Purpose

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.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Criteria

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

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Step 1 (MammaPrint testing)
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
    Undergo MammaPrint testing
    Other names:
    • Genetic Analysis
    • Genetic Examination
    • Genetic Test
Active Comparator
Step 2, Arm 1 (chemotherapy)
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
    Undergo optional collection of tissue and/or blood
    Other names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Drug: Cyclophosphamide
    Given IV
    Other names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Asta B 518
    • B-518
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamide Monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
    • WR-138719
  • Drug: Doxorubicin
    Given IV
    Other names:
    • Adriablastin
    • Hydroxydaunomycin
    • Hydroxyl Daunorubicin
    • Hydroxyldaunorubicin
  • Procedure: Mammography
    Undergo mammography
    Other names:
    • MG
  • Drug: Paclitaxel
    Given IV
    Other names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other names:
    • Quality of Life Assessment
Experimental
Step 2, Arm 2 (chemotherapy, durvalumab)
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
    Undergo optional collection of tissue and/or blood
    Other names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Drug: Cyclophosphamide
    Given IV
    Other names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Asta B 518
    • B-518
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamide Monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
    • WR-138719
  • Drug: Doxorubicin
    Given IV
    Other names:
    • Adriablastin
    • Hydroxydaunomycin
    • Hydroxyl Daunorubicin
    • Hydroxyldaunorubicin
  • Biological: Durvalumab
    Given IV
    Other names:
    • Imfinzi
    • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
    • MEDI-4736
    • MEDI4736
  • Procedure: Mammography
    Undergo mammography
    Other names:
    • MG
  • Drug: Paclitaxel
    Given IV
    Other names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other names:
    • Quality of Life Assessment

Recruiting Locations

MetroHealth Medical Center
Cleveland, Ohio 44109
Contact:
Site Public Contact
216-778-7559
ababal@metrohealth.org

More Details

Status
Recruiting
Sponsor
National Cancer Institute (NCI)

Study Contact

Detailed 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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.