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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01357772
Recruitment Status : Active, not recruiting
First Posted : May 23, 2011
Last Update Posted : February 15, 2019
Associazione Italiana per la Ricerca sul Cancro
European Institute of Oncology
Information provided by (Responsible Party):
Andrea DeCensi, Ente Ospedaliero Ospedali Galliera

Brief Summary:

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 or disease Intervention/treatment Phase
Intraepithelial Carcinoma Drug: Tamoxifen Drug: placebo Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: Randomized Placebo-controlled Phase III Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia
Study Start Date : November 2008
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Incidence of invasive breast cancer [ Time Frame: 36 months ]
    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 :
  1. Incidence of other non-invasive breast disorders [ Time Frame: 36 months ]
    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.

  2. To determine CYP2D6 genotype [ Time Frame: 36 months ]
    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.

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

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 identifier (NCT number): NCT01357772

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Istituto Scientifico Romagnolo per lo studio e la cura dei tumori
Meldola, Forlì-Cesena, Italy, 47521
Ospedale di Carpi "Bernardino Ramazzini"
Carpi, Modena, Italy, 41012
IRCCS Ospedale Oncologico di Bari - Istituto tumori "G. Paolo II"
Bari, Italy, 70124
Fondazione per la ricerca e la Cura dei Tumori "T. Campanella"
Catanzaro, Italy, 88100
E.O. Ospedali Galliera
Genoa, Italy, 16128
AOU IRCSS San Martino - IST
Genova, Italy, 16100
Istituto Europeo di Oncologia
Milano, Italy, 20100
A. O. Universitaria Policlinico di Modena
Modena, Italy, 41100
Istituto nazionale per lo studio e la cura dei tumori, IRCCS "Fondazione Pascale"
Napoli, Italy, 80131
Fondazione Salvatore Maugeri
Pavia, Italy, 27100
Ospedale Santa Maria delle Croci
Ravenna, Italy, 48018
A.O. Universitaria S. Giovanni Battista - "Le Molinette"
Torino, Italy, 10123
Presidio Ospedaliero "SS. Antonio e Margherita"
Tortona, Italy, 15057
Ospedale di Circolo e Fondazione Macchi
Varese, Italy, 21100
A.O. Vicenza
Vicenza, Italy, 36100
Sponsors and Collaborators
Andrea DeCensi
Associazione Italiana per la Ricerca sul Cancro
European Institute of Oncology
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Principal Investigator: Andrea De Censi, MD E.O.Ospedali Galliera
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Andrea DeCensi, Medical Oncology Director, Ente Ospedaliero Ospedali Galliera Identifier: NCT01357772    
Other Study ID Numbers: GAL 01
First Posted: May 23, 2011    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Additional relevant MeSH terms:
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Carcinoma in Situ
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents