Clinical Trial: 4-Hydroxytamoxifen or Tamoxifen Citrate in Treating Women With Newly Diagnosed Ductal Breast Carcinoma in Situ

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Pre-surgical Phase IIb Trial of Transdermal 4-Hydroxytamoxifen vs. Oral Tamoxifen in Women With Ductal Carcinoma in Situ of the Breast

Brief Summary: This randomized phase II trial is studying 4-hydroxytamoxifen to see how well it works compared with tamoxifen citrate in treating women with newly diagnosed ductal breast carcinoma in situ. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the use of estrogen by the tumor cells. It is not yet known whether topical tamoxifen causes less damage to normal tissue than systemic tamoxifen in treating patients with ductal carcinoma in situ.

Detailed Summary:

This is a randomized, double-blind, placebo-controlled presurgical trial of 0.228% 4-hydroxy-tamoxifen (4-OHT) gel vs. oral tamoxifen (TAM) 20 mg daily. The study population will consist of 112 pre- and postmenopausal women with any grade DCIS, ER positive, non-palpable DCIS with no evidence of invasion found on diagnostic core needle biopsy (DCNB). In order to accrue a total of 112 participants with DCIS over a period of 22 months, 20 eligible participants total will be screened at the three participating institutions per month with a planned average monthly recruitment of 5 participants total per month. We assume that 22 women (20% of the recruited population, 11 women per arm) will be inevaluable because of the presence of unanticipated invasive disease in the therapeutic surgical excisional (TSE) specimen, or the absence of residual DCIS in the TSE, so that a total of 90 women (45 per arm) will be evaluable for the study endpoints. These estimates are based on numbers from the Lynn Sage Database of NU: over the six-year period 2000-2005, the fraction of women diagnosed with DCIS on core needle biopsy who were found to have no residual DCIS in the TSE was 2.5% and that of women with invasive disease (T1a or greater) in the TSE when the DCNB showed pure DCIS was 13.3%, very similar to the data reported by Bonnett et. al. [56] who found that 13% of pure DCIS lesions seen on DCNB (29/122) were in fact invasive in the TSE. With regard to racial/ethnic groups, 25.6% of the DCIS population at NU were of non-European ancestry (18% African, 4% Hispanic, 3.5% other). WU has higher fractions of African American women with DCIS (24% and 21% respectively).

The participants will be consented following diagnostic core needle biopsy at the time of initial surgical consultation. Baseline assessments include medical history, nipple aspirate fluid (NAF) collection, explanation of gel ap
Sponsor: Northwestern University

Current Primary Outcome: Difference Between Ki-67 Labeling Index in Tissue Samples Taken at Baseline and Post-treatment [ Time Frame: Baseline and after 4-10 weeks of treatment ]

Original Primary Outcome: Demonstration that once daily topical 4-hydroxytamoxifen (4-OHT) gel application results in a reduction in the Ki-67 labeling index of ductal carcinoma in situ lesions that is not inferior to that seen with oral tamoxifen

Current Secondary Outcome:

• Difference in Mean Score for Vasomotor Symptoms Including Hot Flashes From Baseline to Time of Surgery [ Time Frame: Baseline and after 4-10 weeks of treatment ]
  Hot flashes were assessed by the Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire. This questionnaire measures the incidence of a number of symptoms by asking participants how frequently they experienced them on a scale of 0-4 (0 being Not at All and 4 being Extremely often). BESS questionnaire was administered at baseline and time of surgery. The incidence of vasomotor symptoms (including hot flashes, night sweats, and cold sweats) was measured at baseline (Day 0) and end of treatment prior to surgery (at least 4 weeks later or up to 10 weeks, depending on scheduled surgery date), and changes in the mean score for hot flashes were observed.
• Difference in vWF Coagulation Protein in Blood Collected at Baseline and Just Prior to Surgery [ Time Frame: Baseline to immediately before surgery (after approximately 4-10 weeks) ]
  The difference between vWF coagulation protein in blood samples collected at baseline and before surgery were measured using the immune-turbidimetric assay.
• Difference in Factor VIII Coagulation Protein in Blood Collected at Baseline and Just Prior to Surgery [ Time Frame: Baseline and immediately before surgery (after approximately 4-10 weeks) ]
  The difference between Factor VIII coagulation protein in blood samples collected at baseline and before surgery was measured with VisuLize antigen ELISA Kits.
• Difference in Factor IX Coagulation Protein in Blood Collected at Baseline and Just Prior to Surgery [ Time Frame: Baseline and immediately before surgery (after approximately 4-10 weeks) ]
  The difference between Factor IX coagulation protein in blood samples collected at baseline and before surgery was measured with VisuLize antigen ELISA Kits.
• Difference in Protein S Coagulation Protein in Blood Collected at Baseline and Just Prior to Surgery [ Time Frame: Baseline and immediately before surgery (after approximately 4-10 weeks) ]
  The difference between protein S coagulation protein in blood samples collected at baseline and before surgery was measured using an ELISA Kit.

Original Secondary Outcome:

• Comparison of concentrations of 4-OHT, endoxifen, tamoxifen citrate, its bisphenol metabolite, and estradiol in breast tissue and plasma at the time of surgery
• CYP2D6 polymorphism status and comparison of drug metabolite levels by polymorphism status
• Affect of 4-OHT on known tamoxifen-modulated pathways in the breast and serum by IHC and plasma markers
• Tamoxifen metabolite concentrations and estrogen response markers in nipple aspiration fluid samples from affected and unaffected breast
• Comparison of incidence of hot flashes at baseline and before surgery
• Comparison of changes in coagulation related proteins
• Comparison of Z and E 4-OHT isomers in the plasma

Dates:
Date Received: August 4, 2009
Date Started: December 2009
Date Completion:
Last Updated: July 18, 2015
Last Verified: July 2015