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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 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.

Official Title
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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

Conditions
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Anatomic Stage III Breast Cancer AJCC v8, HER2-Negative Breast Carcinoma, Hormone Receptor-Positive Breast Carcinoma, Anatomic Stage II Breast Cancer AJCC v8

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Biological: Durvalumab
* Other: Genetic Testing
* Procedure: Mammography
* Drug: Paclitaxel
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Step 1 (MammaPrint testing)<br>Patients without a known MP2 score undergo MammaPrint testing on a previously-collected tissue sample. Patients with MP2 score proceed to STEP 2. | Other: Genetic Testing<br>* Undergo MammaPrint testing<br>* Other names: Genetic Test;|
| Active Comparator: Step 2, Arm 1 (chemotherapy)<br>Patients receive paclitaxel 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. 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 SOC surgery, and undergo collection of blood samples prior to STEP 2 treatment, after cycle one of chemotherapy, and one month post-SOC surgery. | Procedure: Biospecimen Collection<br>* Undergo optional collection of tissue and/or blood<br>* Other names: Specimen Collection;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Procedure: Mammography<br>* Undergo mammography<br>* Other names: MG;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Step 2, Arm 2 (chemotherapy, durvalumab)<br>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. 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 SOC surgery, and undergo collection of blood samples prior to STEP 2 treatment, after cycle one of chemotherapy, and one month post-SOC surgery. | Procedure: Biospecimen Collection<br>* Undergo optional collection of tissue and/or blood<br>* Other names: Specimen Collection;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Procedure: Mammography<br>* Undergo mammography<br>* Other names: MG;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 |