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

• ClinicalTrials.gov Identifier: NCT01357772
• Recruitment Status: Active, not recruiting
• First Posted: May 23, 2011
• Last Update Posted: February 15, 2019
• Sponsor: Andrea DeCensi
• Collaborators: Associazione Italiana per la Ricerca sul Cancro; European Institute of Oncology
• Information provided by (Responsible Party): Andrea DeCensi, Ente Ospedaliero Ospedali Galliera

Study Description

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

• 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

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

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

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• 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

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

DeCensi A, Johansson H, Helland T, Puntoni M, Macis D, Aristarco V, Caviglia S, Webber TB, Briata IM, D'Amico M, Serrano D, Guerrieri-Gonzaga A, Bifulco E, Hustad S, Søiland H, Boni L, Bonanni B, Mellgren G. Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial. NPJ Breast Cancer. 2021 Mar 25;7(1):34. doi: 10.1038/s41523-021-00236-6.

DeCensi A, Puntoni M, Guerrieri-Gonzaga A, Caviglia S, Avino F, Cortesi L, Taverniti C, Pacquola MG, Falcini F, Gulisano M, Digennaro M, Cariello A, Cagossi K, Pinotti G, Lazzeroni M, Serrano D, Branchi D, Campora S, Petrera M, Buttiron Webber T, Boni L, Bonanni B. Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia. J Clin Oncol. 2019 Jul 1;37(19):1629-1637. doi: 10.1200/JCO.18.01779. Epub 2019 Apr 11.

• Responsible Party: Andrea DeCensi, Medical Oncology Director, Ente Ospedaliero Ospedali Galliera
• ClinicalTrials.gov Identifier: NCT01357772
• Other Study ID Numbers: GAL 01
• First Posted: May 23, 2011
• Last Update Posted: February 15, 2019
• Last Verified: February 2019

Additional relevant MeSH terms:

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