Adding an Immunotherapy Drug, MEDI4736 (Durvalumab), to the Usual Chemotherapy Treatment (Paclitaxel, Cyclophosphamide, and Doxorubicin) for Stage II-III Breast Cancer

Anatomic Stage III Breast Cancer AJCC v8 Clinical Trial

Official title:

Phase III Trial of Neoadjuvant Durvalumab (NSC 778709) Plus Chemotherapy Versus Chemotherapy Alone for MammaPrint Ultrahigh (MP2) Hormone Receptor (HR) Positive / Human Epidermal Growth Factor Receptor (HER2) Negative Stage II-III Breast Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06058377
• Other study ID #: NCI-2023-04566
• Secondary ID: NCI-2023-04566S2
• Status: Recruiting
• Phase: Phase 3
• Start date: November 27, 2023
• Est. completion date: May 31, 2026

Study information

• Verified date: November 2023
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase III trial compares the addition of an immunotherapy drug (durvalumab) to usual chemotherapy versus usual chemotherapy alone in treating patients with MammaPrint Ultrahigh (MP2) stage II-III hormone receptor positive, HER2 negative breast cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as paclitaxel, doxorubicin, and cyclophosphamide 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. There is some evidence from previous clinical trials that people who have a MammaPrint Ultrahigh Risk result may be more likely to respond to chemotherapy and immunotherapy. Adding durvalumab to usual chemotherapy may be able to prevent the cancer from returning for patients with MP2 stage II-III hormone receptor positive, HER2 negative breast cancer.

Description:

PRIMARY OBJECTIVE: I. To compare breast cancer event-free survival between participants randomized to standard of care neoadjuvant chemotherapy alone versus standard of care neoadjuvant chemotherapy concurrent with durvalumab. SECONDARY OBJECTIVES: I. To compare pathologic complete response rates (ypT0/is, ypN0) in participants randomized to standard of care chemotherapy alone versus (vs.) standard of care neoadjuvant chemotherapy concurrent with durvalumab. II. To compare residual cancer burden distribution between participants randomized to standard of care neoadjuvant chemotherapy vs. standard of care neoadjuvant chemotherapy concurrent with durvalumab. III. To compare distant relapse-free survival between participants randomized to standard of care neoadjuvant chemotherapy vs. standard of care neoadjuvant chemotherapy concurrent with durvalumab. IV. To compare overall survival between participants randomized to standard of care neoadjuvant chemotherapy vs. standard of care neoadjuvant chemotherapy concurrent with durvalumab. V. To compare the frequency and severity of toxicities between participants randomized to standard of care neoadjuvant chemotherapy vs. standard of care neoadjuvant chemotherapy concurrent with durvalumab among those who initiate the assigned treatment. PRIMARY QUALITY OF LIFE (QOL) OBJECTIVES: I. To compare the change in fatigue (Patient Reported Outcomes Measurement Information System [PROMIS] Fatigue) experienced by participants randomized to neoadjuvant durvalumab plus chemotherapy vs. participants randomized to chemotherapy alone at completion of active treatment (at 20 weeks from baseline). II. To compare the change in global physical health (PROMIS Global Health) experienced by participants randomized to neoadjuvant durvalumab plus chemotherapy vs participants randomized to chemotherapy alone at completion of active treatment (at 20 weeks from baseline). SECONDARY QOL OBJECTIVES: I. To compare the change in fatigue and global physical health experienced by participants randomized to neoadjuvant durvalumab plus chemotherapy vs participants randomized to chemotherapy alone during treatment (at 12 weeks from baseline). II. To compare the changes in global physical health and fatigue subsequent to treatment (at years 1 and 2) between the two randomized study arms. III. To compare the changes in global mental health (PROMIS Global Health) during active treatment (weeks 12, 20) and subsequent to treatment (at years 1 and 2) between the two randomized study arms. IV. To compare the severity and frequency of treatment-related symptoms using Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) items (diarrhea, nausea, cough, shortness of breath, rash, and musculoskeletal pain) over time experienced by patients receiving neoadjuvant durvalumab plus chemotherapy versus chemotherapy alone. BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: STEP 1: Patients without a known MammaPrint Ultrahigh (MP2) score undergo MammaPrint testing on a previously-collected tissue sample. Patients with MP2 score proceed to STEP 2. STEP 2: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive paclitaxel intravenously (IV) over 30-60 minutes on days 1 and 8 of each cycle. Treatment repeats every 14 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1 of each cycle. Treatment repeats every 14 days for 4 cycles in the absence of disease progression or unacceptable toxicity. ARM 2: Patients receive paclitaxel IV over 30-60 minutes on days 1 and 8 of every cycle and durvalumab IV over 60 minutes on day 1 of every other cycle. Treatment repeats every 14 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1 of each cycle, and durvalumab IV over 60 minutes on day 1 of every other cycle. Treatment repeats every 14 days for 4 cycles in the absence of disease progression or unacceptable toxicity. All patients also undergo mammography during screening (STEP 1). Patients have the option to also undergo collection of tumor tissue during initial biopsy (STEP 1) and at standard of care (SOC) surgery, and undergo collection of blood samples prior to STEP 2 treatment, after cycle one of chemotherapy, and one month post-SOC surgery. After completion of study treatment, patients are followed until death or 10 years, whichever occurs first.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3680
• Est. completion date: May 31, 2026
• Est. primary completion date: May 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• STEP 1: REGISTRATION (SCREENING): Participants must have histologically confirmed estrogen receptor (ER) positive and/or progesterone receptor (PR) positive (hormone receptor positive) and HER2 negative breast cancer, as per American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines
• NOTE: Participants with HER2 positive disease by ASCO CAP guidelines are ineligible. HER2 negative and HER2 low or equivocal cases as per ASCO CAP guidelines that do not receive HER2 targeted therapy are eligible
• STEP 1: REGISTRATION (SCREENING): Participants must have clinical stage II or III breast cancer
• NOTE: Participants with inflammatory breast cancer are eligible
• STEP 1: REGISTRATION (SCREENING): Participants must not have metastatic disease (i.e., must be clinically M0 or Mx) Systemic staging studies with imaging should follow routine practice as per National Comprehensive Cancer Network (NCCN) and ASCO guidelines
• STEP 1: REGISTRATION (SCREENING): Participants must not have locally recurrent breast cancer
• STEP 1: REGISTRATION (SCREENING): Participants with multifocal disease or synchronous primary tumors are eligible, however, all tumors must be hormone receptor positive and HER2 negative per ASCO CAP guidelines. It is sufficient to have MP2 status on at least one of the lesions
• Participants must have either adequate tissue available to submit on-study or a prior known MammaPrint Index Score that is MP2 status
• Submitting tissue for on-study MammaPrint testing:
• Participants must have a minimum of ten, unstained formalin-fixed paraffin-embedded (FFPE) slides (4-5 micron thickness) available from initial tumor biopsy for MammaPrint assessment
• NOTE: Participants must agree to have this tissue submitted to Agendia for MammaPrint Index Scoring and to have subsequent results disclosed to SWOG Cancer Research Network OR
• Submitting prior known MammaPrint Index Score:
• If a MammaPrint Index Score report from within the last 12 weeks is already known and is MP2 status, the participant must be registered to Step 2 immediately following Step 1 registration provided they meet all other criteria. MP2 status is defined as a MammaPrint Index score between negative 1.0 and negative 0.57 (-1.0 to -0.57, including negative 0.57) tested from initial tumor biopsy
• NOTE: Participants must agree to have their commercial MammaPrint Index Score disclosed to Southwest Oncology Group (SWOG) Cancer Research Network
• NOTE: Participants with prior known MammaPrint result that is not MP2 status should not be enrolled to either step of this study
• STEP 1: REGISTRATION (SCREENING): Participants must not have received any prior treatment for their current breast cancer, including chemotherapy, immunotherapy, biologic or hormonal therapy, and must be candidates for doxorubicin, paclitaxel, and durvalumab therapy
• STEP 1: REGISTRATION (SCREENING): Participants must be >= 18 years old at the time of registration
• STEP 1: REGISTRATION (SCREENING): Participants must have a complete medical history and physical exam within 28 days prior to Step 1 Registration
• STEP 1: REGISTRATION (SCREENING): Participants must have body weight > 30 kg
• STEP 1: REGISTRATION (SCREENING): Participants must have Zubrod Performance Status of 0-2
• STEP 1: REGISTRATION (SCREENING): Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• STEP 1: REGISTRATION (SCREENING): Participant must not have medical contraindications to receiving immunotherapy, including history of non-infectious pneumonitis that required steroids or active autoimmune disease that has required systemic treatment with disease modifying agents, corticosteroids or immunosuppressive drugs in the past two years. Replacement therapy (e.g. thyroxine for pre-existing hypothyroidism, insulin for type I diabetes mellitus, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Intra-articular steroid injections are allowed
• STEP 1: REGISTRATION (SCREENING): NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines
• For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations
• STEP 2: RANDOMIZATION: Participants must have met all eligibility criteria for Step 1 Registration
• STEP 2: RANDOMIZATION: Participants must have MP2 MammaPrint result
• For participants submitting tissue for on-study MammaPrint testing:
• Participants must be registered to Step 2: Randomization within 84 calendar days (12 weeks) after receiving an MP2 status from the MammaPrint Index score. MP2 status is defined as a MammaPrint Index score between negative 1.0 and negative 0.57 (-1.0 to -0.57, including negative 0.57) from initial tumor biopsy OR
• Submitting commercial MammaPrint Index Score:
• If a MammaPrint Index Score report from within the last 12 weeks is already known and is MP2 status, the participant must be registered to Step 2 immediately following Step 1 registration provided they meet all other criteria. MP2 status is defined as a MammaPrint Index score between negative 1.0 and negative 0.57 (-1.0 to -0.57, including negative 0.57) tested from initial tumor biopsy
• STEP 2: RANDOMIZATION: Participants must not have received live vaccines within 28 days prior to study Step 2: Randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines and coronavirus disease 2019 (COVID-19) vaccines are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines, and are not allowed
• STEP 2: RANDOMIZATION: Participants must not be planning to receive any concurrent non-protocol directed chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study
• STEP 2: RANDOMIZATION: Participant must have Zubrod Performance Status of 0-2
• STEP 2: RANDOMIZATION: Participants must not have a history of (non-infectious) pneumonitis that required steroids or evidence of active pneumonitis within two years prior to Step 2: Randomization
• STEP 2: RANDOMIZATION: Participants must not have active autoimmune disease that has required systemic treatment in the past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs) prior to Step 2: Randomization. Replacement therapy (e.g. thyroxine for pre-existing hypothyroidism, insulin for type I diabetes mellitus, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Intra-articular steroid injections are allowed
• STEP 2: RANDOMIZATION: Participant must have a complete medical history and physical exam within 28 days prior to Step 2: Randomization
• STEP 2: RANDOMIZATION: Leukocytes >= 3 x 10^3/uL (within 28 days prior to Step 2:

Randomization)

• STEP 2: RANDOMIZATION: Absolute neutrophil count >=1.5 x 10^3/uL (within 28 days prior to Step 2: Randomization)
• STEP 2: RANDOMIZATION: Platelets >= 100 x 10^3/uL (within 28 days prior to Step 2:

Randomization)

• STEP 2: RANDOMIZATION: Total bilirubin =< institutional upper limit of normal (ULN) unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to Step 2: Randomization)
• STEP 2: RANDOMIZATION: AST/ALT =< 3 × institutional ULN (within 28 days prior to Step 2: Randomization)
• STEP 2: RANDOMIZATION: Participants must have a calculated creatinine clearance >= 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to Step 2: Randomization
• STEP 2: RANDOMIZATION: Participants must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
• STEP 2: RANDOMIZATION: Participants must not have uncontrolled diabetes defined as hemoglobin A1c of 9.0% or greater, within 28 days prior to Step 2: Randomization.
• STEP 2: RANDOMIZATION: Participants with history of human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have an undetectable viral load on the most recent test results obtained within 6 months prior to Step 2: Randomization
• STEP 2: RANDOMIZATION: Participants with history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on the most recent test results obtained while on suppressive therapy within 6 months prior to Step 2: Randomization, if indicated
• STEP 2: RANDOMIZATION: Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load on the most recent test results obtained within 6 months prior to Step 2: Randomization, if indicated
• STEP 2: RANDOMIZATION: Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method during protocol therapy and for 6 months following completion of protocol therapy with details provided as a part of the consent process and must have a negative pregnancy test at screening. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen. Participants should not breastfeed during protocol therapy and for 6 months following completion of protocol therapy.
• STEP 2: RANDOMIZATION: Participants must be offered the opportunity to participate in specimen banking. With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System
• STEP 2: RANDOMIZATION: Participants who can complete questionnaires in English, or Spanish must be offered the opportunity to participate in the Quality of Life study
• STEP 2: RANDOMIZATION: NOTE: As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• STEP 2: RANDOMIZATION: Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines

Related Conditions & MeSH terms

• Anatomic Stage II Breast Cancer AJCC v8
• Anatomic Stage III Breast Cancer AJCC v8
• Breast Neoplasms
• Carcinoma

Intervention

Procedure:
• Biospecimen Collection
Undergo optional collection of tissue and/or blood

Drug:
• Cyclophosphamide
Given IV
• Doxorubicin
Given IV

Biological:
• Durvalumab
Given IV

Other:
• Genetic Testing
Undergo MammaPrint testing

Procedure:
• Mammography
Undergo mammography

Drug:
• Paclitaxel
Given IV

Other:
• Quality-of-Life Assessment
Ancillary studies

Locations

Country	Name	City	State
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Sutter Auburn Faith Hospital	Auburn	California
United States	AIS Cancer Center at San Joaquin Community Hospital	Bakersfield	California
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	UM Upper Chesapeake Medical Center	Bel Air	Maryland
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Tower Cancer Research Foundation	Beverly Hills	California
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Joseph's/Candler - Bluffton Campus	Bluffton	South Carolina
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Caro Cancer Center	Caro	Michigan
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Rex Hematology Oncology Associates-Cary	Cary	North Carolina
United States	Miami Valley Hospital South	Centerville	Ohio
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	University of Illinois	Chicago	Illinois
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Baptist Memorial Hospital and Cancer Center-Collierville	Collierville	Tennessee
United States	Baptist Memorial Hospital and Cancer Center-Golden Triangle	Columbus	Mississippi
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Northwest Cancer Center - Main Campus	Crown Point	Indiana
United States	Carle at The Riverfront	Danville	Illinois
United States	Dayton Blood and Cancer Center	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Smilow Cancer Hospital-Derby Care Center	Derby	Connecticut
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Northwest Oncology LLC	Dyer	Indiana
United States	Shaw Cancer Center	Edwards	Colorado
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Trinitas Hospital and Comprehensive Cancer Center - Williamson Street Campus	Elizabeth	New Jersey
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Smilow Cancer Hospital Care Center-Fairfield	Fairfield	Connecticut
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Palo Alto Medical Foundation-Fremont	Fremont	California
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Rex Hematology Oncology Associates-Garner	Garner	North Carolina
United States	Tidelands Georgetown Memorial Hospital	Georgetown	South Carolina
United States	Smilow Cancer Hospital Care Center at Glastonbury	Glastonbury	Connecticut
United States	Glens Falls Hospital	Glens Falls	New York
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	Miami Valley Cancer Care and Infusion	Greenville	Ohio
United States	Smilow Cancer Hospital Care Center at Greenwich	Greenwich	Connecticut
United States	Baptist Cancer Center-Grenada	Grenada	Mississippi
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Smilow Cancer Hospital Care Center - Guilford	Guilford	Connecticut
United States	The Cancer Institute of New Jersey Hamilton	Hamilton	New Jersey
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	OptumCare Cancer Care at Seven Hills	Henderson	Nevada
United States	South Carolina Cancer Specialists PC	Hilton Head Island	South Carolina
United States	Northwest Cancer Center - Hobart	Hobart	Indiana
United States	Saint Mary Medical Center	Hobart	Indiana
United States	M D Anderson Cancer Center	Houston	Texas
United States	Saint Catherine Hospital	Indianapolis	Indiana
United States	City of Hope at Irvine Lennar	Irvine	California
United States	Jersey City Medical Center	Jersey City	New Jersey
United States	NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro	Jonesboro	Arkansas
United States	Jupiter Medical Center	Jupiter	Florida
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Monmouth Medical Center Southern Campus	Lakewood	New Jersey
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	OptumCare Cancer Care at Charleston	Las Vegas	Nevada
United States	OptumCare Cancer Care at Fort Apache	Las Vegas	Nevada
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Monmouth Medical Center	Long Branch	New Jersey
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Baptist Memorial Hospital and Cancer Center-Memphis	Memphis	Tennessee
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	NYU Winthrop Hospital	Mineola	New York
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Community Medical Hospital	Missoula	Montana
United States	Memorial Medical Center	Modesto	California
United States	Trinity Medical Center	Moline	Illinois
United States	Ochsner LSU Health Monroe Medical Center	Monroe	Louisiana
United States	The Community Hospital	Munster	Indiana
United States	Women's Diagnostic Center - Munster	Munster	Indiana
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Baptist Memorial Hospital and Cancer Center-Union County	New Albany	Mississippi
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	City of Hope Newport Beach	Newport Beach	California
United States	Yale-New Haven Hospital North Haven Medical Center	North Haven	Connecticut
United States	University of Kansas Cancer Center at North Kansas City Hospital	North Kansas City	Missouri
United States	Ascension Providence Hospitals - Novi	Novi	Michigan
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Saint Alphonsus Medical Center-Ontario	Ontario	Oregon
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	University of Kansas Hospital-Indian Creek Campus	Overland Park	Kansas
United States	Baptist Memorial Hospital and Cancer Center-Oxford	Oxford	Mississippi
United States	Desert Regional Medical Center	Palm Springs	California
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	SWOG	Portland	Oregon
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	UNC Rex Cancer Center of Wakefield	Raleigh	North Carolina
United States	UNC Rex Healthcare	Raleigh	North Carolina
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Sutter Roseville Medical Center	Roseville	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
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	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	Kootenai Cancer Clinic	Sandpoint	Idaho
United States	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California
United States	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia
United States	Saint Vincent Hospital Cancer Center at Sheboygan	Sheboygan	Wisconsin
United States	Memorial Hospital East	Shiloh	Illinois
United States	LSU Health Sciences Center at Shreveport	Shreveport	Louisiana
United States	Ochsner LSU Health - Cancer Treatment Center	Shreveport	Louisiana
United States	Robert Wood Johnson University Hospital Somerset	Somerville	New Jersey
United States	City of Hope South Pasadena	South Pasadena	California
United States	Ascension Providence Hospitals - Southfield	Southfield	Michigan
United States	Baptist Memorial Hospital and Cancer Center-Desoto	Southhaven	Mississippi
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Smilow Cancer Hospital Care Center at Long Ridge	Stamford	Connecticut
United States	Saint Vincent Hospital Cancer Center at Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California
United States	BJC Outpatient Center at Sunset Hills	Sunset Hills	Missouri
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Northwest Medical Specialties PLLC	Tacoma	Washington
United States	Ascension Saint Joseph Hospital	Tawas City	Michigan
United States	Community Medical Center	Toms River	New Jersey
United States	Smilow Cancer Hospital-Torrington Care Center	Torrington	Connecticut
United States	Upper Valley Medical Center	Troy	Ohio
United States	Smilow Cancer Hospital Care Center-Trumbull	Trumbull	Connecticut
United States	Legacy Meridian Park Hospital	Tualatin	Oregon
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	City of Hope Upland	Upland	California
United States	Carle Cancer Center	Urbana	Illinois
United States	Sutter Solano Medical Center/Cancer Center	Vallejo	California
United States	Northwest Cancer Center - Valparaiso	Valparaiso	Indiana
United States	Legacy Cancer Institute Medical Oncology and Day Treatment	Vancouver	Washington
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	Smilow Cancer Hospital-Waterbury Care Center	Waterbury	Connecticut
United States	Smilow Cancer Hospital Care Center - Waterford	Waterford	Connecticut
United States	Saint Mary's Oncology/Hematology Associates of West Branch	West Branch	Michigan
United States	Smilow Cancer Hospital Care Center - Westerly	Westerly	Rhode Island
United States	William E Kahlert Regional Cancer Center/Sinai Hospital	Westminster	Maryland
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Breast cancer event-free survival (BC-EFS)	Defined as the earliest occurrence of any of the following events: Local-regional or distant progression during neoadjuvant therapy or local/regional, or distant invasive breast tumor recurrence post-surgery, invasive ipsilateral breast tumor recurrence, new invasive contralateral breast cancer, or death from any cause. The primary analysis of BC-EFS is a log-rank test between the treatment arms with stratification by the three stratification factors. Additionally, Cox regression will be used to estimate the treatment hazard ratio and 95% confidence interval including the three stratification variables as terms in the model. Kaplan-Meier graphs will show BC-EFS descriptively over time and provide 5-year estimates and 95% confidence intervals. A forest plot will show whether the treatment effect varies over the stratification variables and other selected factors.	Up to 10 years after completion of study treatment
Secondary	Pathologic complete response (pCR) rates	Defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast and specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (ypT0/Tis ypN0). At the completion of all treatment and surgery for all enrolled participants, there will be a comparison of pCR rates between the treatment arms. pCR rates will be compared by a test of two proportions followed by logistic regression to estimate the odds ratio after adjustment for the stratification factors.	Up to 10 years after completion of study treatment
Secondary	Residual cancer burden (RCB)	Defined as a continuous measure of the extent of residual cancer after neoadjuvant chemotherapy that combines the largest diameter of the cancer in the breast, the tumor cell cellularity of the cancer, and the largest diameter and number of involved axillary lymph nodes into a single RCB score. RCB will be analyzed by comparing RCB 2-3 to RCB 0-1.	Up to 10 years after completion of study treatment
Secondary	Distant relapse-free survival (DRFS)	Analyses will be performed using log-rank testing, Cox regression, and Kaplan-Meier estimation.	Time from date of randomization (2nd Registration) to date of invasive distant disease recurrence or death due to any cause, assessed up to 10 years after completion of study treatment
Secondary	Overall survival (OS)	Analyses will be performed using log-rank testing, Cox regression, and Kaplan-Meier estimation. Will also be conducted at alpha = 0.05 (2-sided).	Time from date of randomization (2nd Registration) to date of death due to any cause, assessed up to 10 years after completion of study treatment