Title A Phase III Clinical Trial Comparing Trastuzumab Given Concurrently with Radiation Therapy and Radiation Therapy Alone for Women with HER2-Positive Ductal Carcinoma In Situ Resected by Lumpectomy
IRB NSABP B43
Hospital Beachwood, Fairview, Hillcrest, Independence, Main Campus, North Coast Cancer, Strongsville, Wooster
Phase Phase 3
Primary aim and endpoint
- The primary aim is to determine the value of trastuzumab given during radiation therapy (RT) compared to RT alone in preventing the subsequent occurrence of ipsilateral breast cancer recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS (IIBCR-SCR-DCIS) in women with HER2-positive DCIS resected by lumpectomy.
- The primary endpoint is time from randomization to IIBCR-SCR-DCIS defined as ipsilateral invasive breast cancer, ipsilateral skin cancer recurrence, or ipsilateral DCIS. An IIBCR-SCR-DCIS event is defined as recurrent tumor in the ipsilateral breast parenchyma, skin of the ipsilateral breast or ipsilateral DCIS occurring after lumpectomy. In the determination of time to an IIBCR-SCR-DCIS, no statistical censoring will be performed with respect to any previous local, regional, distant recurrences or second primary cancers.
Secondary aims and endpoints
- Invasive or DCIS disease-free survival (IDFS-DCIS)
- Aim: Determine the value of trastuzumab given during RT compared to RT alone in prolonging IDFS-DCIS.
- Endpoint: Events for analysis of IDFS-DCIS include: local recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral breast cancer, second primary cancer (other than squamous and basal cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the colon and cervix), or death from any cause prior to recurrence or second primary cancer.
- Invasive or DCIS recurrence-free interval (IRFI-DCIS)
- Aim: Determine the value of trastuzumab given during RT compared to RT alone in increasing invasive or DCIS recurrence-free interval.
- Endpoint: Time from randomization to first diagnosis of a local, regional or distant recurrence regardless of any intervening contralateral or other second primary cancer.
- Invasive regional or distant recurrence
- Aim: Determine the value of trastuzumab given during RT compared to RT alone in improving regional or distant recurrence.
- Endpoint: Time from randomization to first diagnosis of regional or distant recurrence.
- Contralateral breast cancer (invasive or DCIS)
- Aim: Determine the value of trastuzumab given during RT compared to RT alone in improving the incidence of contralateral invasive or DCIS breast cancer.
- Endpoint: Time from randomization to first diagnosis of contralateral invasive or DCIS breast cancer.
- Overall survival (OS)
- Aim: Determine the value of trastuzumab given during RT compared to RT alone in improving survival.
- Endpoint: Time from randomization to death from any cause.
- Ovarian function
- Aim: To explore the effect of trastuzumab on ovarian function.
- Endpoint: The incidence of post-treatment amenorrhea in women who were premenopausal at the time of study entry. Post-treatment amenorrhea, defined as the absence of menstrual period for at least 12 months, will be assessed when the patient has been on study for 18 months.
- Correlative outcomes
- Aim: To determine if the benefit of trastuzumab added to RT will be significantly higher in cMYC-amplified tumors than in the cMYC nonamplified subset.
- Aim: To determine if the benefit of trastuzumab added to RT will be less in tumors with mutations in the PI3 Kinase gene than in tumors without PI3 Kinase gene mutations.
- The patient must have consented to participate and must have signed and dated an appropriate IRB-approved consent form that conforms to federal and institutional guidelines for the study treatment and for the pre-entry tumor block submission for HER2 testing and B-43 correlative studies (see Section 6.1).
- Patients must be female.
- Patients must be 18 years of age or older.
- Patients must have an ECOG performance status of 0 or 1 (0 = fully active, able to carry on all pre-disease performance without restriction; 1 = restricted in physically strenuous activity but ambulatory).
- On histologic examination, the tumor must be ductal carcinoma in situ (DCIS). (Patients with mixed DCIS and lobular carcinoma in situ [LCIS] are eligible.)
- The DCIS must be HER2-positive as determined by central testing (see Sections 6.1 and 6.2 for details).
- Estrogen and/or progesterone receptor status must be determined prior to randomization. (Patients with DCIS that is hormone receptor positive or negative are eligible.)
- All DCIS must have been resected by lumpectomy.
- The margins of the resected specimen must be histologically free of DCIS. For patients in whom pathologic examination demonstrates DCIS present at the line of resection, re-excision(s) may be performed to obtain clear margins. (Patients who require mastectomy are not eligible.)
- If axillary staging is performed, nodal staging must be pN0, pN0(i-), pN0(i+) which is defined as isolated tumor cells ≤ 0.2 mm, regardless of the method of detection, i.e., IHC or H&E, pN0(mol-), or pN0(mol+). Note: Axillary staging is not required. (Refer to AJCC Staging Criteria in the Treatment Trial Information section in the Members’ Area of the NSABP Web site for TNM nomenclature and staging information.)
- The interval between the last surgery for excision of DCIS (lumpectomy or reexcision of lumpectomy margins) and randomization must be no more than 120 days.
- Invasive (including microinvasion staged as T1mic) breast cancer. (Patients with DCIS suspicious for microinvasion, but not confirmed, are eligible.)
- Nodal staging of pN1 (including pN1mi). (Note: Axillary staging is not required.)
- DCIS present in more than one quadrant (multicentric).
- Masses or clusters of calcification that are clinically or mammographically suspicious unless biopsied and proven to be benign. (If DCIS is found, the patient is eligible if the DCIS was in the same quadrant of the ipsilateral breast and was resected with clear margins.)
- Contralateral breast cancer (including DCIS).
- Whole breast irradiation administered before randomization. (Partial breast irradiation is prohibited.)
- Prior history of breast cancer, including DCIS. (Patients with a history of LCIS are eligible.)
- Prior anthracycline chemotherapy for any malignancy.
- Cardiac disease that would preclude the use of the drugs included in the B-43 treatment regimens. This includes but is not confined to:
- Active cardiac disease:
- angina pectoris that requires the use of anti-anginal medication;
- ventricular arrhythmias except for benign premature ventricular contractions (PVCs) controlled by medication;
- conduction abnormality requiring a pacemaker;
- supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; and
- clinically significant valvular disease.
- History of cardiac disease:
- myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function;
- documented congestive heart failure; or
- documented cardiomyopathy.
- Active cardiac disease:
- Uncontrolled hypertension, i.e., systolic BP greater than 180 mm/Hg and/or diastolic BP greater than 100 mm/Hg. (Patients with hypertension that is well controlled on medication are eligible.)
- Other nonmalignant systemic disease that would preclude a patient from receiving trastuzumab or radiation therapy or would prevent prolonged follow-up.
- Other malignancies unless the patient is considered to be disease-free for 5 or more years prior to randomization and is deemed by her physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
- Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing according to institutional standards should be performed for women of childbearing potential.)
- Administration of any investigational agent within 30 days before study entry.