Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia (TAM-01)

This study is currently recruiting participants.
Verified October 2013 by Ente Ospedaliero Ospedali Galliera
Sponsor:
Collaborators:
Associazione Italiana per la Ricerca sul Cancro
European Institute of Oncology
Information provided by (Responsible Party):
Andrea DeCensi, Ente Ospedaliero Ospedali Galliera
ClinicalTrials.gov Identifier:
NCT01357772
First received: May 17, 2011
Last updated: October 14, 2013
Last verified: October 2013
  Purpose

The long-lasting phase of precursors of invasive cancer, i.e. dysplasia or intraepithelial neoplasia (IEN), is particularly relevant among risk determinants. At present, about 15-20% of all breast cancers are diagnosed in a non-invasive phase. Despite their good prognosis, women with breast IEN (lobular and ductal intraepithelial neoplasia, LIN and DIN) have a 10-15/1000 annual risk of invasive disease (8-10 times the same age general population), and thus represent an important target for chemoprevention. In the National Surgical Adjuvant Breast and Bowel Project (NSABP-P1 trial), tamoxifen use at 20 mg/day was associated with a 86% reduction of invasive breast cancer in women with previous atypical ductal hyperplasia (ADH) (RR=0.14, 95% IC, 0.03-0.47) and with a 56% risk reduction in women with previous Lobular Carcinoma in situ (LCIS) (RR=0.44, 95% IC, 0.16-1.06). However, tamoxifen use in this setting is hampered by serious adverse events attributable to its partial estrogenic activity, such as increased risk of endometrial cancer and of venous thromboembolism, which have significantly limited its broad use in chemoprevention.

To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed. Recent trials from our group have shown that the dose can be reduced up to 1 mg/day with no loss of tamoxifen antiproliferative activity on breast cancer. By contrast, a dose of 5 mg/day does not increase endometrial proliferation and is associated with a decrease of the estrogenic activity of tamoxifen on insulin like growth factor (IGF-I), sex hormone-binding globulin (SHBG) and antithrombin-III, with a potential decrease of venous thromboembolic events. Moreover, tamoxifen exhibits a high tissue distribution, so that a dose of 5 mg/day attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro. The promising clinical activity of 5 mg/day of tamoxifen is supported by an ongoing 2x2 phase IIb trial of low-dose tamoxifen and fenretinide in premenopausal women, where tamoxifen lowers breast cancer events compared with placebo. The cytochromeP450 2D6 (CYP2D6) enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of tamoxifen. The single nucleotide polymorphism (SNP) CYP2D6*4 (1846G>A) allele accounts for 75% of CYP2D6 poor metabolizer phenotype and poor metabolizers showed a trend to a higher risk to develop a breast event compared to wildtype.


Condition Intervention Phase
Intraepithelial Carcinoma
Drug: Tamoxifen
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: Randomized Placebo-controlled Phase III Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia

Resource links provided by NLM:


Further study details as provided by Ente Ospedaliero Ospedali Galliera:

Primary Outcome Measures:
  • Incidence of invasive breast cancer [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    The Primary endpoint of the proposed trial is to assess if tamoxifen at a low dose, 5mg/d reduces the incidence of invasive breast cancer and ductal carcinoma in situ (DIN 1c, 2, 3) of the breast, in woman operated for lobular intraepithelial neoplasia (LIN1, 2 and 3) or ER-positive ductal intraepithelial neoplasia (DIN 1b, DIN2, DIN3, 1a excluded) of the breast.


Secondary Outcome Measures:
  • Incidence of other non-invasive breast disorders [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    The secondary endpoint will evaluate the incidence of other non-invasive breast disorders (i.e., LIN, ductal atypical hyperplasia), endometrial cancer, clinical bone fractures, cardiovascular events, venous thromboembolic events, and clinically manifest cataract and overall mortality.

  • To determine CYP2D6 genotype [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]
    To determine whether CYP2D6 genotype and blood concentrations of drug and metabolites can explain tamoxifen modulation of surrogate biomarkers tamoxifen efficacy and safety, including circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes, tamoxifen efficacy and toxicity on clinical events.


Estimated Enrollment: 1400
Study Start Date: November 2008
Estimated Study Completion Date: November 2017
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tamoxifen
tamoxifen at daily dose of 5 mg for a total treatment time of 3 years
Drug: Tamoxifen
at daily dose of 5 mg for a total treatment time of 3 years
Placebo Comparator: placebo
placebo at daily dose of 5 mg for a total treatment time of 3 years
Drug: placebo
placebo at daily dose of 5 mg for a total treatment time of 3 years

Detailed Description:

The time interval between Study Start Date (November 2008) and Study First Release (May 17, 2011) was related to bureaucratic problems.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Women of age < 75 years
  • Women operated on for lobular (LIN 2 and 3) or ER positive or unknown ductal (DIN 1-3, excluded DIN 1a) intraepithelial neoplasia. Both incident (diagnosis within 12 months) and prevalent cases (diagnosis between previous 12 and 60 months) will be included, upon stratification.
  • Written informed consent

Exclusion Criteria:

  • Any type of malignancy, with the exclusion of non-melanoma skin cancer;
  • Active proliferative disorders of the endometrium such as atypical hyperplasia, history of active endometriosis, unresected polyps;
  • Alterations of metabolic, liver, renal and cardiac grade 2 function (NCI criteria grade 2 or higher);
  • Any type of retinal disorders or severe cataract;
  • Presence of significant risk factors for venous events, including immobilization within the last 3 months for longer than 2 weeks following surgery or trauma, deep venous thrombophlebitis or other significant venous thrombotic event (VTE) (pulmonary embolism, stroke, etc.);
  • Use of tamoxifen, raloxifene or other selective estrogen receptor modulator (SERMs) within the last 4 weeks;
  • Anticoagulant therapy in progress (heparin or dicoumarol);
  • Active infections;
  • Severe psychiatric disorders or inability to comply to the protocol procedures.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01357772

Locations
Italy
E.O. Ospedali Galliera Recruiting
Genoa, Italy, 16128
Contact: Andrea U De Censi, MD    0039 563 ext 4501    andrea.decensi@galliera.it   
Sub-Investigator: Silvia Zanardi, MD         
Sub-Investigator: Mauro D'Amico, MD         
Sub-Investigator: Alessandra Gennari, MD         
Sponsors and Collaborators
Andrea DeCensi
Associazione Italiana per la Ricerca sul Cancro
European Institute of Oncology
Investigators
Principal Investigator: Andrea De Censi, MD E.O.Ospedali Galliera
  More Information

No publications provided

Responsible Party: Andrea DeCensi, Medical Oncology Director, Ente Ospedaliero Ospedali Galliera
ClinicalTrials.gov Identifier: NCT01357772     History of Changes
Other Study ID Numbers: GAL 01
Study First Received: May 17, 2011
Last Updated: October 14, 2013
Health Authority: Italy: The Italian Medicines Agency

Additional relevant MeSH terms:
Neoplasms
Carcinoma
Carcinoma in Situ
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Tamoxifen
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Bone Density Conservation Agents
Estrogen Antagonists

ClinicalTrials.gov processed this record on April 17, 2014