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

Study Description

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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.

Study Design

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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

Arms and Interventions

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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

Outcome Measures

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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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Senior)
Sexes 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

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Locations

Italy
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

Investigators

Principal Investigator:	Andrea De Censi, MD	E.O.Ospedali Galliera

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Andrea DeCensi, Medical Oncology Director, Ente Ospedaliero Ospedali Galliera
ClinicalTrials.gov Identifier:	NCT01357772 History of Changes
Other Study ID Numbers:	GAL 01
First Posted:	May 23, 2011
Last Update Posted:	August 4, 2015
Last Verified:	August 2015

Additional relevant MeSH terms:

Carcinoma in Situ; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Tamoxifen; 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