Study of Anastrozole, Letrozole, or Exemestane With or Without Tamoxifen in Treating Postmenopausal Women With Hormone-Responsive Breast Cancer That Has Been Completely Removed By Surgery

• ClinicalTrials.gov Identifier: NCT00541086
• Recruitment Status: Unknown
• First Posted: October 8, 2007
• Last Update Posted: February 7, 2020
• Sponsor: Gruppo Italiano Mammella (GIM)
• Information provided by (Responsible Party): Gruppo Italiano Mammella (GIM)

Study Description

Brief Summary:

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking use of estrogen by the tumor cells. Anastrozole, letrozole, and exemestane may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether giving tamoxifen followed by anastrozole, letrozole, or exemestane is more effective than giving anastrozole, letrozole, or exemestane alone in treating breast cancer.

PURPOSE: This randomized phase III trial is studying giving tamoxifen followed by either anastrozole, letrozole, or exemestane to see how well it works compared to anastrozole, letrozole, or exemestane alone in treating postmenopausal women with hormone-responsive invasive breast cancer that has been completely removed by surgery.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: anastrozole; Drug: exemestane; Drug: letrozole; Drug: tamoxifen citrate	Phase 3

Detailed Description:

OBJECTIVES:

• To compare sequential tamoxifen for 2 years followed by anastrozole, letrozole, or exemestane for 3 years vs anastrozole, letrozole, or exemestane for 5 years in terms of disease-free survival in postmenopausal women with nonrecurrent, nonmetastatic invasive endocrine-responsive breast cancer.
• To compare disease-free survival in patients treated with anastrozole vs letrozole vs exemestane.

OUTLINE: This is a multicenter study. Patients are stratified according to hormone receptor status (estrogen receptor [ER]-positive and progesterone [PgR] receptor-positive disease vs ER-positive and PgR-negative disease vs ER-negative and PgR-positive disease vs ER- or PgR-positive disease or ER or PgR status unknown), HER-2/neu status (positive [3+ by IHC or positive by fluorescence in situ hybridization ( FISH)] vs negative vs unknown), prior chemotherapy (none vs adjuvant vs neoadjuvant vs both adjuvant and neoadjuvant), and nodal status (pN0 vs pN1 vs pN2 vs pN3). Patients are randomized to 1 of 6 treatment arms.

• Arm I: Patients receive oral anastrozole once daily for 5 years.
• Arm II: Patients receive oral exemestane once daily for 5 years.
• Arm III: Patients receive oral letrozole once daily for 5 years.
• Arm IV: Patients receive oral tamoxifen citrate once daily for 2 years followed by oral anastrazole once daily for 3 years.
• Arm V: Patients receive oral tamoxifen citrate once daily for 2 years followed by oral exemestane once daily for 3 years.
• Arm VI: Patients receive oral tamoxifen citrate once daily for 2 years followed by oral letrozole once daily for 3 years.

Treatment in all arms continues in the absence of disease recurrence or unacceptable toxicity.

After completion of study therapy, patients are followed periodically.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 3697 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Study Comparing Anastrozole, Letrozole and Exemestane, Upfront (for 5 Years) or Sequentially (for 3 Years After 2 Years of Tamoxifen), as Adjuvant Treatment of Postmenopausal Patients With Endocrine-responsive Breast Cancer
• Actual Study Start Date: March 2007
• Estimated Primary Completion Date: July 2020
• Estimated Study Completion Date: July 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: A - anastrozole; Up-front adjuvant anastrozole for 5 years	Drug: anastrozole; 1 mg per day, orally
Experimental: B - exemestane; Up-front adjuvant exemestane for 5 years	Drug: exemestane; 25 mg per day, orally
Experimental: C - letrozole; Up-front adjuvant letrozole for 5 years	Drug: letrozole; 2.5 mg per day, orally
Active Comparator: D - tamoxifen followed by anastrozole; Switch adjuvant treatment with tamoxifen for 2 years followed by anastrozole for 3 years	Drug: anastrozole; 1 mg per day, orally; Drug: tamoxifen citrate; 20 mg per day, orally
Active Comparator: E - tamoxifen followed by exemestane; Switch adjuvant treatment with tamoxifen for 2 years followed by exemestane for 3 years	Drug: exemestane; 25 mg per day, orally; Drug: tamoxifen citrate; 20 mg per day, orally
Active Comparator: F - tamoxifen followed by letrozole; Switch adjuvant treatment with tamoxifen for 2 years followed by letrozolefor 3 years	Drug: letrozole; 2.5 mg per day, orally; Drug: tamoxifen citrate; 20 mg per day, orally

Outcome Measures

Primary Outcome Measures :

1. Disease-free survival [ Time Frame: 5 years ]

Secondary Outcome Measures :

1. Overall Survival [ Time Frame: 5 years ]
2. Distant metastasis-free survival [ Time Frame: 5 years ]
3. Cumulative incidence of contralateral breast cancer as first event [ Time Frame: 5 years ]
4. Breast cancer-free survival [ Time Frame: 5 years ]
5. Cumulative incidence and type of second non-breast invasive cancer [ Time Frame: 5 years ]
6. Effects on lipid profile [ Time Frame: 5 years ]
7. Toxicity as assessed by NCI CTCAE v3.0 [ Time Frame: 5 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive breast cancer completely removed by surgery

  • Any T, any N
  • No recurrent or metastatic disease

• Estrogen or progesterone receptor-positive disease in primary tumor, as defined by 1 of the following:

  • At least 10% of tumor cells positive by immunohistochemistry
  • At least 10 fmol/mg cytosol protein by ligand binding assay
• Patients with HER-2/neu positive tumors are eligible provided they receive trastuzumab (Herceptin®) according to the registered schedule

PATIENT CHARACTERISTICS:

• Female

• Postmenopausal, defined by ≥ 1 of the following:

  • Age ≥ 60 years

  • Age 45-59 and satisfying 1 or more of the following criteria:

    • Amenorrhea for ≥ 12 months AND intact uterus
    • Amenorrhea (secondary to hysterectomy, hormone replacement therapy (HRT), or chemotherapy) for < 12 months AND follicle-stimulating hormone within the postmenopausal range
  • Underwent prior bilateral oophorectomy at any age >18 years
• No concurrent illness that contraindicates adjuvant endocrine treatment
• No other invasive breast cancer or invasive malignancy within the past 10 years, except adequately cone-biopsied squamous cell or basal cell skin cancer or carcinoma in situ of the cervix
• No concurrent disease that would place the patient at unusual risk

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Adjuvant or neoadjuvant chemotherapy must be completed prior to study entry
• At least 1 month since prior and no concurrent HRT
• More than 30 days since prior systemic investigational drugs
• No prior tamoxifen as part of any breast cancer prevention study
• Prior or concurrent locoregional radiotherapy allowed
• No other concurrent experimental drugs
• No concurrent bisphosphonates, unless indicated as treatment for osteoporosis

Contacts and Locations

Locations

Italy

Federico II University Medical School

Naples, Italy, 80131

Istituto Nazionale per lo Studio e la Cura dei Tumori

Naples, Italy, 80131

Seconda Universita di Napoli

Naples, Italy, 80138

Arcispedale S. Maria Nuova

Reggio Emilia, Italy, 42100

Istituti Fisioterapici Ospitalieri - Roma

Rome, Italy, 00128

Sponsors and Collaborators

Gruppo Italiano Mammella (GIM)

Investigators

• Study Chair: Sabino De Placido, MD; Federico II University

More Information

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

De Placido S, Gallo C, De Laurentiis M, Bisagni G, Arpino G, Sarobba MG, Riccardi F, Russo A, Del Mastro L, Cogoni AA, Cognetti F, Gori S, Foglietta J, Frassoldati A, Amoroso D, Laudadio L, Moscetti L, Montemurro F, Verusio C, Bernardo A, Lorusso V, Gravina A, Moretti G, Lauria R, Lai A, Mocerino C, Rizzo S, Nuzzo F, Carlini P, Perrone F; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):474-485. doi: 10.1016/S1470-2045(18)30116-5. Epub 2018 Feb 23. Erratum In: Lancet Oncol. 2018 Apr;19(4):e184.

• Responsible Party: Gruppo Italiano Mammella (GIM)
• ClinicalTrials.gov Identifier: NCT00541086
• Other Study ID Numbers: CDR0000570041; GIM-3-FATA; EUDRACT-2006-004018-42; EU-20764
• First Posted: October 8, 2007
• Last Update Posted: February 7, 2020
• Last Verified: February 2020

Keywords provided by Gruppo Italiano Mammella (GIM):

stage IA breast cancer; stage IB breast cancer; stage II breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer; estrogen receptor-positive breast cancer; progesterone receptor-positive breast cancer

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Tamoxifen; Letrozole; Anastrozole; Exemestane; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Bone Density Conservation Agents