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

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ClinicalTrials.gov Identifier: NCT04331067
Recruitment Status : Recruiting
First Posted : April 2, 2020
Last Update Posted : March 15, 2021
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Drug: Paclitaxel Drug: Carboplatin Biological: Nivolumab Biological: Cabiralizumab Procedure: Tumor biopsy Procedure: Bone marrow Procedure: Blood draw Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib/II Study to Evaluate Safety and Tolerability of Cabiralizumab in Combination With Nivolumab and Neoadjuvant Chemotherapy in Patients With Localized Triple-negative Breast Cancer
Actual Study Start Date : November 19, 2020
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : February 28, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Nivolumab

Arm Intervention/treatment
Active Comparator: Arm A: Neoadjuvant chemo + nivolumab
-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
-Given standard of care
Other Name: Taxol

Drug: Carboplatin
-Given standard of care
Other Name: Paraplatin

Biological: Nivolumab
-Given standard of care
Other Names:
  • Opdivo
  • BMS-936558

Procedure: Tumor biopsy
-Baseline, week 5, surgery, and at time of relapse (optional)

Procedure: Bone marrow
-Time of port placement (baseline), time of surgery, and time of recurrence (optional)

Procedure: Blood draw
-Baseline, week 5, prior to surgery , and disease progression (optional)

Experimental: Arm B: Neoadjuvant chemo + nivolumab + cabiralizumab
  • 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
-Given standard of care
Other Name: Taxol

Drug: Carboplatin
-Given standard of care
Other Name: Paraplatin

Biological: Nivolumab
-Given standard of care
Other Names:
  • Opdivo
  • BMS-936558

Biological: Cabiralizumab
-Will be provided by Bristol Myers Squibb
Other Name: BMS-986227

Procedure: Tumor biopsy
-Baseline, week 5, surgery, and at time of relapse (optional)

Procedure: Bone marrow
-Time of port placement (baseline), time of surgery, and time of recurrence (optional)

Procedure: Blood draw
-Baseline, week 5, prior to surgery , and disease progression (optional)




Primary Outcome Measures :
  1. Percent change in tumor infiltrating lymphocytes (TILs) [ Time Frame: Baseline to after initiation of therapy (4 weeks) ]
  2. Percent change in tumor associated macrophages [ Time Frame: Baseline to after initiation of therapy (4 weeks) ]
  3. Safety of the regimen as measured by incidence of adverse events (safety lead-in only) [ Time Frame: From start of treatment through 4 weeks after last infusion of nivolumab and/or cabiralizumab or surgery whichever occurs first (approximately 16 weeks) ]
    -The first six patients randomized to each arm will be part of a safety run-in.


Secondary Outcome Measures :
  1. Pathological complete response (pCR) [ Time Frame: At time of surgery (estimated to be 12 weeks) ]
    -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.

  2. Recurrence-free survival (RFS) [ Time Frame: Through completion of follow-up (estimated to be 15 months) ]
    -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.

  3. Safety of the combination of nivolumab +/- cabiralizumab + neoadjuvant chemotherapy as measured by rate of grade 3 or higher adverse events related to the study drugs [ Time Frame: From start of treatment through 4 weeks after last infusion of nivolumab and/or cabiralizumab or surgery whichever occurs first (approximately 16 weeks) ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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.
  • 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 10 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.
  • Concomitant use of statins while on study (there is a 14-day washout). However, a participant using statins for over 3 months prior to study drug administration and in stable status without CK rise may be permitted to enroll.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel, carboplatin, nivolumab, cabiralizumab, or other agents used in the study. Known history of sensitivity to infusions containing Tween 20 (polysorbate 20) and Tween 80 (polysorbate 80).
  • 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.
  • Current or history of clinically significant muscle disorders (e.g., myositis), recent unresolved muscle injury, or any condition known to elevate serum CK levels.
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04331067


Contacts
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Contact: Leonel Hernandez Aya, M.D. 314-362-5654 lhernandezaya@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Leonel Hernandez Aya, M.D.    314-362-5654    lhernandezaya@wustl.edu   
Principal Investigator: Leonel Hernandez Aya, M.D.         
Sub-Investigator: Katherine Welbaecher, M.D.         
Sub-Investigator: Rebecca Aft, M.D., Ph.D.         
Sub-Investigator: Mark A Watson, M.D., Ph.D.         
Sub-Investigator: David DeNardo, Ph.D.         
Sub-Investigator: Jingqin (Rosy) Luo, Ph.D.         
Sub-Investigator: Foluso Ademuyiwa, M.D.         
Sub-Investigator: Nusayba Bagegni, M.D.         
Sub-Investigator: Ron Bose, M.D.         
Sub-Investigator: Katherine Clifton, M.D.         
Sub-Investigator: Ashley Frith, M.D.         
Sub-Investigator: Cynthia Ma, M.D., Ph.D.         
Sub-Investigator: Peter Oppelt, M.D.         
Sub-Investigator: Mateusz Opyrchal, M.D.         
Sub-Investigator: Lindsay Peterson, M.D.         
Sub-Investigator: Timothy Rearden, M.D.         
Sub-Investigator: Caron Rigden, M.D.         
Sub-Investigator: Anna Roshal, M.D.         
Sub-Investigator: Rama Suresh, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Bristol-Myers Squibb
Investigators
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Principal Investigator: Leonel Hernandez Aya, M.D. Washington University School of Medicine
Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT04331067    
Other Study ID Numbers: 202007016
First Posted: April 2, 2020    Key Record Dates
Last Update Posted: March 15, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Carboplatin
Nivolumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological