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

Breast Neoplasms Clinical Trial

— TAM-01  

Official title:

Randomized Placebo-controlled Phase III Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia - Long Term Follow-up

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01357772
• Other study ID #: GAL 01
• Secondary ID: 2007-007740-10
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 12, 2008
• Est. completion date: December 31, 2028

Study information

• Verified date: July 2023
• Source: Ente Ospedaliero Ospedali Galliera
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 500
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Women of age = 18 and < 75 years

2. 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

3. ECOG Performance status = 1

4. Written informed consent

Exclusion Criteria:

1. Any type of malignancy, with the exclusion of non-melanoma skin cancer

2. Proliferative disorders of the endometrium such as atypical hyperplasia, endometriosis, unresected polyps, symptomatic myoma

3. Liver, kidney and heart function impairment grade = 2 (CTCAE criteria v.3.0)

4. Any type of retinal disorders, severe cataract and glaucoma

5. 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.)

6. Use of tamoxifen, raloxifene or other selective estrogen receptor modulator (SERMs)

7. Use of anastrozole and other aromatase inhibitors (AI) in the last 12 months for = 6 months

8. Dicoumarol anticoagulant therapy in progress

9. Active infections

10. Severe psychiatric disorders or inability to comply to the protocol procedures

11. Geographic inaccessibility or difficulties in ensuring adequate compliance

12. Women who are pregnant or breastfeeding

13. Any other factor which, at the discretion of the investigator, may controindicate the use of tamoxifen

Related Conditions & MeSH terms

• Atypical Hyperplasia
• Breast Neoplasms
• Carcinoma, Intraductal, Noninfiltrating
• Hyperplasia
• Neoplasm Recurrence, Local
• Neoplasms
• Recurrence
• Recurrence, Local Neoplasm

Intervention

Drug:
• Tamoxifen

• placebo

Locations

Country	Name	City	State
Italy	IRCCS Istituto Tumori Giovanni Paolo II	Bari
Italy	Ospedale di Carpi "Bernardino Ramazzini"	Carpi	Modena
Italy	Azienda Ospedaliera Mater Domini Catanzaro	Catanzaro
Italy	E.O. Ospedali Galliera	Genoa
Italy	Istituto Scientifico Romagnolo per lo studio e la cura dei tumori	Meldola	Forlì-Cesena
Italy	IEO - European Institute of Oncology IRCCS	Milan
Italy	Azienda Ospedaliera-Universitaria Policlinico di Modena	Modena
Italy	Istituto Nazionale Tumori IRCCS Fondazione G. Pascale	Napoli
Italy	ICS Maugeri -Centro Medico di Pavia	Pavia
Italy	AUSL - Oncologia Medica	Ravenna
Italy	Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino	Torino
Italy	Ospedali riuniti ASL AL - Ospedale SS. Antonio e Margherita	Tortona	Alessandria
Italy	Azienda Socio-Sanitaria Territoriale Sette Laghi, Varese	Varese
Italy	Azienda ULSS8 Berica	Vicenza

Sponsors (3)

Lead Sponsor	Collaborator
Andrea DeCensi	Associazione Italiana per la Ricerca sul Cancro, European Institute of Oncology

Country where clinical trial is conducted

Italy, 

References & Publications (4)

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, Soiland H, Boni L, Bonanni B, Mellgren G. Association of CYP2D6 genotype and tamoxifen me — View Citation

DeCensi A, Puntoni M, Johansson H, Guerrieri-Gonzaga A, Caviglia S, Avino F, Cortesi L, Ponti A, Pacquola MG, Falcini F, Gulisano M, Digennaro M, Cariello A, Cagossi K, Pinotti G, Lazzeroni M, Serrano D, Briata IM, Buttiron Webber T, Boni L, Bonanni B. Ef — View Citation

Lazzeroni M, Puntoni M, Guerrieri-Gonzaga A, Serrano D, Boni L, Buttiron Webber T, Fava M, Briata IM, Giordano L, Digennaro M, Cortesi L, Falcini F, Serra P, Avino F, Millo F, Cagossi K, Gallerani E, De Simone A, Cariello A, Aprile G, Renne M, Bonanni B, — View Citation

Lazzeroni M, Serrano D, Dunn BK, Heckman-Stoddard BM, Lee O, Khan S, Decensi A. Oral low dose and topical tamoxifen for breast cancer prevention: modern approaches for an old drug. Breast Cancer Res. 2012 Oct 29;14(5):214. doi: 10.1186/bcr3233. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of invasive breast cancer events and DCIS	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.	20 years
Secondary	Number of other non-invasive breast events	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.	20 years
Secondary	Metabolites of tamoxifen and hormone blood level (in a subgroup of women)	Blood concentrations of metabolites including circulating IGF-I,IGFBP-3, SHBG, hormones (testosterone, estradiol, SHBG, CRP), tamoxifen metabolites (4OH tamoxifen and endoxifen).	20 years
Secondary	CYP2D6 polymorphisms analysis	Esploratory analisis of some SNPS of the cytochrome P450 genes involved in tamoxifen metabolism such as CYP2D6.	20 years

External Links

•   PMID: 36917758
•   PubMed ID: 23106852
•   PubMed ID: 33608319
•   PubMed ID: 33767162