Clinical Trials /

Carboplatin and Paclitaxel With or Without Atezolizumab Before Surgery in Treating Patients With Newly Diagnosed, Stage II-III Triple-Negative Breast Cancer

NCT02883062

Description:

This phase II trial studies how well carboplatin and paclitaxel with or without atezolizumab before surgery works in treating patients with newly diagnosed, stage II-III triple negative breast cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carboplatin and 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. Giving carboplatin and paclitaxel with or without atezolizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Carboplatin and Paclitaxel With or Without Atezolizumab Before Surgery in Treating Patients With Newly Diagnosed, Stage II-III Triple-Negative Breast Cancer
  • Official Title: Randomized Phase 2 Study of Neoadjuvant Chemotherapy, Carboplatin and Paclitaxel, With or Without Atezolizumab in Triple Negative Breast Cancer (TNBC)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01301
  • SECONDARY ID: NCI-2016-01301
  • SECONDARY ID: 10013
  • SECONDARY ID: 10013
  • SECONDARY ID: UM1CA186704
  • NCT ID: NCT02883062

Conditions

  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Invasive Breast Carcinoma
  • Progesterone Receptor Negative
  • Stage II Breast Cancer AJCC v6 and v7
  • Stage IIA Breast Cancer AJCC v6 and v7
  • Stage IIB Breast Cancer AJCC v6 and v7
  • Stage III Breast Cancer AJCC v7
  • Stage IIIA Breast Cancer AJCC v7
  • Stage IIIB Breast Cancer AJCC v7
  • Stage IIIC Breast Cancer AJCC v7
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm B (atezolizumab, paclitaxel, carboplatin, breast surgery)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A (paclitaxel, carboplatin, mastectomy, lumpectomy)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm A (paclitaxel, carboplatin, mastectomy, lumpectomy)

Purpose

This randomized phase II trial studies how well carboplatin and paclitaxel with or without atezolizumab before surgery works in treating patients with newly diagnosed, stage II-III triple negative breast cancer. Monoclonal antibodies, such as atezolizumab, may block tumor growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as carboplatin and 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. Giving carboplatin and paclitaxel with or without atezolizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To test the hypothesis that the combination of chemotherapy and atezolizumab will increase
      tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in patients
      with newly diagnosed triple negative breast cancer (TNBC) being treated with neoadjuvant
      chemotherapy.

      II. To test the hypothesis that the combination of chemotherapy and atezolizumab will
      increase the pathologic complete response (pCR) rate compared to chemotherapy alone in
      patients with newly diagnosed TNBC being treated with neoadjuvant chemotherapy.

      SECONDARY OBJECTIVES:

      I. To evaluate the safety of the treatment combination of atezolizumab + carboplatin +
      paclitaxel.

      TERTIARY OBJECTIVES:

      I. To evaluate potential biomarkers of response to chemotherapy in combination with
      atezolizumab in patients with newly diagnosed TNBC.

      II. To evaluate the impact of chemotherapy in combination with atezolizumab on the immune
      response in patients with newly diagnosed TNBC.

      III. To evaluate the impact of chemotherapy in combination with atezolizumab on
      neoantigen-specific T cell responses in patients with newly diagnosed TNBC.

      IV. To evaluate the impact of chemotherapy in combination with atezolizumab on long-term
      clinical endpoints such as overall survival (OS) and disease-free survival (DFS) in patients
      with newly diagnosed TNBC.

      OUTLINE: Patients are randomized into 1 of 2 arms.

      ARM A: Patients receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 30
      minutes. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease
      progression or unacceptable toxicity.

      ARM B: Patients receive atezolizumab IV over 30-60 minutes, paclitaxel IV over 1 hour, and
      carboplatin IV over 30 minutes. Treatment repeats every 3 weeks for up to 6 courses in the
      absence of disease progression or unacceptable toxicity.

      In both arms, within 3-6 weeks, patients undergo mastectomy or lumpectomy.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (paclitaxel, carboplatin, mastectomy, lumpectomy)Active ComparatorPatients receive paclitaxel IV over 1 hour and carboplatin IV over 30 minutes. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3-6 weeks, patients undergo mastectomy or lumpectomy.
  • Carboplatin
  • Paclitaxel
Arm B (atezolizumab, paclitaxel, carboplatin, breast surgery)ExperimentalPatients receive atezolizumab IV over 30-60 minutes, paclitaxel IV over 1 hour, and carboplatin IV over 30 minutes. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3-6 weeks, patients undergo mastectomy or lumpectomy.
  • Atezolizumab
  • Carboplatin
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed new diagnosis of breast cancer

          -  Estrogen receptor (ER) and progesterone receptor (PR) < Allred score of 3 or < 1%
             positive staining cells in the invasive component of the tumor

          -  Human epidermal growth factor receptor 2 (HER2) negative by fluorescence in situ
             hybridization (FISH) or immunohistochemistry (IHC) staining 0 or 1+ according to
             National Comprehensive Cancer Network (NCCN) guidelines

          -  Clinical stage T2-T4c, any N, M0 primary tumor by American Joint Committee on Cancer
             (AJCC) 7th edition clinical staging

          -  Eligible for neoadjuvant chemotherapy

          -  No prior therapy for this disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 2,500/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 150,000/mcL

          -  Hemoglobin >= 10 g/dL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients
             with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
             3 x ULN

          -  Alkaline phosphatase =< 2.5 x ULN

          -  Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault

          -  International normalized ratio (INR) =< 1.5 x ULN (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)

          -  Activated partial thromboplastin time (aPPT) =< 1.5 x ULN (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 child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for
             the duration of study participation, and for 180 days after the last dose of
             paclitaxel; should a woman become pregnant or suspect she is pregnant while she or her
             partner is participating in this study, she should inform her treating physician
             immediately

          -  Ability to understand and the willingness to sign an Institutional Review Board (IRB)
             approved written informed consent document

        Exclusion Criteria:

          -  Known metastatic disease

          -  Invasive cancer in the contralateral breast

          -  Patients with a previous history of non-breast malignancy are eligible only if they
             meet the following criteria for a cancer survivor: (1), and (2)

               -  Has undergone potentially curative therapy for all prior malignancies

               -  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)

          -  Patients with prior allogeneic bone marrow transplantation or prior solid organ
             transplantation

          -  Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1

          -  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

          -  Patients taking bisphosphonate therapy for symptomatic hypercalcemia; use of
             bisphosphonate therapy for other reasons (e.g., osteoporosis) is allowed

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to other agents used in study

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease

               -  Patients with past or resolved hepatitis B infection (defined as having a
                  negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
                  [antibody to hepatitis B core antigen] antibody test) are eligible

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

          -  History or risk of autoimmune disease, including, but not limited to, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
             syndrome, Bell's palsy, Guillain-Barre 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; history of radiation pneumonitis in the radiation field
             (fibrosis) is permitted

          -  Patients with active tuberculosis (TB) are excluded

          -  Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limited
             to, hospitalization for complications of infection, bacteremia, or severe pneumonia

          -  Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1

          -  Received oral or intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1;
             patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
             infection or chronic obstructive pulmonary disease) are eligible

          -  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

          -  Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or
             anticipation that such a live, attenuated vaccine will be required during the study
             and up to 5 months after the last dose of atezolizumab

               -  Influenza vaccination should be given during influenza season only; patients must
                  not receive live, attenuated influenza vaccine within 4 weeks prior to cycle 1,
                  day 1 or at any time during the study

          -  Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) who cannot
             discontinue it before treatment with atezolizumab

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia (including sinus bradycardia), or psychiatric illness/social situations
             that would limit compliance with study requirements

          -  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

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with atezolizumab
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Increase in tumor infiltrating lymphocyte (TIL) percentage measured by histopathologic assay
Time Frame:Up to the time of surgery
Safety Issue:
Description:The TIL percentage after initiation of therapy will be compared between patients receiving neoadjuvant chemotherapy alone (Arm A), and patients receiving neoadjuvant chemotherapy in combination with atezolizumab (Arm B). The post-treatment TIL percentages between two arms will be summarized using descriptive statistics at each time point and compared by two-way analysis of variance (ANOVA) for repeated measurement data.

Secondary Outcome Measures

Measure:Increase in pathologic complete response (pCR) rate
Time Frame:Up to 30 days
Safety Issue:
Description:Pathologic complete response rates will be summarized using contingency tables and compared using Fisher's exact test between patients receiving neoadjuvant chemotherapy alone (Arm A), and patients receiving neoadjuvant chemotherapy in combination with atezolizumab (Arm B).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 5, 2018