Letrozole in Treating Postmenopausal Women With Ductal Carcinoma in Situ

Breast Cancer Clinical Trial

Official title:

Phase II Study of Neoadjuvant Letrozole for Postmenopausal Women With Estrogen Receptor Positive Ductal Carcinoma In SITU (DCIS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01439711
• Other study ID #: CALGB-40903
• Secondary ID: CDR0000701992U10
• Status: Completed
• Phase: Phase 2
• First received: September 21, 2011
• Last updated: February 26, 2018
• Start date: February 2012
• Est. completion date: January 2018

Study information

• Verified date: February 2018
• Source: Alliance for Clinical Trials in Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells or by lowering the amount of estrogen the body makes.

PURPOSE: This phase II trial is studying how well letrozole works in treating women with ductal carcinoma in situ.

Description:

Treatment with letrozole begins within 21 days of registration, and only after notification has been received from the UCSF Breast MRI Research Laboratory that the baseline MRI is acceptable. Protocol therapy will consist of 6 months of letrozole, administered orally at a dose of 2.5 mg/day. Patients will have a MRI for disease evaluation at months 3 and 6. All patients will continue to take study drug until the day prior to surgery, whether at month 3 or at month 6 or may stop if they experience unacceptable toxicity. It is expected that decisions regarding any adjuvant treatment (eg, radiation and hormonal therapy) will be made individually based on the best practice guidelines, using informed and shared decision making between patient and provider. The primary and secondary objectives are provided below.

Primary objective:

1. To estimate the mean change in MRI tumor volume from pretreatment to completion of preoperative endocrine therapy in estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS), as well as to determine whether 3-month change in volume correlates with 6-month change.

Secondary objectives:

1. To assess radiographic-pathologic correlation between MRI findings and histopathology, including the prevalence of occult invasive cancer in patients undergoing neoadjuvant endocrine therapy for DCIS.

2. To compare changes in MRI maximum lesion diameter and mammographic extent at baseline and following treatment. These are two additional radiographic parameters which may also biological response to therapy.

3. To determine practice patterns of adjuvant hormonal and radiation therapy in patients who complete neoadjuvant letrozole therapy for DCIS.

4. To determine whether Ki67 is reduced with neoadjuvant letrozole treatment for DCIS, and to compare the reduction in proliferation between radiographic responders and non-responders.

5. To identify baseline IHC and expression biomarkers predictive of response to treatment, with response determined by extent of Ki67 reduction. Subsets showing the greatest reduction in Ki67 would be the most likely candidates for non-operative treatment in future studies.

6. To examine whether germline polymorphisms are associated with clinical endpoints, including treatment-related toxicity or efficacy outcomes, or with expression of biomarkers in serum or tumor.

7. To assess quality-of-life and musculoskeletal symptoms associated with neoadjuvant letrozole for ER positive DCIS.

Patients will be followed up to 6 months post-surgery.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 108
• Est. completion date: January 2018
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Eligibility Criteria:

1. Histologic documentation: Pathologic confirmation of ductal carcinoma in situ (DCIS) of the female breast without invasive cancer, with diagnosis rendered on core biopsy only, completed within 60 days before registration. Patients diagnosed with DCIS on the basis of surgical biopsy are not eligible for this study.

1. Patients with microinvasion on diagnostic core biopsy, defined as tumor = 1 mm in greatest dimension, will be allowed to participate.

2. All patients must have a clip placed, either at the time of the diagnostic biopsy or at the time of the baseline MRI prior to the start of treatment.

2. Tissue samples: Patient has diagnostic tissue available for correlative studies.

3. Clinical stage: Tis or T1mi N0, M0

4. Hormone receptor status: DCIS must express estrogen and/or progesterone receptor, as determined by immunohistochemical methods on the diagnostic pathology sample, according to the local institution's standard protocol. Greater than or equal to 1% cells will be considered to be positive.

5. Menopausal status: Patients must be postmenopausal defined as:

1. Age = 55 years and one year or more of amenorrhea

2. Age < 55 years and one year or more amenorrhea, with an estradiol assay < 20pg/ml

3. Surgical menopause with bilateral oophorectomy (at least 28 days must elapse from surgery to time of study registration)

The use of GnRH analogs to achieve post menopausal status is not allowed.

6. Prior treatment:

1. No prior surgical excision in the index breast for current DCIS diagnosis of DCIS

2. Any exogenous hormone therapy must be completed 4 weeks prior to registration

3. Any patients with a history of tamoxifen or raloxifene use within two years of current DCIS diagnosis are not eligible

4. No prior neoadjuvant/adjuvant therapy for current DCIS diagnosis

7. Contraindication to MRI: No contraindications to breast MRI

8. Measurable disease: Mammographic extent of calcifications must be accurately measurable in at least one dimension with each lesion = 1 cm and = 7 cm

1. DCIS must be visible on MRI based on central review.

2. Patients with palpable DCIS or adenopathy are not eligible to participate.

3. Patients with multifocal or bilateral disease are eligible.

9. History of osteoporosis: Women diagnosed with osteoporosis may participate in this trial provided they are receiving appropriate therapy or if they have declined therapy.

10. Age: Patients = 18 years of age

11. Performance Status: ECOG performance status 0 or 1

12. Pregnancy/nursing status: Not pregnant or nursing

13. Required Initial Laboratory Values:

1. ANC = 1,000/µL

2. Platelet count = 100,000/µL

3. Serum creatinine = 1.7 mg/dL

4. Bilirubin = 2.0 mg/dL

5. AST/ALT = 2.5 times upper limit of normal

6. Serum estradiol level assay < 20 pg/mL *Required for patients < 55 years of age and one year or more of amenorrhea

Related Conditions & MeSH terms

• Breast Cancer
• Carcinoma
• Carcinoma in Situ
• Carcinoma, Ductal
• Carcinoma, Intraductal, Noninfiltrating

Intervention

Drug:
• letrozole

Procedure:
• MRI

• conventional surgery

Locations

Country	Name	City	State
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Grant Medical Center	Columbus	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Exempla Saint Joseph Hospital	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	Saint Elizabeth Medical Center South	Edgewood	Kentucky
United States	Saint Elizabeth Fort Thomas	Fort Thomas	Kentucky
United States	Sentara Cancer Institute at Sentara CarePlex Hospital	Hampton	Virginia
United States	Margaret R Pardee Memorial Hospital	Hendersonville	North Carolina
United States	M. D. Anderson Cancer Center	Houston	Texas
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	Sparrow Hospital	Lansing	Michigan
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Regional Hematology and Oncology PA	Newark	Delaware
United States	Sentara Hospitals	Norfolk	Virginia
United States	Sentara Leigh Hospital	Norfolk	Virginia
United States	Bay Area Tumor Institute	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Northwest Hospital Center	Randallstown	Maryland
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	UCSF Medical Center-Mount Zion	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 3 (V3)	Mean total MRI FTV change from baseline to month 3 (V3): For patients with more than one measureable lesion on the MRI, the sum over all measureable lesions on the MRI was calculated at each time point. V3 was calculated by subtracting the total MRI FTV measured (i.e. the sum over all lesions present with MRI FTV measurements) at 3 months from the total MRI FTV measured at baseline. For V3 the raw change in the volume will be calculated for each patient and a mean and 95% confidence interval will be constructed using two-sided t-tests.	up to 3 months from start of treatment
Primary	Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 6 (V6)	Mean total MRI FTV change from baseline to month 6 (V6): For patients with more than one measureable lesion on the MRI, the sum over all measureable lesions on the MRI was calculated at each time point. V6 was calculated by subtracting the total MRI FTV measured at 6 months from the total MRI FTV measured at baseline. For V6 the raw change in the volume will be calculated for each patient and a mean and 95% confidence interval will be constructed using two-sided t-tests.	up to 6 months from start of treatment
Secondary	Mean Total MRI Tumor Diameter Change From Baseline to Month 3	To ascertain the change in maximum tumor diameter from baseline to 3 months (D3) the same methods as in Primary outcome #1 will be used but on diameter instead of volume. For patients with more than one lesion longest diameter measurement, the sum of all lesion longest diameter measurements was calculated.	3-months
Secondary	Change in Maximum Diameter at 6-months Based on Mammographic Measurement (MD6)	Change in maximum diameter at 6-months based on mammographic measurement (MD6) will be estimated using the methods in Primary Outcome #1, but using the mammographic measurements instead.	6-months
Secondary	Type of Primary Surgery (Mastectomy or Lumpectomy)	Rate of Mastectomy will be estimated as the number of mastectomies divided by the number of surgeries. A 95% confidence interval will be constructed using exact binomial methods. Rate of Lumpectomy will be estimated as the number of lumpectomies divided by the number of surgeries. A 95% confidence interval will be constructed using exact binomial methods.	up to 6 months
Secondary	Number of Re-excisions Required to Obtain Clear Margins		3-months and 6-months
Secondary	Extent of Residual DCIS Post Surgery		Up to 6 months post-surgery
Secondary	Presence of Invasive Cancer at Surgery		3-months and 6-months
Secondary	Size of Margins (Smallest) at Surgery		3-months and 6-months
Secondary	Incidence of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0	The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The percentage of patients with a maximum grade 3 or higher adverse event at least possibly related to the study treatment are reported below.	Up to 6 months post surgery
Secondary	Mean Total MRI Tumor Diameter Change From Baseline to Month 6	Mean total MRI tumor diameter change from baseline to month 6: To ascertain the change in maximum tumor diameter from baseline to 6 months (D6) the same methods as in Primary Outcome #2 will be used but on diameter instead of volume.	6 months
Secondary	Mean Total MRI Tumor Diameter Change From Baseline to Month 6	To ascertain the change in maximum tumor diameter from baseline to 6 months (D6) the same methods as in Primary outcome #2 will be used but on diameter instead of volume. For patients with more than one lesion longest diameter measurement, the sum of all lesion longest diameter measurements was calculated.	6 months