TAM-01: Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up

Sponsor

Andrea DeCensi (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01357772

Collaborator

Associazione Italiana per la Ricerca sul Cancro (Other), European Institute of Oncology (Other)

500

Enrollment

Locations

Arms

241.6

Duration (Months)

35.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of the study is to evaluate whether tamoxifen at a low dose of 5mg/d reduces in the long term the incidence of invasive breast cancer and ductal carcinoma in situ, DCIS (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.

To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed.

Biomarker trials revealed that 5 mg/d was noninferior to 20 mg/d in inhibiting proliferation of breast cancer and normal endometrial tissue.

By contrast, the risk of endometrial cancer si dose-dependent, and the dose reduction can lead a substantial decrease. Morover a dose of 5 mg/day is associated with an overall decrease of the estrogenic activity of tamoxifen on insulin like growth factor (IGF-I), sex hormone-binding globulin (SHBG) and antithrombin-III, with a 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.

A prospective cohort study also showed that 10 mg on alternate days halves recurrence of DCIS in postmenopausal women.

It has been shown that the treatment of dysplasia or pre-cancer drives the reduction of the invasive neoplasms onset. This is a chemoprevention trial designed to validatate the low-dose Tamoxifen in women with diseases at high evolutionary risk. The demonstration of efficacy and safety of such a treatment for the prevention of the invasive breast cancer would lead improvements in term of survival and quality of life for the patients at increased risk.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Intraductal, Noninfiltrating Recurrence, Local Neoplasm Breast Neoplasms Atypical Hyperplasia	Drug: Tamoxifen Drug: placebo	Phase 3

Detailed Description

Italian, multicenter, phase III trial: controlled, parallel group comparision, randomized (1:1) duble blind, tamoxifen 5 mg/d versus placebo administered for 3 years. A total of 500 women 75 years of age or younger with newly diagnosed non-invasive breast cancer have been included in the study. The long-term study implies a minimum 10 year follow up after treatment completion.

Study Design

Study Type:

Interventional

Actual Enrollment :

500 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 - Long Term Follow-up

Study Start Date :

Nov 12, 2008

Anticipated Primary Completion Date :

Dec 31, 2028

Anticipated Study Completion Date :

Dec 31, 2028

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 Other Names: Tamoxifen citrate (ATC code: L02BA01)
Placebo Comparator: placebo placebo at daily dose of 5 mg for a total treatment time of 3 years	Drug: placebo

Arm

Intervention/Treatment

Experimental: Tamoxifen

tamoxifen at daily dose of 5 mg for a total treatment time of 3 years

Drug: Tamoxifen

Other Names:

Tamoxifen citrate (ATC code: L02BA01)

Placebo Comparator: placebo

placebo at daily dose of 5 mg for a total treatment time of 3 years

Drug: placebo

Outcome Measures

Primary Outcome Measures

Number of invasive breast cancer events and DCIS [20 years]
Number of neoplastic events, i.e., invasive breast cancer or ductal carcinoma in situ of the breast from the start of treatment up to at least 16 years from treatment initiation.

Secondary Outcome Measures

Number of other non-invasive breast events [20 years]
Number of other non-invasive breast disorders (LCIS, atypical ductal or lobular hyperplasia), endometrial cancer, ovarian cancer, thromboembolic events; bone fractures, cardiovascular and thromboembolic events, clinically manifested cataracts and melanoma; change of mammographic density from the start of treatment up to at least 16 years from treatment initiation.
Metabolites of tamoxifen and hormone blood level (in a subgroup of women) [20 years]
Blood concentrations of metabolites including circulating IGF-I,IGFBP-3, SHBG, hormones (testosterone, estradiol, SHBG, CRP), tamoxifen metabolites (4OH tamoxifen and endoxifen).
CYP2D6 polymorphisms analysis [20 years]
Esploratory analisis of some SNPS of the cytochrome P450 genes involved in tamoxifen metabolism such as CYP2D6.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Women of age ≥ 18 and < 75 years
Women operated on for lobular (LIN 2 and 3) or ER positive or unknown ductal DCIS, i.e DIN 1-3, but DIN 1a excluded) intraepithelial neoplasia in the 5 years (60 months) prior the inclusion in the study. Both incident (diagnosis < 12 months) and prevalent cases diagnosis ≥12, and < 60 months) will be included, including recurrent cases
ECOG Performance status ≤ 1
Written informed consent

Exclusion Criteria:

Any type of malignancy, with the exclusion of non-melanoma skin cancer
Proliferative disorders of the endometrium such as atypical hyperplasia, endometriosis, unresected polyps, symptomatic myoma
Liver, kidney and heart function impairment grade ≥ 2 (CTCAE criteria v.3.0)
Any type of retinal disorders, severe cataract and glaucoma
Presence of significant risk factors for venous events, including immobilization after trauma within the last 3 months for longer than 2 weeks, 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)
Use of anastrozole and other aromatase inhibitors (AI) in the last 12 months for ≥ 6 months
Dicoumarol anticoagulant therapy in progress
Active infections
Severe psychiatric disorders or inability to comply to the protocol procedures
Geographic inaccessibility or difficulties in ensuring adequate compliance
Women who are pregnant or breastfeeding
Any other factor which, at the discretion of the investigator, may controindicate the use of tamoxifen

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedali riuniti ASL AL - Ospedale SS. Antonio e Margherita	Tortona	Alessandria	Italy	15057
2	Istituto Scientifico Romagnolo per lo studio e la cura dei tumori	Meldola	Forlì-Cesena	Italy	47521
3	Ospedale di Carpi "Bernardino Ramazzini"	Carpi	Modena	Italy	41012
4	IRCCS Istituto Tumori Giovanni Paolo II	Bari		Italy	70124
5	Azienda Ospedaliera Mater Domini Catanzaro	Catanzaro		Italy	88100
6	E.O. Ospedali Galliera	Genoa		Italy	16128
7	IEO - European Institute of Oncology IRCCS	Milan		Italy	20100
8	Azienda Ospedaliera-Universitaria Policlinico di Modena	Modena		Italy	41100
9	Istituto Nazionale Tumori IRCCS Fondazione G. Pascale	Napoli		Italy	80131
10	ICS Maugeri -Centro Medico di Pavia	Pavia		Italy
11	AUSL - Oncologia Medica	Ravenna		Italy	48018
12	Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino	Torino		Italy	10123
13	Azienda Socio-Sanitaria Territoriale Sette Laghi, Varese	Varese		Italy	21100
14	Azienda ULSS8 Berica	Vicenza		Italy	36100