- •Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of durvalumab (MEDI4736) and tremelimumab in combination with neoantigen vaccine in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 60%).
- •Body weight \> 30 kg.
Exclusion Criteria
- •Patients who are not considered to be candidates for carboplatin + gemcitabine for first line therapy of their metastatic triple negative breast cancer are not eligible.
- •Patients who have had chemotherapy, radiotherapy (to more than 30% of the bone marrow), or biologic therapy within 30 days (42 days for nitrosoureas or mitomycin C) prior to entering the study.
- •Patients who have received prior immunotherapy for metastatic disease.
- •Patients who have not recovered from grade \>= 2 adverse events due to prior anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
- •Patients with grade \>= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician.
- •Patients with grade \>= 2 endocrinological adverse events (AEs), (e.g., hypothyroidism, adrenal insufficiency, hypopituitarism, or diabetes mellitus), must have been on a stable dose of supplemental therapy for at least 2 weeks before screening to be eligible for this study, and the endocrinological AE must be stable in the opinion of the treating physician.
- •Patients who are receiving any other investigational agents or who have received an investigational agent within the last 30 days.
- •Receipt of live attenuated vaccination within 6 months prior to study entry or within 30 days of receiving durvalumab (MEDI4736) and tremelimumab.
- •Note: Patients, if enrolled, should not receive live vaccine whilst receiving study treatment and up to 30 days after the last dose of study treatment.
- •Major surgical procedure within 28 days prior to the first dose of durvalumab (MEDI4736) and tremelimumab. Local surgery of isolated lesions for palliative intent is acceptable.
Arms & Interventions
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Sacituzumab Govitecan
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Tremelimumab
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Biopsy Procedure
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Biospecimen Collection
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Carboplatin
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Computed Tomography
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Durvalumab
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Gemcitabine Hydrochloride
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Nab-paclitaxel
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Sacituzumab Govitecan
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Tremelimumab
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Poly ICLC
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Biopsy Procedure
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Biospecimen Collection
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Carboplatin
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Computed Tomography
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Durvalumab
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Gemcitabine Hydrochloride
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Magnetic Resonance Imaging
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Nab-paclitaxel
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Personalized Synthetic Long Peptide Vaccine
Arm II (durvalumab, nab-paclitaxel)
See Detailed Description.
Intervention: Magnetic Resonance Imaging
Outcomes
Primary Outcomes
Progression-free survival (PFS)
Time Frame: From initiation of Part B to progression or death, assessed at 6 and 12 months
The median PFS in each arm and their 80% confidence intervals will be assessed using Kaplan-Meier product limit methods and compared by log-rank test.
Secondary Outcomes
- Incidence of adverse events(Up to day 22)
- Clinical response rate(Up to 52 weeks)
- Clinical benefit rate (complete response, partial response, stable disease)(Up to 52 weeks)
- Overall survival (OS)(Up to 52 weeks)