Testing the Role of FDG-PET/CT to Predict Response to Therapy Prior to Surgery for HER2-positive Breast Cancer, The DIRECT Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVE: I. 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: I. 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: I. 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.

Official Title
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Interim FDG-PET/CT for PreDIcting REsponse of HER2+ Breast Cancer to Neoadjuvant Therapy: DIRECT Trial

Conditions
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Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, HER2-Positive Breast Carcinoma, Invasive Breast Carcinoma

Intervention / Treatment
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* Drug: Chemotherapy
* Procedure: Computed Tomography
* Other: Fludeoxyglucose F-18
* Procedure: Positron Emission Tomography
* Procedure: Surgical Procedure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diagnostic (FDG-PET/CT scan)<br>Patients receive FDG IV, undergo PET/CT, receive standard of care chemotherapy, and undergo standard of care surgery on study. | Drug: Chemotherapy<br>* Receive standard of care chemotherapy<br>* Other names: Chemotherapy, Cancer, General;Procedure: Computed Tomography<br>* Undergo PET/CT<br>* Other names: tomography;Other: Fludeoxyglucose F-18<br>* Given IV<br>* Other names: Fluorodeoxyglucose F18;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;Procedure: Surgical Procedure<br>* Undergo standard of care surgery<br>* Other names: Type of Surgery;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | Up to 5 years |