Clinical Trials /

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

NCT04331067

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabiralizumab in Combination With Nivolumab and Neoadjuvant Chemotherapy in Patients With Localized Triple-negative Breast Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 20-x053
  • NCT ID: NCT04331067

Conditions

  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
PaclitaxelTaxolArm A: Neoadjuvant chemo + nivolumab
CarboplatinParaplatinArm A: Neoadjuvant chemo + nivolumab
NivolumabOpdivo, BMS-936558Arm A: Neoadjuvant chemo + nivolumab
CabiralizumabBMS-986227Arm B: Neoadjuvant chemo + nivolumab + cabiralizumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm A: Neoadjuvant chemo + nivolumabActive Comparator-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.
  • Paclitaxel
  • Carboplatin
  • Nivolumab
Arm B: Neoadjuvant chemo + nivolumab + cabiralizumabExperimentalNeoadjuvant 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.
  • Paclitaxel
  • Carboplatin
  • Nivolumab
  • Cabiralizumab

Eligibility 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.

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percent change in tumor infiltrating lymphocytes (TILs)
Time Frame:Baseline to after initiation of therapy (4 weeks)
Safety Issue:
Description:-The first six patients randomized to each arm will be part of a safety run-in.

Secondary Outcome Measures

Measure:Pathological complete response (pCR)
Time Frame:At time of surgery (estimated to be 12 weeks)
Safety Issue:
Description:-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.
Measure:Recurrence-free survival (RFS)
Time Frame:Through completion of follow-up (estimated to be 15 months)
Safety Issue:
Description:-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.
Measure: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)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

March 30, 2020