Anatomic Stage II Breast Cancer AJCC v8Phase 2NCT05710328
Testing the Role of FDG-PET/CT to Predict Response to Therapy Prior to Surgery for HER2-positive Breast Cancer, The DIRECT Trial
A Phase 2 study testing Chemotherapy, Computed Tomography and Fludeoxyglucose F-18 in people with Anatomic Stage II Breast Cancer AJCC v8 and Anatomic Stage III Breast Cancer AJCC v8, run by ECOG-ACRIN Cancer Research Group at 102 sites in 2 countries.
Trial summary
This phase II trial tests how well an imaging procedure called fludeoxyglucose F-18 (FDG) positron emission tomography/computed tomography (PET/CT) works in predicting response to standard of care chemotherapy prior to surgery in patients with HER2-positive stage IIa-IIIc breast cancer. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, HER2-Positive Breast Carcinoma
- What is being tested?
- Chemotherapy, Computed Tomography and Fludeoxyglucose F-18
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 235 participants
- Where
- 102 sitesin 2 countries
- Study dates
- 10 May 2023to 31 Dec 2029
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients (all genders) must be >= 18 years of age.
- Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible.
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
- Patient must have histologically confirmed HER2-positive primary invasive breast carcinoma by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines that has been determined by local testing.
- Patient must have known (either positive or negative) hormone receptor (estrogen receptor [ER] or progesterone receptor [PR]) status by local testing, per ASCO/CAP guidelines. Patients with either hormone receptor-positive or hormone receptor- negative HER2-positive breast cancer are eligible.
- Patient must have American Joint Committee on Cancer (AJCC) 8th Edition stage IIa-IIIc according to anatomic staging table at diagnosis and below criteria.
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- Patients without nodal involvement (cN0) are eligible if T size > 2.0 cm (T2-4)
- Patients with nodal involvement (cN1-3) are eligible if T2-4
- Patients with clinical T4d are not eligible
- Patients with bilateral invasive breast cancers are eligible if both cancers are HER2-positive and at least one meets all protocol eligibility criteria and neither cancer renders the patient ineligible.
- Patients with multiple ipsilateral invasive tumors are eligible as long as all tumors are HER2-positive and at least one tumor focus meets all eligibility criteria. Multiple lesions that appear part of the same index tumor do not require additional biopsy/HER2 testing.
- Patient must plan to start a standard neoadjuvant pertuzumab (or other biosimilars) based regimen.
- Patients 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 this imaging intervention are eligible for this trial.
- Patients with human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.
- Patient must be participating in the trial at an institution which has agreed to perform the imaging research studies, completed the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Center Group (ECOG-ACRIN) defined PET/CT scanner qualification procedures and received ECOG-ACRIN PET/CT scanner approval.
- For patients who completed the baseline (T0) FDG-PET/CT PRIOR to registration, neoadjuvant pertuzumab-based regimen must start after study registration and within 21 days after the T0 scan.
- Patients must not have used colony stimulating growth factors within 14 days prior to completing a T0 scan done prior to registration.
Who cannot join
- Patient must not have any prior treatment for the current breast cancer, including surgery, chemotherapy, hormonal therapy, radiation or experimental therapy.
- Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the teratogenic effects of FDG in addition to the radiation exposure during PET/CT. All patients of childbearing potential must have a blood test or urine study within 7 days prior to registration to rule out pregnancy.
- NOTE: A pregnancy test within 7 days prior to the T0 scan is also required but will only need to be done if a) the T0 scan is completed after study registration and b) if the pregnancy test done prior to registration is completed outside of the 7-day window.
- A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
- Patient must not have any contraindication to FDG-PET/CT imaging which includes routine glucose values > 200 mg/dL and severe claustrophobia.
Trial locations and contacts
102 sites in 2 countries.
102 sites in 2 countries
United States97 sites
Hawaii Cancer Care - Westridge
‘Aiea, Hawaii, 96701
Dell Seton Medical Center at The University of Texas
Austin, Texas, 78701
University of Texas at Austin
Austin, Texas, 78712
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Indu and Raj Soin Medical Center
Beavercreek, Ohio, 45431
Nebraska Medicine-Bellevue
Bellevue, Nebraska, 68123
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Bryn Mawr Hospital
Bryn Mawr, Pennsylvania, 19010
Roswell Park Cancer Institute
Buffalo, New York, 14263
Aurora Cancer Care-Southern Lakes VLCC
Burlington, Wisconsin, 53105
Minnesota Oncology - Burnsville
Burnsville, Minnesota, 55337
Cooper Hospital University Medical Center
Camden, New Jersey, 08103
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
Northwestern University
Chicago, Illinois, 60611
MetroHealth Medical Center
Cleveland, Ohio, 44109
Baptist Memorial Hospital and Cancer Center-Collierville
Collierville, Tennessee, 38017
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Mercy Hospital
Coon Rapids, Minnesota, 55433
Carle at The Riverfront
Danville, Illinois, 61832
Geisinger Medical Center
Danville, Pennsylvania, 17822
Northwestern Medicine Cancer Center Kishwaukee
DeKalb, Illinois, 60115
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201
Marshfield Medical Center-EC Cancer Center
Eau Claire, Wisconsin, 54701
Carle Physician Group-Effingham
Effingham, Illinois, 62401
Northwestern Medicine Cancer Center Delnor
Geneva, Illinois, 60134
Aurora Health Care Germantown Health Center
Germantown, Wisconsin, 53022
Saint Vincent Hospital Cancer Center Green Bay
Green Bay, Wisconsin, 54301
Saint Vincent Hospital Cancer Center at Saint Mary's
Green Bay, Wisconsin, 54303
Hawaii Cancer Care Inc - Waterfront Plaza
Honolulu, Hawaii, 96813
Queen's Cancer Cenrer - POB I
Honolulu, Hawaii, 96813
Queen's Medical Center
Honolulu, Hawaii, 96813
University of Hawaii Cancer Center
Honolulu, Hawaii, 96813
Queen's Cancer Center - Kuakini
Honolulu, Hawaii, 96817
Kapiolani Medical Center for Women and Children
Honolulu, Hawaii, 96826
Mayo Clinic in Florida
Jacksonville, Florida, 32224-9980
Castle Medical Center
Kailua, Hawaii, 96734
Kettering Medical Center
Kettering, Ohio, 45429
Marshfield Medical Center - Ladysmith
Ladysmith, Wisconsin, 54848
Northwestern Medicine Lake Forest Hospital
Lake Forest, Illinois, 60045
Wilcox Memorial Hospital and Kauai Medical Clinic
Lihue, Hawaii, 96766
Los Angeles General Medical Center
Los Angeles, California, 90033
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033
The James Graham Brown Cancer Center at University of Louisville
Louisville, Kentucky, 40202
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792
Minnesota Oncology Hematology PA-Maplewood
Maplewood, Minnesota, 55109
Marshfield Medical Center-Marshfield
Marshfield, Wisconsin, 54449
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois, 61938
Riddle Memorial Hospital
Media, Pennsylvania, 19063
Baptist Memorial Hospital and Cancer Center-Memphis
Memphis, Tennessee, 38120
Aurora Saint Luke's Medical Center
Milwaukee, Wisconsin, 53215
Aurora Sinai Medical Center
Milwaukee, Wisconsin, 53233
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407
Marshfield Clinic-Minocqua Center
Minocqua, Wisconsin, 54548
Morristown Medical Center
Morristown, New Jersey, 07960
Inspira Medical Center Mullica Hill
Mullica Hill, New Jersey, 08062
Marshfield Medical Center - Neillsville
Neillsville, Wisconsin, 54456
Louisiana State University Health Science Center
New Orleans, Louisiana, 70112
University Medical Center New Orleans
New Orleans, Louisiana, 70112
Bryn Mawr Health Center
Newtown Square, Pennsylvania, 19073
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Nebraska Medicine-Village Pointe
Omaha, Nebraska, 68118
University of Nebraska Medical Center
Omaha, Nebraska, 68198
Baptist Memorial Hospital and Cancer Center-Oxford
Oxford, Mississippi, 38655
Paoli Memorial Hospital
Paoli, Pennsylvania, 19301
Saint Joseph's Regional Medical Center
Paterson, New Jersey, 07503
Cancer Center at Saint Joseph's
Phoenix, Arizona, 85004
Marshfield Medical Center-Rice Lake
Rice Lake, Wisconsin, 54868
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, 23298
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, 55416
United Hospital
Saint Paul, Minnesota, 55102
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
Saint John's Cancer Institute
Santa Monica, California, 90404
Guthrie Medical Group PC-Robert Packer Hospital
Sayre, Pennsylvania, 18840
Community Medical Center
Scranton, Pennsylvania, 18510
FHCC South Lake Union
Seattle, Washington, 98109
Fred Hutchinson Cancer Center
Seattle, Washington, 98109
University of Washington Medical Center - Montlake
Seattle, Washington, 98195
Baptist Memorial Hospital and Cancer Center-Desoto
Southhaven, Mississippi, 38671
CoxHealth South Hospital
Springfield, Missouri, 65807
Mercy Hospital South
St Louis, Missouri, 63128
Marshfield Medical Center-River Region at Stevens Point
Stevens Point, Wisconsin, 54482
Montefiore Medical Center-Einstein Campus
The Bronx, New York, 10461
Saint Luke's Cancer Institute - Twin Falls
Twin Falls, Idaho, 83301
Carle Cancer Center
Urbana, Illinois, 61801
Inspira Medical Center Vineland
Vineland, New Jersey, 08360
MD Anderson Cancer Center at Cooper-Voorhees
Voorhees Township, New Jersey, 08043
Northwestern Medicine Cancer Center Warrenville
Warrenville, Illinois, 60555
Sibley Memorial Hospital
Washington D.C., District of Columbia, 20016
Aurora West Allis Medical Center
West Allis, Wisconsin, 53227
Chester County Hospital
West Chester, Pennsylvania, 19380
Marshfield Medical Center - Weston
Weston, Wisconsin, 54476
Geisinger Wyoming Valley/Henry Cancer Center
Wilkes-Barre, Pennsylvania, 18711
Marshfield Clinic - Wisconsin Rapids Center
Wisconsin Rapids, Wisconsin, 54494
Minnesota Oncology Hematology PA-Woodbury
Woodbury, Minnesota, 55125
Lankenau Medical Center
Wynnewood, Pennsylvania, 19096
Puerto Rico5 sites
Cancer Center-Metro Medical Center Bayamon
Bayamón, 00959-5060
Doctors Cancer Center
Manati, 00674
San Juan Community Oncology Group
San Juan, 00917
Centro Comprensivo de Cancer de UPR
San Juan, 00927
San Juan City Hospital
San Juan, 00936
About this study
Official title: Interim FDG-PET/CT for PreDIcting REsponse of HER2+ Breast Cancer to Neoadjuvant Therapy: DIRECT Trial
This phase II trial tests how well an imaging procedure called fludeoxyglucose F-18 (FDG) positron emission tomography/computed tomography (PET/CT) works in predicting response to standard of care chemotherapy prior to surgery in patients with HER2-positive stage IIa-IIIc breast cancer. FDG is a radioactive tracer that is given in a vein before PET/CT imaging and helps to identify areas of active cancer. PET and CT are imaging techniques that make detailed, computerized pictures of areas inside the body. The use of FDG-PET/CT may help doctors better decide if a patient needs more or less treatment before surgery in order to get the best response. This study evaluates whether FDG-PET/CT is useful in predicting a patient's response to standard of care chemotherapy.
Read the detailed description
PRIMARY OBJECTIVE:
- To estimate the negative predictive value (NPV) of neoadjuvant interim (ni)FDG-PET/CT for pathologic complete response (pCR), using delta maximum standardized uptake value corrected for lean body mass day 15 (deltaSULmaxD15), completed through central review, of the primary breast cancer at a threshold of 40%, in patients treated with neoadjuvant HER2-directed therapy.
SECONDARY OBJECTIVES:
- To estimate the sensitivity, specificity, and positive predictive value (PPV) of niFDG-PET/CT for pCR, using deltaSULmaxD15 of the primary breast cancer at a threshold of 40%, in patients treated with neoadjuvant HER2-directed therapy.
II. To evaluate the performance of niFDG-PET/CT, using deltaSULmaxD15 of the primary breast cancer at a threshold of 40%, as a predictor of 3-year event-free survival (EFS) from time of study registration.
EXPLORATORY OBJECTIVES:
- To estimate the NPV of niFDG-PET/CT for pCR, using deltaSULmaxD15 of the primary breast cancer at a grid of alternative thresholds ranging from 30% to 60%, in patients treated with neoadjuvant HER2-directed therapy.
II. To compare deltaSULmaxD15 using automated image analysis of FDG-PET/CT by AutoPERCIST (trademark) to standard PET analysis software.
OUTLINE:
Patients receive FDG intravenously (IV), undergo PET/CT, receive standard of care chemotherapy, and undergo standard of care surgery on study.
- Conditions
- Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, HER2-Positive Breast Carcinoma, Invasive Breast Carcinoma
- Being tested
- Chemotherapy, Computed Tomography, Fludeoxyglucose F-18, Positron Emission Tomography, Surgical Procedure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ChemotherapyDrug
Also called Chemo, Chemotherapy (NOS), Chemotherapy, Cancer, General
Receive standard of care chemotherapy
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo PET/CT
Fludeoxyglucose F-18Other
Also called 18FDG, FDG, Fludeoxyglucose (18F), fludeoxyglucose F 18
Given IV
Positron Emission TomographyProcedure or surgery
Also called Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron Emission Tomography Scan
Undergo PET/CT
Surgical ProcedureProcedure or surgery
Also called Operation, Surgery, Surgery Type, Surgical
Undergo standard of care surgery
| Study group | Role | What they receive |
|---|---|---|
| Diagnostic (FDG-PET/CT scan) | Experimental | Patients receive FDG IV, undergo PET/CT, receive standard of care chemotherapy, and undergo standard of care surgery on study. Receives: Drug: Chemotherapy; Procedure: Computed Tomography; Other: Fludeoxyglucose F-18; Procedure: Positron Emission Tomography; Procedure: Surgical Procedure |
What is being measured
The primary outcome is the main question the study is designed to answer.
Negative predictive value of neoadjuvant interim (ni) fludeoxyglucose F-18 (FDG) positron emission tomography/computed tomography (PET/CT) for pathologic complete response (pCR)
The analysis set for this objective will comprise all patients who enrolled in the study and had a FDG-PET/CT scan at T0 and T1 timepoint. The negative predictive value is defined as the probability that pCR will not be achieved by study participants who experience a using delta maximum standardized uptake value corrected for lean body mass day 15 (deltaSULmaxD15) below 40% and will be estimated via an exact, two-sided 95% confidence interval.
Measured: Up to 5 years
Secondary outcomes (4)
Sensitivity of niFDG-PET/CT for pCR
The analysis set for this objective will be the same as for the primary objective. The estimation approach will also be similar.
Measured: Up to 5 years
Specificity of niFDG-PET/CT for pCR
The analysis set for this objective will be the same as for the primary objective. The estimation approach will also be similar.
Measured: Up to 5 years
Positive predictive value of niFDG-PET/CT for pCR
The analysis set for this objective will be the same as for the primary objective. The estimation approach will also be similar.
Measured: Up to 5 years
Performance of niFDG-PET/CT as predictor of 3-year event-free survival
Using deltaSULmaxD15 of the primary breast cancer at a threshold of 40%. The analysis set for this objective will be the same as for the primary objective. The analysis will compare estimates of 3-year event-free survival between participants with deltaSULmaxD15 above and below the 40% threshold using a log-rank test.
Measured: Up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2023
- Study start10 May 2023
- Primary completion31 May 2027 (estimated)
- Study completion31 Dec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Anatomic Stage II Breast Cancer AJCC v8Studies of the same condition, open and under way.
- More trials run by ECOG-ACRIN Cancer Research GroupThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 235 participants (estimated)
Sponsor and investigators
- Lead sponsor
- ECOG-ACRIN Cancer Research Group
- Sponsor type
- Research network
- Responsible party
- Sponsor
- Investigators
- Heather Jacene, Principal investigator, ECOG-ACRIN Cancer Research Group
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05710328
- Sponsor's protocol ID
- EA1211
- Other IDs
- NCI-2022-10172, EA1211, EA1211, U10CA180820
- Status last verified
- Oct 2026
- First submitted
- 24 Jan 2023
- Last updated
- 19 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Hennessy MA, Gatsonis C, Jacene H, Connolly RM, Burnette BL, Stringer-Reasor EM, Romanoff J, Taurone A, O'Sullivan CC, Le-Petross HT, Stearns V, Fowler AM, Tang SC, Sepulveda KA, DeMichele AM, Mankoff DA, Wolff AC. EA1211: interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy (DIRECT trial). Future Oncol. 2025 Nov;21(26):3377-3384. doi: 10.1080/14796694.2025.2567840. Epub 2025 Oct 5.
PubMed 41047708