S0226 Anastrozole With or Without Fulvestrant as First-Line Therapy in Postmenopausal Women With Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT00075764
• Recruitment Status: Completed
• First Posted: January 13, 2004
• Results First Posted: April 4, 2017
• Last Update Posted: January 13, 2021
• Sponsor: SWOG Cancer Research Network
• Collaborators: National Cancer Institute (NCI); NCIC Clinical Trials Group
• Information provided by (Responsible Party): SWOG Cancer Research Network

Tracking Information

• First Submitted Date: January 9, 2004
• First Posted Date: January 13, 2004
• Results First Submitted Date: October 26, 2016
• Results First Posted Date: April 4, 2017
• Last Update Posted Date: January 13, 2021
• Study Start Date: April 2004
• Actual Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 15, 2017)

Time to Tumor Progression [ Time Frame: Every 4 weeks while on treatment. Then every 3 months until progression, then six months for two years then annually until four years or until death, which ever occurs first. ]

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target measurable lesions over the smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Unequivocal progression of non-measurable disease in the opinion of the treating physician. Appearance of any new lesion/site. Death due to disease without prior documentation of progression and without symptomatic deterioration. From date of randomization to time of first documentation of progression, symptomatic deterioration or death due to any cause. Patients last known to be alive and progression free are considered at last date of contact.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: February 15, 2017)

• Clinical Benefit (CR, PR, Confirmed or Unconfirmed, or Stable Disease >= 24 Weeks). [ Time Frame: Every 4 weeks while on treatment. Then every 3 months until progression, then six months for two years then annually until four years or until death, which ever occurs first. ]
  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable, Does not qualify for CR, PR, Progression or Symptomatic Deterioration. Clinical Benefit = CR + PR + Stable >= 24 weeks
• Overall Survival [ Time Frame: Every 4 weeks while on treatment. Then every 3 months until progression, then six months for two years then annually until four years or until death, which ever occurs first. ]
  From date of randomization to date of death due to any cause. Patients last known to be alive are censored at last date of contact.
• Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Patients were assessed for adverse events after each cycle (1 cycle = 28 days) while on treatment. ]
  Adverse Events (AEs) are reported by CTCAE version 3.0 terminology. For each patient, worst grade of each event type is reported. Grade3 (Severe), Grade4 (Life-threatening), Grade 5 (Fatal)

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

Descriptive Information

• Brief Title: S0226 Anastrozole With or Without Fulvestrant as First-Line Therapy in Postmenopausal Women With Metastatic Breast Cancer
• Official Title: Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as First Line Therapy for Post Menopausal Women With Metastatic Breast Cancer

Brief Summary

RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using drugs such as anastrozole and fulvestrant may fight breast cancer by blocking the use of estrogen. It is not yet known whether anastrozole is more effective with or without fulvestrant in treating breast cancer.

PURPOSE: This randomized phase III trial is studying giving anastrozole together with fulvestrant to see how well it works compared to anastrozole alone as first-line therapy in treating postmenopausal women with metastatic breast cancer.

Detailed Description

OBJECTIVES:

• Compare the time to tumor progression in postmenopausal women with metastatic breast cancer treated with anastrozole with or without fulvestrant as first-line therapy.
• Compare the clinical benefit (complete or partial response, confirmed or unconfirmed, or stable disease ≥ 24 weeks) and overall survival of patients treated with these regimens.
• Compare adverse events in patients treated with these regimens.
• Determine the prognostic significance of estrogen receptor positivity and HER2/neu status in patients treated with these regimens.
• Determine parameters of estrogen and clinical pharmacology and estrogen levels in patients treated with these regimens.
• Compare anastrozole plasma levels at 8, 16, and 24 weeks in patients treated with these regimens (closed as of 4/16/2009).
• Compare estradiol serum levels at 8, 16, and 24 weeks in patients treated with these regimens (closed as of 4/16/2009).

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior adjuvant tamoxifen therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral anastrozole once daily on days 1-28.
• Arm II: Patients receive oral anastrozole as in arm I. Patients also receive fulvestrant intramuscularly on days 1, 14, and 28 during course 1 and then on day 28 of the subsequent courses.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients are followed for up to 4 years.

PROJECTED ACCRUAL: A total of 690 patients (345 per treatment arm) will be accrued for this study within 3 years.

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

Intervention

• Drug: anastrozole
  Given orally
• Drug: fulvestrant
  Given intramuscularly

Study Arms

• Active Comparator: Arm I
  Patients receive oral anastrozole once daily on days 1-28.
  Intervention: Drug: anastrozole
• Experimental: Arm II
  Patients receive oral anastrozole as in arm I. Patients also receive fulvestrant intramuscularly on days 1, 14, and 28 during course 1 and then on day 28 of the subsequent courses.
  Interventions:

  • Drug: anastrozole
  • Drug: fulvestrant

Publications *

• Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Linden HH, Livingston RB, Hortobagyi GN. Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer. N Engl J Med. 2019 Mar 28;380(13):1226-1234. doi: 10.1056/NEJMoa1811714. Erratum In: N Engl J Med. 2019 Jun 06;380(23):2282.
• Unger JM, LeBlanc M, Blanke CD. The Effect of Positive SWOG Treatment Trials on Survival of Patients With Cancer in the US Population. JAMA Oncol. 2017 Oct 1;3(10):1345-1351. doi: 10.1001/jamaoncol.2017.0762.
• Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. doi: 10.1056/NEJMoa1201622.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 15, 2017): 695
• Original Enrollment: Not Provided
• Actual Study Completion Date: October 1, 2018
• Actual Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed breast cancer meeting 1 of the following criteria:

  • Metastatic disease (M1)
  • Multiple sites of new disease that is clinically obvious metastatic disease (e.g., multiple sites of new osseous disease)
• Measurable or nonmeasurable disease
• No known brain or CNS metastases

• Hormone receptor status:

  • Estrogen-receptor positive* AND/OR
  • Progesterone-receptor positive* NOTE: *Positivity defined as estrogen binding of > 10 fmol/mg cytosol protein by ligand binding assay or positive by immunohistochemistry

PATIENT CHARACTERISTICS:

Age

• Not specified

Sex

• Female

Menopausal status

• Postmenopausal, as defined by 1 of the following:

  • Prior bilateral oophorectomy
  • More than 12 months since last menstrual period with no prior hysterectomy
  • At least 55 years of age with prior hysterectomy
  • Under 55 years of age with a prior hysterectomy without oophorectomy and with estradiol and follicle-stimulating hormone levels consistent with menopause

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• No bleeding diathesis (e.g., disseminated intravascular coagulation or clotting factor deficiency)

Hepatic

• INR ≤ 1.6

Renal

• Not specified

Other

• HIV negative
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior immunotherapy for recurrent or metastatic disease

Chemotherapy

• No prior chemotherapy for recurrent or metastatic disease
• More than 12 months since prior adjuvant or neoadjuvant chemotherapy
• No concurrent chemotherapy for malignancy

Endocrine therapy

• Prior adjuvant hormonal therapy allowed

• At least 12 months since prior adjuvant luteinizing hormone-releasing hormone (LHRH) analogues

  • Menstrual periods must not have resumed since LHRH therapy
• More than 12 months since prior adjuvant or neoadjuvant aromatase inhibitors (e.g., anastrozole, letrozole, or exemestane)
• More than 12 months since prior fulvestrant
• No prior hormonal therapy for recurrent or metastatic disease
• No other concurrent hormonal therapy for malignancy
• No concurrent hormone replacement therapy

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No long-term anticoagulant therapy (except antiplatelet therapy)

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: Canada, United States

Administrative Information

• NCT Number: NCT00075764
• Other Study ID Numbers: CDR0000349337; U10CA032102 ( U.S. NIH Grant/Contract ); S0226 ( Other Identifier: SWOG ); CAN-NCIC-MAC7 ( Other Identifier: NCIC-CTG )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: SWOG Cancer Research Network
• Original Responsible Party: Not Provided
• Current Study Sponsor: SWOG Cancer Research Network
• Original Study Sponsor: Same as current

Collaborators

• National Cancer Institute (NCI)
• NCIC Clinical Trials Group

Investigators

• Study Chair: Rita S. Mehta, MD; Chao Family Comprehensive Cancer Center
• Study Chair: Theodore A. Vandenberg, MD; London Health Sciences Centre

• PRS Account: SWOG Cancer Research Network
• Verification Date: January 2021