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

Invasive Breast Carcinoma Clinical Trial

Official title:

Randomized Phase 2 Study of Neoadjuvant Chemotherapy, Carboplatin and Paclitaxel, With or Without Atezolizumab in Triple Negative Breast Cancer (TNBC)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02883062
• Other study ID #: NCI-2016-01301
• Secondary ID: NCI-2016-0130120
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: August 2, 2017
• Est. completion date: January 23, 2025

Study information

• Verified date: May 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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. Patients also undergo the collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up at 6 months and 1 year.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 67
• Est. completion date: January 23, 2025
• Est. primary completion date: December 18, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

• Age >= 18 years

• 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

Related Conditions & MeSH terms

• Breast Neoplasms
• Carcinoma
• Invasive Breast Carcinoma
• Stage II Breast Cancer AJCC v6 and v7
• Stage III Breast Cancer AJCC v7
• Triple Negative Breast Neoplasms
• Triple-Negative Breast Carcinoma

Intervention

Drug:
• Atezolizumab
Given IV

Procedure:
• Biospecimen Collection
Undergo collection of blood samples

Drug:
• Carboplatin
Given IV

Procedure:
• Lumpectomy
Undergo lumpectomy
• Mastectomy
Undergo mastectomy

Drug:
• Paclitaxel
Given IV

Locations

Country	Name	City	State
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Duke University Medical Center	Durham	North Carolina
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Mayo Clinic in Arizona	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Ademuyiwa FO, Gao F, Street CR, Chen I, Northfelt DW, Wesolowski R, Arora M, Brufsky A, Dees EC, Santa-Maria CA, Connolly RM, Force J, Moreno-Aspitia A, Herndon JM, Carmody M, Davies SR, Larson S, Pfaff KL, Jones SM, Weirather JL, Giobbie-Hurder A, Rodig — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of Potential Biomarkers of Response	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.	Up to the time of surgery
Other	Change in Immune Response by Immune Signature	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).	Up to the time of surgery
Other	Change in Immune Response PD-L1 Expression	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).	Up to the time of surgery
Other	Neoantigen-specific T Cell Response	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.	Up to 1 year
Other	Overall Survival (OS)	The distribution of OS in the two treatment arms will be described using Kaplan-Meier product limit methods and compared by log-rank tests.	Time from randomization to death due to any causes, assessed up to 1 year
Other	Disease Free Survival (DFS)	The distribution of DFS in the two treatment arms will be described using Kaplan-Meier product limit methods and compared by log-rank tests.	Time from randomization to disease recurrence or death due to any causes, assessed up to 1 year
Primary	Change in Tumor Infiltrating Lymphocyte (TIL) Percentage	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.	Baseline and between days 18-22 following completion of cycle 1 (each cycle is 3 weeks)
Primary	Pathologic Complete Response (pCR) Rate	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).; 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.	At the time of surgery (3-6 weeks after last dose of neoadjuvant chemotherapy, neoadjuvant chemotherapy will be up to 12 weeks in length)
Secondary	Safety of the Treatment Regimen as Measured by the Number of Grade 3 or 4 Adverse Events Experienced by Participant	Adverse events were classified and graded using CTCAE version 5.	From start of treatment of through completion of AE follow-up (median length of follow-up 2.98 months, full range 0.26-6.56 months)