Neoadjuvant Nivolumab and Chemotherapy in Patients With Localized Triple-negative Breast Cancer

Study Overview
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Brief Summary
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Prior to Amendment #7: The hypothesis of this study is that the combination of cabiralizumab and nivolumab with neoadjuvant chemotherapy will decrease tumor associated macrophages (TAMs) and increase tumor infiltrating lymphocytes (TIL) compared to neoadjuvant chemotherapy plus nivolumab in patients with early stage triple-negative breast cancer (TNBC) and improve clinical outcomes. As of Amendment #7 IRB approved 10/13/2022: The study will no longer enroll to Arm B. Cabiralizumab will no longer be given. The hypothesis of this study is that on-treatment tumor associated macrophages (TAMs) and tumor infiltrating lymphocytes (TILs) will improve (reduced TAMs, increased TILs) following neoadjuvant nivolumab with chemotherapy.

Official Title
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Phase Ib/II Study to Evaluate Safety and Tolerability of Neoadjuvant Nivolumab and Chemotherapy in Patients With Localized Triple-negative Breast Cancer

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Carboplatin
* Biological: Nivolumab
* Biological: Cabiralizumab
* Procedure: Tumor biopsy
* Procedure: Bone marrow
* Procedure: Blood draw


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed newly diagnosed ER-/HER2- breast cancer. ER and PR < Allred score of 3 or < 1% positive staining cells in the invasive component of the tumor. HER2 negative by FISH or IHC staining 0 or 1+ according to NCCN guidelines. Clinical stage II or III (by AJCC 8th edition at least T2, any N, M0 or if N+ then any T) breast cancer eligible for neoadjuvant chemotherapy with complete surgical excision of the breast cancer after neoadjuvant therapy as the treatment goal. Tumor size at least 2 cm in one dimension by clinical or radiographic exam (WHO criteria). Patients with histologically confirmed or clinically palpable lymph nodes may be enrolled regardless of tumor size. A palpable mass is not required as long as the mass is at least 2 cm in one dimension by radiographic exam. 2D measurements should be completed during screening if available. No prior therapy for this disease At least 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 Normal bone marrow and organ function as defined below: Leukocytes ≥ 2,000/mcL (stable off any growth factor within 4 weeks of first study treatment administration) Absolute neutrophil count ≥ 1,500/mcL (stable off any growth factor within 4 weeks of first study treatment administration) Platelets ≥ 100,000/mcL (stable off any growth factor within 4 weeks of first study treatment administration) Hemoglobin ≥8.5 g/dl (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration) Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except participants with Gilbert's Syndrome who must have normal direct bilirubin) AST(SGOT)/ALT(SGPT) ≤ 2.0 x IULN Alkaline phosphatase <2.5 x ULN Serum creatinine < 1.5 x ULN or creatinine clearance > 40 mL/min by Cockcroft-Gault Albumin ≥ 3 g/dL INR and aPTT <1.5 x IULN (This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose). Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment. Women must not be breastfeeding. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment(s) and for a total of 5 months post-treatment completion. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Consent for fresh pre-treatment, on-treatment, biopsy samples at acceptable clinical risk, as judged by the investigator. Participants must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing Exclusion Criteria: Prior treatment with immunotherapy for cancer Known metastatic disease Known invasive cancer in contralateral breast Patients with a previous history of non-breast malignancy are eligible only if they meet the following criteria for a cancer survivor: Has undergone potentially curative therapy for all prior malignancies AND Has been considered disease-free for at least 1 year (with the exception of basal cell or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix. Currently receiving any other investigational agents. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel, carboplatin, nivolumab, or other agents used in the study. Patients who have received multiple blood transfusions. Evidence of uncontrolled ongoing or active infection, requiring parenteral anti-bacterial, anti-viral, or anti-fungal therapy ≤ 7 days prior to administration of study treatment. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible. Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation. History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible. Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations Rash must cover less than 10% of body surface area (BSA) Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids) History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. Uncontrolled or significant cardiovascular disease History of any chronic hepatitis as evidenced by the following: Positive test for hepatitis B surface antigen Positive test for qualitative hepatitis C viral load (by polymerase chain reaction [PCR]). Positive test for latent tuberculosis (TB) at screening (e.g. T-SPOT or Quantiferon test) or evidence of active TB. Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study with the exception of the planned breast cancer surgery that is part of the trial design. Participants must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment. Any uncontrolled medical condition which, in the opinion of the Investigator, would pose a risk to participant safety or interfere with study participation or interpretation of individual participant results. Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1. Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. The use of replacement doses of prednisone or other corticosteroid for adrenocortical insufficiency is allowed Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. Evidence of coagulopathy or bleeding diathesis. Ascites needing paracentesis or medical management. Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have: A stable regimen of highly active anti-retroviral therapy (HAART) No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Neoadjuvant chemo + nivolumab<br>-Neoadjuvant chemotherapy consists of paclitaxel and carboplatin. Paclitaxel will be given intravenously (IV) at a dose of 80 mg/m^2 on a weekly basis for 12 weeks. Carboplatin will be given IV at a dose of AUC 5 every 3 weeks for 12 weeks. Nivolumab will be given IV at a dose of 240 mg every 2 weeks for 12 weeks. Nivolumab will be administered first, followed by carboplatin, followed by paclitaxel. | Drug: Paclitaxel<br>* -Given standard of care<br>* Other names: Taxol;Drug: Carboplatin<br>* -Given standard of care<br>* Other names: Paraplatin;Biological: Nivolumab<br>* -Given standard of care<br>* Other names: BMS-936558;Procedure: Tumor biopsy<br>* -Baseline, week 5, surgery, and at time of relapse (optional)<br>Procedure: Bone marrow<br>* -Time of port placement (baseline), time of surgery, and time of recurrence (optional)<br>Procedure: Blood draw<br>* -Baseline, week 5, prior to surgery , post-surgery follow-up (typically 3-4 weeks post-surgery), and disease progression (optional)<br>|
| Experimental: Arm B: Neoadjuvant chemo + nivolumab + cabiralizumab<br>As of Amendment #7 IRB approved 10/13/2022: The study will no longer enroll to Arm B. Cabiralizumab will no longer be given. Neoadjuvant chemotherapy consists of paclitaxel and carboplatin. Paclitaxel will be given intravenously (IV) at a dose of 80 mg/m^2 on a weekly basis for 12 weeks. Carboplatin will be given IV at a dose of AUC 5 every 3 weeks for 12 weeks. Nivolumab will be given IV at a dose of 240 mg every 2 weeks for 12 weeks. Nivolumab will be administered first, followed by carboplatin, followed by paclitaxel. Cabiralizumab will be given IV at a dose of 4 mg/kg every 2 weeks for 12 weeks. | Drug: Paclitaxel<br>* -Given standard of care<br>* Other names: Taxol;Drug: Carboplatin<br>* -Given standard of care<br>* Other names: Paraplatin;Biological: Nivolumab<br>* -Given standard of care<br>* Other names: BMS-936558;Biological: Cabiralizumab<br>* -Will be provided by Bristol Myers Squibb<br>* Other names: BMS-986227;Procedure: Tumor biopsy<br>* -Baseline, week 5, surgery, and at time of relapse (optional)<br>Procedure: Bone marrow<br>* -Time of port placement (baseline), time of surgery, and time of recurrence (optional)<br>Procedure: Blood draw<br>* -Baseline, week 5, prior to surgery , post-surgery follow-up (typically 3-4 weeks post-surgery), and disease progression (optional)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in tumor infiltrating lymphocytes (TILs) | -Stromal TIL score is defined as the percentage of tumor stroma area that was occupied by mononuclear inflammatory cells). | Baseline and week 5 | 
| Percent change in tumor associated macrophages (TAMs) |  | Baseline and week 5 | 
| Safety of the regimen as measured by incidence of adverse events (safety lead-in only) |  | From start of treatment through 100 days after last day of study treatment or surgery whichever occurs first (approximately 16 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) | -A pathologic complete response (pCR) is defined as no histology evidence of invasive tumor cells in the surgical breast specimen and sentinel or axillary lymph nodes. | At time of surgery (estimated to be 12 weeks) | 
| Recurrence-free survival (RFS) | -RFS is defined from time of surgery to the earliest time of recurrence, time to development of a second cancer, or time to death from any cause. | Through completion of follow-up (estimated to be 3 years and 12 weeks) | 
| Adverse events measured by rate of treatment-related grade 3 or higher adverse events |  | From start of treatment through 100 days after last infusion of study treatment or surgery whichever occurs first (approximately 16 weeks) | 
| Compare the percent change of tumor associated macrophages (TAMs) between participants who achieve pCR versus those who do not | -A pathologic complete response (pCR) is defined as no histology evidence of invasive tumor cells in the surgical breast specimen and sentinel or axillary lymph nodes. | At time of surgery (estimated to be 12 weeks) | 
| Compare the percent change of tumor infiltrating lymphocytes (TILs) between participants who achieve pCR versus those who do not | Stromal TIL score is defined as the percentage of tumor stroma area that was occupied by mononuclear inflammatory cells). A pathologic complete response (pCR) is defined as no histology evidence of invasive tumor cells in the surgical breast specimen and sentinel or axillary lymph nodes. | At time of surgery (estimated to be 12 weeks) |