Clinical Trials /

Carboplatin With or Without Atezolizumab in Treating Patients With Stage IV Triple Negative Breast Cancer

NCT03206203

Description:

This randomized phase II trial studies how well carboplatin with or without atezolizumab works in treating patients with stage IV triple negative breast cancer. Drugs used in chemotherapy, such as carboplatin, 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. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Giving carboplatin with atezolizumab may work better in treating patients with stage IV triple negative breast cancer

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Carboplatin With or Without Atezolizumab in Treating Patients With Stage IV Triple Negative Breast Cancer
  • Official Title: A Phase II Trial of Atezolizumab (Anti-PDL1) With Carboplatin in Patients With Metastatic Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: VICC BRE 15136
  • SECONDARY ID: NCI-2017-01150
  • NCT ID: NCT03206203

Conditions

  • Triple Negative Breast Cancer
  • Stage IV Breast Cancer
  • HER2 Negative
  • Invasive Breast Cancer

Interventions

DrugSynonymsArms
AtezolizumabArm 1 (atezolizumab, carboplatin)
CarboplatinArm 1 (atezolizumab, carboplatin)

Purpose

This randomized phase II trial studies how well carboplatin with or without atezolizumab works in treating patients with stage IV triple negative breast cancer. Drugs used in chemotherapy, such as carboplatin, 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. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Giving carboplatin with atezolizumab may work better in treating patients with stage IV triple negative breast cancer

Detailed Description

      Primary objective:

      To evaluate the efficacy, as measured by progression free survival (PFS) of carboplatin +
      atezolizumab (using irRECIST) versus carboplatin alone (using RECIST) in patients with triple
      negative metastatic breast cancer

      Secondary objectives:

        -  To determine overall response rate.

        -  To evaluate the efficacy, as measured by clinical benefit rate, of carboplatin +
           atezolizumab (using irRECIST) versus carboplatin (using RECIST) alone in patients with
           triple negative metastatic breast cancer. Clinical benefit rate is defined as complete
           response plus partial response plus stable disease for 6 months.

        -  To determine the duration of response for patients achieving a partial or complete
           response.

        -  To evaluate the overall survival (OS) of carboplatin + atezolizumab versus carboplatin
           alone in patients with triple negative metastatic breast cancer.

      TERTIARY OBJECTIVES:

        -  To perform the following correlative studies from biopsies taken at baseline:

             1. Tumor infiltrating lymphocyte frequency and phenotype (TILs) at baseline

             2. PD-L1 expression from the baseline pre-treatment tissue and at progression lesion,
                performed by IHC (SP142 clone)

             3. HER2 (IHC, FISH) and ER/PR levels (IHC) from a metastatic site

             4. Perform RNA-seq to determine non-synonymous mutation burden in expressed genes and
                gene expression to assign a triple negative subtype at baseline for correlations
                with clinic outcome

             5. Immune phenotyping (IHC) for markers of T cell subsets and activation (CD4, CD8,
                FoxP3, CD25, Glut1) and exhaustion (PD1, CTLA4) and test feasibility of flow
                cytometric analyses to include additional markers

        -  To assess the effect of BRCA mutations on response to the study drugs

        -  To evaluate the effect of steroids on the efficacy of atezolizumab To assess the
           prognostic effects of TILs on PFS and CBR in patients receiving atezolizumab
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1 (atezolizumab, carboplatin)ExperimentalPatients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Carboplatin
Arm 2 (atezolizumab, carboplatin)ExperimentalPatients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression.
  • Atezolizumab
  • Carboplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must provide informed written consent

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Clinical stage IV ER, PR, HER2 negative invasive mammary carcinoma, previously
             documented by histological analysis and that meets the following criteria:

               -  HER2 negativity is defined as any of the following by local laboratory
                  assessment: In-situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 <
                  2.0 or single probe average HER2 gene copy number < 4 signals/cell), or IHC 0 or
                  IHC 1+ (if more than one test result is available and not all results meet the
                  inclusion criterion definition, all results should be discussed with the protocol
                  chair to establish eligibility of the patient)

               -  ER and PR negativity are defined as =< 5% of cells expressing hormonal receptors
                  via IHC analysis

          -  Willing to undergo biopsy of a metastatic lesion (in patients with reasonably
             accessible metastatic lesions such as chest wall, skin, subcutaneous tissue, lymph
             nodes, bones, peripheral lung, and liver metastases)

          -  Measurable disease, defined as at least one lesion that can be accurately measured in
             at least one dimension by RECIST criteria version (v)1.1

          -  Zero or one prior chemotherapy regimens for metastatic disease

          -  No prior treatment with carboplatin

          -  Absolute neutrophil count (ANC) >= 1500/mm^3 (without granulocyte colony-stimulating
             factor [G-CSF] support within 2 weeks prior to cycle 1, day 1)

          -  Lymphocyte count >= 500/uL

          -  Platelet count >= 100,000/mm^3 (without transfusion within 2 weeks prior to cycle 1,
             day 1)

          -  Hemoglobin >= 9.0 g/dL

             * Patients may be transfused or receive erythropoietic treatment to meet this
             criterion

          -  Calculated creatinine clearance >= 30 mL/min using the Calvert Formula

          -  Bilirubin =< 2.5 x upper limits of normal if no liver metastases present; serum total
             bilirubin must be =< 3 x upper limits of normal for patients with Gilbert disease;
             total bilirubin =< 5 x upper limits of normal if liver metastases present

          -  Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase
             (SGPT) =< 2.5 x upper limits of normal if no liver metastases present; SGOT, SGPT =< 5
             x upper limits of normal if liver metastases present

          -  Alkaline phosphatase =< 2.5 x upper limits of normal if no liver metastases present;
             alkaline phosphatase =< 5 x upper limits of normal if liver metastases present

          -  For patients who are not postmenopausal (women) or surgically sterile (absence of
             ovaries and/or uterus or vasectomy), agreement to remain abstinent or to use two
             adequate methods of contraception (e.g., condoms, diaphragm, vasectomy/vasectomized
             partner, tubal ligation), during the treatment period and for at least 30 days after
             the last dose of study treatment; hormone based oral contraceptives are not allowed on
             study; postmenopausal is defined as:

               -  Age >= 60 years

               -  Age =< 60 years and amenorrheic for 12 months in the absence of chemotherapy,
                  tamoxifen, toremifene, or ovarian suppression; or follicle stimulating hormone
                  and estradiol in the postmenopausal range

          -  Subjects must complete all baseline screening assessments

        Exclusion Criteria:

          -  CANCER-SPECIFIC EXCLUSION CRITERIA

          -  Spinal cord compression not definitively treated with surgery and/or radiation, or
             previously diagnosed and treated spinal cord compression without evidence that disease
             has been clinically stable for > 2 weeks prior to randomization

          -  Known central nervous system (CNS) disease, except for treated asymptomatic CNS
             metastases, provided all of the following criteria are met: measurable disease outside
             the CNS, only supratentorial metastases allowed (i.e., no metastases to midbrain,
             pons, medulla, or spinal cord), no evidence of progression or hemorrhage after
             completion of CNS-directed therapy, no ongoing requirement for dexamethasone as
             therapy for CNS disease (anticonvulsants at a stable dose are allowed), no
             stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to
             randomization

          -  Leptomeningeal disease

          -  Uncontrolled tumor-related pain: patients requiring narcotic pain medication must be
             on a stable regimen at registration; symptomatic lesions (e.g., bone metastases or
             metastases causing nerve impingement) amenable to palliative radiotherapy should be
             treated prior to randomization; patients should be recovered from the effects of
             radiation; there is no required minimum recovery period; asymptomatic metastatic
             lesions whose further growth would likely cause functional deficits or intractable
             pain (e.g., epidural metastasis that is not presently associated with spinal cord
             compression) should be considered for loco-regional therapy if appropriate prior to
             randomization

          -  Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or
             corrected serum calcium > upper limit of normal [ULN]) or symptomatic hypercalcemia
             requiring continued use of bisphosphonate therapy; patients who are receiving
             denosumab must discontinue denosumab use and replace it with a bisphosphonate instead
             while on study; patients receiving a bisphosphonate for skeletal metastases are not
             excluded and can continue treatment

          -  Malignancies other than triple negative breast cancer (TNBC) within 5 years prior to
             randomization, with the exception of those with a negligible risk of metastasis or
             death and treated with expected curative outcome (such as adequately treated carcinoma
             in situ of the cervix or basal or squamous cell skin cancer)

          -  Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
             immunotherapy, hormonal therapy, biological therapy) other than the ones specified in
             the protocol; any other investigational drugs should be discontinued 2 weeks prior to
             the first dose of study medication

          -  GENERAL MEDICAL EXCLUSION CRITERIA

          -  Women only: pregnancy or lactation

          -  Evidence of significant uncontrolled concomitant disease that in the opinion of the
             investigator could affect compliance with the protocol or interpretation of results,
             including significant liver disease (such as cirrhosis, uncontrolled major seizure
             disorder, or superior vena cava syndrome)

          -  Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac
             disease (class II or greater), myocardial infarction within 3 months prior to
             randomization, unstable arrhythmias, or unstable angina; patients with a known left
             ventricular ejection fraction (LVEF) < 40% will be excluded; patients with known
             coronary artery disease, congestive heart failure not meeting the above criteria, or
             LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the
             treating physician, in consultation with a cardiologist if appropriate

          -  Severe infection requiring systemic treatment within 4 weeks prior to randomization,
             including but not limited to hospitalization for complications of infection,
             bacteremia, or severe pneumonia

          -  Major surgical procedure within 4 weeks prior to randomization or anticipation of the
             need for a major surgical procedure during the course of the study other than for
             diagnosis; placement of central venous access catheter(s) (e.g., port or similar) is
             not considered a major surgical procedure and is therefore permitted

          -  History of severe reactions (e.g. allergic, anaphylactic, or other hypersensitivity)
             to chimeric or humanized antibodies or fusion proteins

          -  Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or any component of the atezolizumab formulation

          -  History of autoimmune disease, including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
             syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome,
             multiple sclerosis, vasculitis, or glomerulonephritis; patients with a history of
             autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are
             eligible for this study; patients with controlled type 1 diabetes mellitus on a stable
             insulin regimen are eligible for this study

          -  Prior allogeneic stem cell or solid organ transplantation

          -  History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
             pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
             organizing pneumonia), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan; history of radiation pneumonitis in the radiation field
             (fibrosis) is permitted

          -  Positive test for human immunodeficiency virus (HIV) (testing required prior to
             registration)

          -  Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]
             test at screening) or hepatitis C

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

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

          -  Active tuberculosis

          -  Receipt of a live, attenuated vaccine within 4 weeks prior to initiation of study drug
             (cycle 1, day 1 [C1D1]) or anticipation that such a live, attenuated vaccine will be
             required during the study

          -  Prior treatment with CD137 agonists, anti−PD-1, or anti−PD-L1 therapeutic antibody or
             pathway-targeting agents

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is
             shorter) prior to randomization

          -  Treatment with systemic corticosteroids or other systemic immunosuppressant
             medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
             azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [TNF] agents)
             within 2 weeks prior to cycle 1, day 1, or anticipated requirement for systemic
             immunosuppressive medications during the trial; patients who have received acute,
             low-dose, systemic immunosuppressant medications (e.g., a one-time dose of
             dexamethasone for nausea) may be enrolled in the study; patients with a history of
             allergic reaction to IV contrast requiring steroid pre-treatment should have baseline
             and subsequent tumor assessments performed using magnetic resonance imaging (MRI); the
             use of inhaled corticosteroids for chronic obstructive pulmonary disease,
             mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension,
             and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed

          -  Psychiatric illness/social situations that would compromise patient safety or limit
             compliance with study requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Up to 3 years.
Safety Issue:
Description:The overall PFS data will be estimated using the Kaplan-Meier method with 95% confidence intervals. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percents and frequencies for categorical parameters, will be presented. Investigation for outliers and assumptions for statistical analysis, e.g., normality and homoscedasticity, will be made.

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 3 years
Safety Issue:
Description:Will calculate the ORR and corresponding 95% confidence intervals. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percents and frequencies for categorical parameters, will be presented. Investigation for outliers and assumptions for statistical analysis, e.g., normality and homoscedasticity, will be made.
Measure:Clinical benefit rate (CBR)
Time Frame:Up to 3 years
Safety Issue:
Description:Will calculate the CBR and corresponding 95% confidence intervals. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percents and frequencies for categorical parameters, will be presented. Investigation for outliers and assumptions for statistical analysis, e.g., normality and homoscedasticity, will be made.
Measure:Duration of response (DOR)
Time Frame:Up to 3 years
Safety Issue:
Description:Will calculate the DOR and corresponding 95% confidence intervals. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percents and frequencies for categorical parameters, will be presented. Investigation for outliers and assumptions for statistical analysis, e.g., normality and homoscedasticity, will be made.
Measure:Overall survival (OS)
Time Frame:Up to 3 years.
Safety Issue:
Description:Will calculate the OS and corresponding 95% confidence intervals. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percents and frequencies for categorical parameters, will be presented. Investigation for outliers and assumptions for statistical analysis, e.g., normality and homoscedasticity, will be made.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

Last Updated

August 29, 2017