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)

Tracking Information

• First Submitted Date: October 5, 2007
• First Posted Date: October 8, 2007
• Last Update Posted Date: February 7, 2020
• Actual Study Start Date: March 2007
• Estimated Primary Completion Date: July 2020 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: January 20, 2015): Disease-free survival [ Time Frame: 5 years ]
• Original Primary Outcome Measures (submitted: October 5, 2007): Disease-free survival

Current Secondary Outcome Measures (submitted: January 20, 2015)

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

Original Secondary Outcome Measures (submitted: October 5, 2007)

• Overall Survival
• Distant metastasis-free survival
• Cumulative incidence of contralateral breast cancer as first event
• Breast cancer-free survival
• Cumulative incidence and type of second non-breast invasive cancer
• Effects on lipid profile
• Toxicity as assessed by NCI CTCAE v3.0

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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

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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: anastrozole
  1 mg per day, orally
• Drug: exemestane
  25 mg per day, orally
• Drug: letrozole
  2.5 mg per day, orally
• Drug: tamoxifen citrate
  20 mg per day, orally

Study Arms

• Experimental: A - anastrozole
  Up-front adjuvant anastrozole for 5 years
  Intervention: Drug: anastrozole
• Experimental: B - exemestane
  Up-front adjuvant exemestane for 5 years
  Intervention: Drug: exemestane
• Experimental: C - letrozole
  Up-front adjuvant letrozole for 5 years
  Intervention: Drug: letrozole
• Active Comparator: D - tamoxifen followed by anastrozole
  Switch adjuvant treatment with tamoxifen for 2 years followed by anastrozole for 3 years
  Interventions:

  • Drug: anastrozole
  • Drug: tamoxifen citrate
• Active Comparator: E - tamoxifen followed by exemestane
  Switch adjuvant treatment with tamoxifen for 2 years followed by exemestane for 3 years
  Interventions:

  • Drug: exemestane
  • Drug: tamoxifen citrate
• Active Comparator: F - tamoxifen followed by letrozole
  Switch adjuvant treatment with tamoxifen for 2 years followed by letrozolefor 3 years
  Interventions:

  • Drug: letrozole
  • Drug: tamoxifen citrate

• Publications *: 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.

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: July 31, 2017): 3697
• Original Enrollment (submitted: October 5, 2007): 10000
• Estimated Study Completion Date: July 2020
• Estimated Primary Completion Date: July 2020 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT00541086
• Other Study ID Numbers: CDR0000570041; GIM-3-FATA; EUDRACT-2006-004018-42; EU-20764
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Gruppo Italiano Mammella (GIM)
• Original Responsible Party: Not Provided
• Current Study Sponsor: Gruppo Italiano Mammella (GIM)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Gruppo Italiano Mammella (GIM)
• Verification Date: February 2020