Radiation Therapy With or Without Trastuzumab in Treating Women With Ductal Carcinoma In Situ Who Have Undergone Lumpectomy

• ClinicalTrials.gov Identifier: NCT00769379
• Recruitment Status: Active, not recruiting
• First Posted: October 9, 2008
• Results First Posted: February 23, 2022
• Last Update Posted: May 16, 2023
• Sponsor: National Cancer Institute (NCI)
• Collaborator: NRG Oncology
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: October 8, 2008
• First Posted Date: October 9, 2008
• Results First Submitted Date: March 23, 2021
• Results First Posted Date: February 23, 2022
• Last Update Posted Date: May 16, 2023
• Actual Study Start Date: November 10, 2008
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 31, 2022)

Ipsilateral Invasive Breast Cancer, Ipsilateral Skin Cancer Recurrence, or Ipsilateral DCIS-Free Survival [ Time Frame: 5 years ]

Patients who are free from Ipsilateral Invasive Breast Cancer, Ipsilateral Skin Cancer Recurrence or Ipsilateral DCIS as estimated by (1- cumulative incidence) x 100%.

• Original Primary Outcome Measures (submitted: October 8, 2008): Time from randomization to ipsilateral invasive breast cancer, ipsilateral skin cancer recurrence, or ipsilateral ductal carcinoma in situ (DCIS)

Current Secondary Outcome Measures (submitted: January 31, 2022)

• Invasive or DCIS Disease-free Survival [ Time Frame: 5 years ]
  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 breast cancer, ipsilateral recurrence, and contralateral breast cancer will be compared across treatment arms using cumulative incidence functions. Percentage of patients by a Kaplan-Meier analysis who are free of invasive or DCIS disease
• Invasive or DCIS Recurrence-free Interval [ Time Frame: 5 years ]
  Cox proportional hazards models will be used to evaluate the effect of treatment on time to event. The distributions of time to event will be estimated by the Kaplan-Meier method for each treatment group and will be compared between treatments by simple and stratified log-rank tests. Compared across treatment arms using cumulative incidence functions.Percentage of patients who are invasive or DCIS recurrence free estimated by (1-cumulative incidence) x 100%.
• Invasive Regional or Distant-Free Recurrence [ Time Frame: 5 years ]
  Percentage of patients who are free of invasive regional or distant recurrence as estimated by (1 - cumulative incidence) x 100%.
• Contralateral Breast Cancer (Invasive or DCIS) - Free Survival [ Time Frame: 5 years ]
  Percentage of patients free of Contralateral Breast Cancer (Invasive or DCIS) as estimated by (1- cumulative incidence) x 100%.
• Overall Survival [ Time Frame: 5 years ]
  Percentage of patients surviving as estimated by a Kaplan-Meier
• Incidence of Post-treatment Amenorrhea in Women Who Were Premenopausal at the Time of Study Entry Premenopausal at the Time of Study Entry [ Time Frame: 18 months ]
  Proportion of patients who were pre-menopausal at randomization and who self-reported as not having menstrual periods afterwards

Original Secondary Outcome Measures (submitted: October 8, 2008)

• Invasive or DCIS disease-free survival as assessed by time to local recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral breast cancer, second primary cancer (other than squamous cell and b ...
• Time from randomization to first diagnosis of a local, regional or distant recurrence regardless of any intervening contralateral or other second primary cancer
• Time from randomization to first diagnosis of regional or distant recurrence
• Time from randomization to first diagnosis of contralateral invasive or DCIS breast cancer
• Time from randomization to death from any cause
• Incidence of post-treatment amenorrhea (absence of menstrual period for at least 12 months) at 18 months in women who were premenopausal at the time of study entry
• Correlation of cMYC-amplification status with trastuzumab (Herceptin®) in addition to radiotherapy
• Correlation of PI3 kinase gene mutation status with trastuzumab in addition to radiotherapy

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Radiation Therapy With or Without Trastuzumab in Treating Women With Ductal Carcinoma In Situ Who Have Undergone Lumpectomy
• Official 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
• Brief Summary: This randomized phase III trial studies radiation therapy to see how well it works with or without trastuzumab in treating women with ductal carcinoma in situ who have undergone lumpectomy. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether radiation therapy is more effective with or without trastuzumab in treating ductal carcinoma in situ.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the value of trastuzumab given during radiation therapy (RT) compared to RT alone in preventing subsequent occurrence of ipsilateral breast cancer recurrence, ipsilateral skin cancer recurrence, or ipsilateral ductal carcinoma in situ (IIBCR-SCR-DCIS) in women with human epidermal growth factor receptor 2 (HER2)-positive DCIS resected by lumpectomy.

SECONDARY OBJECTIVES:

I. Determine the value of trastuzumab given during RT compared to RT alone in prolonging invasive or DCIS disease-free survival (IDFS)-DCIS.

II. Determine the value of trastuzumab given during RT compared to RT alone in increasing invasive or DCIS recurrence-free interval.

III. Determine the value of trastuzumab given during RT compared to RT alone in improving regional or distant recurrence.

IV. Determine the value of trastuzumab given during RT compared to RT alone in improving the incidence of contralateral invasive or DCIS breast cancer.

V. Determine the value of trastuzumab given during RT compared to RT alone in improving survival.

VI. To explore the effect of trastuzumab on ovarian function.

TERTIARY OBJECTIVES:

I. To determine if the benefit of trastuzumab added to RT will be significantly higher in v-myc avian myelocytomatosis viral oncogene homolog (cMYC)-amplified tumors than in the cMYC non-amplified subset.

II. To determine if the benefit of trastuzumab added to RT will be less in tumors with mutations in the phosphatidylinositol 3 (PI3) kinase gene than in tumors without PI3 kinase gene mutations.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo standard whole breast irradiation (WBI) over 5-6 weeks.

ARM II: Patients receive trastuzumab intravenously (IV) over 30-90 minutes once in weeks 1 and 4. Patients also undergo WBI as in Arm I.

After completion of study treatment, patients are followed up every 6 months for 5 years and then every 12 months for 5 years.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Ductal Carcinoma In Situ

Intervention

• Other: Laboratory Biomarker Analysis
  Correlative studies
• Biological: Trastuzumab
  Given IV
  Other Names:

  • ABP 980
  • ALT02
  • Anti-c-ERB-2
  • Anti-c-erbB2 Monoclonal Antibody
  • Anti-ERB-2
  • Anti-erbB-2
  • Anti-erbB2 Monoclonal Antibody
  • Anti-HER2/c-erbB2 Monoclonal Antibody
  • Anti-p185-HER2
  • c-erb-2 Monoclonal Antibody
  • HER2 Monoclonal Antibody
  • Herceptin
  • Herceptin Biosimilar PF-05280014
  • Herceptin Trastuzumab Biosimilar PF-05280014
  • Herzuma
  • Kanjinti
  • MoAb HER2
  • Monoclonal Antibody c-erb-2
  • Monoclonal Antibody HER2
  • Ogivri
  • Ontruzant
  • PF-05280014
  • rhuMAb HER2
  • RO0452317
  • SB3
  • Trastuzumab Biosimilar ABP 980
  • Trastuzumab Biosimilar ALT02
  • trastuzumab biosimilar EG12014
  • Trastuzumab Biosimilar HLX02
  • Trastuzumab Biosimilar PF-05280014
  • Trastuzumab Biosimilar SB3
  • Trastuzumab Biosimilar SIBP-01
  • Trastuzumab-anns
  • Trastuzumab-dkst
  • Trastuzumab-dttb
  • Trastuzumab-pkrb
  • Trastuzumab-qyyp
  • Trazimera
• Radiation: Whole Breast Irradiation
  Undergo standard whole breast irradiation

Study Arms

• Experimental: Arm I (standard WBI)
  Patients undergo standard WBI over 5-6 weeks.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Radiation: Whole Breast Irradiation
• Experimental: Arm II (WBI, trastuzumab)
  Patients receive trastuzumab IV over 30-90 minutes once in weeks 1 and 4. Patients also undergo WBI as in Arm I.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Biological: Trastuzumab
  • Radiation: Whole Breast Irradiation

Publications *

• Cobleigh MA, Anderson SJ, Siziopikou KP, Arthur DW, Rabinovitch R, Julian TB, Parda DS, Seaward SA, Carter DL, Lyons JA, Dillmon MS, Magrinat GC, Kavadi VS, Zibelli AM, Tiriveedhi L, Hill ML, Melnik MK, Beriwal S, Mamounas EP, Wolmark N. Comparison of Radiation With or Without Concurrent Trastuzumab for HER2-Positive Ductal Carcinoma In Situ Resected by Lumpectomy: A Phase III Clinical Trial. J Clin Oncol. 2021 Jul 20;39(21):2367-2374. doi: 10.1200/JCO.20.02824. Epub 2021 Mar 19.
• Duggal S, Robin J, Julian TB. Ductal carcinoma in situ: an overview. Expert Rev Anticancer Ther. 2013 Aug;13(8):955-62. doi: 10.1586/14737140.2013.820557.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 29, 2020): 2014
• Original Estimated Enrollment (submitted: October 8, 2008): 2000
• Study Completion Date: Not Provided
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• The patient must have consented to participate and must have signed and dated an appropriate Institutional Review Board (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
• Patients must have an Eastern Cooperative Oncology Group (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
• 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., immunohistochemistry (IHC) or hematoxylin & eosin (H&E), pN0(mol-), or pN0(mol+); note: axillary staging is not required
• The interval between the last surgery for excision of DCIS (lumpectomy or re-excision of lumpectomy margins) and randomization must be no more than 120 days

Exclusion Criteria:

• 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 left ventricular (LV) function;
    • Documented congestive heart failure; or
    • Documented cardiomyopathy
• Uncontrolled hypertension, i.e., systolic blood pressure [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 child-bearing potential)
• Administration of any investigational agent within 30 days before study entry

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Korea, Republic of, Puerto Rico, United States

Administrative Information

• NCT Number: NCT00769379
• Other Study ID Numbers: NCI-2009-00702; NCI-2009-00702 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000615085; B-43; NSABP-B-43 ( Other Identifier: NRG Oncology ); NSABP-B-43 ( Other Identifier: CTEP ); U10CA012027 ( U.S. NIH Grant/Contract ); U10CA180868 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Not Provided
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: NSABP Foundation Inc
• Collaborators: NRG Oncology

Investigators

• Principal Investigator: Melody A Cobleigh; NRG Oncology

• PRS Account: National Cancer Institute (NCI)
• Verification Date: March 2023