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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02883062
Recruitment Status : Active, not recruiting
First Posted : August 30, 2016
Last Update Posted : October 20, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE August 29, 2016
First Posted Date  ICMJE August 30, 2016
Last Update Posted Date October 20, 2020
Actual Study Start Date  ICMJE May 17, 2017
Estimated Primary Completion Date July 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2019)
Increase in tumor infiltrating lymphocyte (TIL) percentage [ Time Frame: Up to the time of surgery ]
Will be measured by histopathologic assay. 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 29, 2016)
Increase in TIL percentage measured by histopathologic assay [ Time Frame: Up to the time of surgery ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 9, 2018)
Increase in pathologic complete response (pCR) rate [ Time Frame: Up to 1 year ]
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).
Original Secondary Outcome Measures  ICMJE
 (submitted: August 29, 2016)
Increase in pCR rate [ Time Frame: Up to 30 days ]
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).
Current Other Pre-specified Outcome Measures
 (submitted: October 26, 2018)
  • Incidence of potential biomarkers of response [ Time Frame: Up to the time of surgery ]
    Potential biomarkers include baseline TIL percentage, baseline PD-L1 expression in the tumor and tumor infiltrating immune cells, baseline immune signature, and baseline neoantigen load. Univariate and multivariate logistic regression models will be used to evaluate predictive ability of these baseline biomarkers on the response to carboplatin-based chemotherapy in combination with atezolizumab therapy. To take full advantage of such a randomized design, each model will also include the interaction term between treatment assignment and the baseline biomarker. This allows not only to answer the question whether the biomarker is predictive of pCR, but also whether the predictive ability is the same across two arms. The predictive ability will also be summarized using the area under receiver operating characteristic curves (AUC), and the 95% confidence intervals of AUC will be obtained using bootstrap resampling methods.
  • Change in immune response by immune signature [ Time Frame: Up to the time of surgery ]
    The immune signature and PD-L1 expression in the tumor and tumor-infiltrating immune cells will be evaluated at baseline, after initiation of therapy (day 18-22), and at the time of surgery. The temporal changes of immune signature and PD-L1 expression in each arm will be summarized using contingency tables or descriptive statistics (means, standard deviations, medians, etc.) as appropriate. The differences of temporal change between treatment groups (Arm A versus [vs.] Arm B) or their association with clinical outcome (pCR vs. non-pCR) will also be assessed musing mixed model (PD-L1 expression) or generalized linear mixed model (immune signatures).
  • Change in immune response PD-L1 expression [ Time Frame: Up to the time of surgery ]
    The immune signature and PD-L1 expression in the tumor and tumor-infiltrating immune cells will be evaluated at baseline, after initiation of therapy (day 18-22), and at the time of surgery. The temporal changes of immune signature and PD-L1 expression in each arm will be summarized using contingency tables or descriptive statistics (means, standard deviations, medians, etc.) as appropriate. The differences of temporal change between treatment groups (Arm A vs. Arm B) or their association with clinical outcome (pCR vs. non-pCR) will also be assessed musing mixed model (PD-L1 expression) or generalized linear mixed model (immune signatures).
  • Neoantigen-specific T cell response [ Time Frame: Up to 1 year ]
    The frequency and function of neoantigen-specific T cell across the two arms in the peripheral blood at each time point will be summarized using tools for high throughput analysis. The differences of temporal changes in neoantigen-specific T cell between treatment groups (Arm A versus Arm B) or their association with clinical outcome (pCR vs. non-pCR) will also be assessed using mixed models, followed by ad-hoc adjustment for multiple comparisons.
  • Overall survival (OS) [ Time Frame: Time from randomization to death due to any causes, assessed up to 1 year ]
    The distribution of OS in the two treatment arms will be described using Kaplan-Meier product limit methods and compared by log-rank tests.
  • Disease free survival (DFS) [ Time Frame: Time from randomization to disease recurrence or death due to any causes, assessed up to 1 year ]
    The distribution of DFS in the two treatment arms will be described using Kaplan-Meier product limit methods and compared by log-rank tests.
Original Other Pre-specified Outcome Measures
 (submitted: August 29, 2016)
  • Change in immune response by immune signature [ Time Frame: Up to 18 days ]
    The immune signature and PD-L1 expression in the tumor and tumor-infiltrating immune cells will be evaluated at baseline and after initiation of therapy. Two-way ANOVA for repeated measurement data will be used to compare the changes of PD-L1 expression over time as well as the between-group differences (treatment arms, pCR vs. non-pCR, and their interactions), while a generalized linear mixed model will be used to assess the impact of treatment on immune signatures.
  • Change in immune response PD-L1 expression [ Time Frame: Up to 18 days ]
    The immune signature and PD-L1 expression in the tumor and tumor-infiltrating immune cells will be evaluated at baseline and after initiation of therapy. Two-way ANOVA for repeated measurement data will be used to compare the changes of PD-L1 expression over time as well as the between-group differences (treatment arms, pCR vs. non-pCR, and their interactions), while a generalized linear mixed model will be used to assess the impact of treatment on immune signatures.
  • DFS [ Time Frame: Time from randomization to disease recurrence or death due to any causes, assessed up to 30 days ]
    The distribution of OS and DFS in the two treatment arms will be described using Kaplan-Meier product limit methods and compared by log-rank tests.
  • Incidence of potential biomarkers of response [ Time Frame: Up to the time of surgery ]
    Potential biomarkers include baseline TIL percentage, baseline Programmed Cell Death 1 Ligand 1 (PD-L1) expression in the tumor and tumor infiltrating immune cells, baseline immune signature, and baseline neoantigen load. Multivariate logistic regression models will be used to evaluate predictive ability of these baseline biomarkers on the response to carboplatin-based chemotherapy in combination with atezolizumab therapy. To take full advantage of such a randomized design, each model will also include the interaction term between treatment assignment and the baseline biomarker. This allows no
  • Neoantigen-specific T cell response [ Time Frame: Up to 30 days ]
    The neoantigen-specific T cell responses across the two arms will be summarized using contingency tables and compared by Fisher's exact test.
  • OS [ Time Frame: Time from randomization to death due to any causes, assessed up to 30 days ]
    The distribution of OS and DFS in the two treatment arms will be described using Kaplan-Meier product limit methods and compared by log-rank tests.
 
Descriptive Information
Brief Title  ICMJE Carboplatin and Paclitaxel With or Without Atezolizumab Before Surgery in Treating Patients With Newly Diagnosed, Stage II-III Triple-Negative Breast Cancer
Official Title  ICMJE Randomized Phase 2 Study of Neoadjuvant Chemotherapy, Carboplatin and Paclitaxel, With or Without Atezolizumab in Triple Negative Breast Cancer (TNBC)
Brief Summary 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.
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 OBJECTIVE:

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

EXPLORATORY 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 carboplatin intravenously (IV) over 30 minutes once every 3 weeks (Q3W) and paclitaxel IV over 1 hour once weekly (QW). Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV over 30 minutes Q3W, and paclitaxel IV over 1 hour QW. Treatment repeats every 3 weeks for up to 4 cycles 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 at 6 months and 1 year.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Invasive Breast Carcinoma
  • 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
Intervention  ICMJE
  • Drug: Atezolizumab
    Given IV
    Other Names:
    • MPDL 3280A
    • MPDL 328OA
    • MPDL-3280A
    • MPDL3280A
    • MPDL328OA
    • RG7446
    • RO5541267
    • Tecentriq
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Procedure: Lumpectomy
    Undergo lumpectomy
    Other Names:
    • Lumpectomy of Breast
    • Partial Mastectomy
  • Procedure: Mastectomy
    Undergo mastectomy
    Other Name: Mammectomy
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
Study Arms  ICMJE
  • Active Comparator: Arm A (carboplatin, paclitaxel, mastectomy, lumpectomy)
    Patients receive carboplatin IV over 30 minutes Q3W and paclitaxel IV over 1 hour QW. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Carboplatin
    • Procedure: Lumpectomy
    • Procedure: Mastectomy
    • Drug: Paclitaxel
  • Experimental: Arm B (atezolizumab, carboplatin, paclitaxel, breast surgery)
    Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV over 30 minutes Q3W, and paclitaxel IV over 1 hour QW. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Atezolizumab
    • Drug: Carboplatin
    • Procedure: Lumpectomy
    • Procedure: Mastectomy
    • Drug: Paclitaxel
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: June 11, 2019)
72
Original Estimated Enrollment  ICMJE
 (submitted: August 29, 2016)
60
Estimated Study Completion Date  ICMJE July 1, 2021
Estimated Primary Completion Date July 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically confirmed new diagnosis of breast cancer
  • Estrogen receptor (ER) and progesterone receptor (PR) < Allred score of 3 or =< 5% positive staining cells in the invasive component of the tumor (provided the patient is being treated as triple negative breast cancer)
  • 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)
  • Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; 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%, fluocinolone 0.01%, desonide 0.05%, alclometasone 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 (approximately October to March); 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 symptomatic 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 because atezolizumab is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding should be discontinued if the mother is treated with atezolizumab; these potential risks may also apply to other agents used in this study
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02883062
Other Study ID Numbers  ICMJE NCI-2016-01301
NCI-2016-01301 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
201706104
10013 ( Other Identifier: Duke University - Duke Cancer Institute LAO )
10013 ( Other Identifier: CTEP )
UM1CA186704 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: William E Gillanders Duke University - Duke Cancer Institute LAO
PRS Account National Cancer Institute (NCI)
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP