4-Hydroxytamoxifen or Tamoxifen Citrate in Treating Women With Newly Diagnosed Ductal Breast Carcinoma in Situ
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|ClinicalTrials.gov Identifier: NCT00952731|
Recruitment Status : Completed
First Posted : August 6, 2009
Results First Posted : July 21, 2015
Last Update Posted : July 21, 2015
|Condition or disease||Intervention/treatment||Phase|
|Ductal Breast Carcinoma in Situ Estrogen Receptor-positive Breast Cancer||Drug: oral placebo Drug: afimoxifene Drug: tamoxifen citrate Drug: placebo gel||Phase 2|
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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.  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 application, BESS questionnaire (symptom assessment) and blood draw for clinical and research labs including plasma estradiol, progesterone and FSH (rushed), CBC, chemistry profile, liver and renal function tests, Factor VIII, von Willebrand Factor, Factor IX, and total protein S, plasma for insulin-like growth factor (IGF-1) and sex hormone-binding globulin (SHBG), and DNA extraction for assessment of polymorphisms in tamoxifen metabolism genes. At Northwestern plasma and RNA from blood will be collected pre- and post-treatment and will be stored for future proteomic and gene expression fingerprinting
No run-in period is planned. The intervention phase will begin within 5 days following randomization and end on the day prior to surgical resection. The 4-OHT group will apply active gel 2 mg daily to each breast for 4-10 weeks and take oral placebo. The TAM group will take 20 mg TAM orally daily and apply gel placebo. The last dose of study medication will be used on the morning of the day prior to surgery.
Participants will be shipped two 100 ml canisters of 4-OHT or placebo gel plus 130 capsules of tamoxifen or oral placebo at the time of randomization. Participants will take study agents for 4-10 week (minimum). However, if surgery needs to be delayed beyond the 8 week study period for clinical reasons (eg scheduling with plastic surgery) the participant will be sent additional medication by mail to allow continuation of therapy until the day before surgery up to a maximum duration of 10 weeks.
On the day prior to surgery, baseline assessments will be repeated (with the exception of menopausal determination and tamoxifen metabolism gene polymorphisms, but with the addition of blood draw for tamoxifen metabolites and E and Z 4-OHT isomer determination). Under unavoidable circumstances, the end of intervention visit will be allowed on the day of surgery prior to TSE. During the TSE breast adipose tissue from the surgical sample will be snap frozen and stored at -800C for measurement of TAM metabolites. The paraffin block of the DCNB and TSE samples will be acquired by the recruiting institution and 10 sections from each specimen submitted to the NU Pathology Core Facility (NU PCF). The sections will be cut in batches (with pre- and post-samples in the same batch), shipped cold, and processed for immunohistochemistry within a week of sectioning.
Compliance assessment will occur through patient diaries, pill counts and the weighing of returned drug (gel) canisters.
Patients will be assessed for adverse events at the post-surgical visit (approximately 7-14 days after surgery) and by phone at 30 days following the last dose of study agent.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||27 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Investigator)|
|Official Title:||Pre-surgical Phase IIb Trial of Transdermal 4-Hydroxytamoxifen vs. Oral Tamoxifen in Women With Ductal Carcinoma in Situ of the Breast|
|Study Start Date :||December 2009|
|Actual Primary Completion Date :||September 2011|
Experimental: oral placebo, afimoxifene
4-hydroxytamoxifen gel 2mg/breast applied daily. Oral placebo taken daily.
Drug: oral placebo
Oral placebo taken daily for 4-10 weeks.
Other Name: PLCB
2mg/breast applied daily in the form of a gel for 4-10 weeks.
Active Comparator: tamoxifen citrate, placebo gel)
Placebo gel applied to the breasts daily. 20mg oral tamoxifen taken daily (taken as two (2) 10mg capsules).
Drug: tamoxifen citrate
20mg oral tamoxifen taken daily (taken as two (2) 10mg capsules) for 4-10 weeks.
Drug: placebo gel
Placebo gel applied to breasts daily for 4-10 weeks.
Other Name: PLCB
- 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 ]Ki-67 was measured in matched core and excision tissue samples containing DCIS (Ductal Carcinoma In-Situ) lesions, the core sample was at baseline while the excision sample was at surgery (after approximately 4-10 weeks of treatment).
- 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.
- Compare Concentrations of Tamoxifen and Its Metabolites (4-hydroxytamoxifen, Endoxifen, N-desmethyl Tamoxifen (NDT)) Obtained From Samples on the Day of Surgery [ Time Frame: Day of surgery (after approximately 4-10 weeks) ]Concentrations of tamoxifen and its metabolites: 4-hydroxytamoxifen, endoxifen, and NDT were measured in breast tissue, blood, and Nipple Aspirate Fluid (NAF) that was collected on the day of surgery.
- Drug Metabolite Levels in the Two Study Groups by CYP2D6 Polymorphism Status [ Time Frame: 28-70 days ]Descriptive statistics and confidence intervals will be provided.
- 4-OHT Affects Known Tamoxifen-modulated Pathways [ Time Frame: 28-70 days ]Descriptive statistics and confidence intervals will be provided.
- TAM Metabolite Concentrations and Estrogen Response Markers in Nipple Aspiration Fluid (NAF) [ Time Frame: 28-70 days ]Descriptive statistics and confidence intervals will be provided.
- E and Z 4-OHT Isomers [ Time Frame: 28-70 days ]Descriptive statistics and confidence intervals will be provided.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00952731
|United States, Illinois|
|Chicago, Illinois, United States, 60611|
|Principal Investigator:||Seema Khan||Northwestern University|