Fulvestrant (F)/Goserelin (G) vs Anastrozole (A)/G vs G for Premenopausal Women (FLAG)

• ClinicalTrials.gov Identifier: NCT01266213
• Recruitment Status: Unknown
• First Posted: December 24, 2010
• Last Update Posted: May 1, 2017
• Sponsor: Samsung Medical Center
• Collaborators: Asan Medical Center; Seoul National University Hospital; Severance Hospital; Ulsan University Hospital; Kosin University Gospel Hospital; Korea University Guro Hospital; Korea University Anam Hospital
• Information provided by (Responsible Party): Young-Hyuck Im, Samsung Medical Center

Tracking Information

• First Submitted Date: December 19, 2010
• First Posted Date: December 24, 2010
• Last Update Posted Date: May 1, 2017
• Study Start Date: December 2010
• Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 22, 2010)

Time to Progression (TTP) [ Time Frame: from the date of therapy to the date of progression every 3 months ]

To measure TTP, disease status will be measured every 3 cycles or clinically documented till progression

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 22, 2010)

• overall response [ Time Frame: after 3 months from the first date of therapy ]
  Before start of 4th cycle of therapy, outcome measure will be perfomred to evaluate response
• overall survival [ Time Frame: from the first date of therapy till death ]
  from time to the first day of therapy to death
• Toxicity [ Time Frame: from the first date of therapy to death every cycle of therapy (monthly) ]

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

Descriptive Information

• Brief Title: Fulvestrant (F)/Goserelin (G) vs Anastrozole (A)/G vs G for Premenopausal Women
• Official Title: Randomized Phase II Study OF Goserelin (G) Plus Fulvestrant (F) vs. G Plus Anastrozole (A)vs. G Alone for HR+, Tamoxifen Pretreated, Premenopausal Woman

Brief Summary

Fulvestrant is an ER antagonist with no agonist effects, which binds, blocks and degrades the ER. Fulvestrant is comparable to third-generation aromatase inhibitors in terms of efficacy and tolerability for patients who have progressed on prior tamoxifen therapy and past studies have found all three-third-generation AIs to be at least as good as tamoxifen in first-line metastatic therapy in postmenopausal women. Fulvestrant has been studied little in premenopausal women despite of its attractive mechanism of actions. The clinical effectiveness of fulvestrant as a treatment for advanced breast cancer has previously been demonstrated at the standard dose (AD; 250 mg/mo) in several phase III clinical trials in postmenopausal women. However, there is evidence to suggest that doses of fulvestrant higher than 250 mg may have greater pharmacodynamic activity against the ER pathway. Moreover, dose-dependent clinical activity has been observed for fulvestrant. The activity of a fulvestrant high-dose (HD; 500 mg/mo) regimen has been investigated in two recent studies. A pilot Japanese study showed fulvestrant HD to have clinical activity in the treatment of advanced or recurrent breast cancer, to be well tolerated, and to result in plasma levels approximately double those seen with fulvestrant low-dose. Subsequently, a neoadjuvant study comparing fulvestrant low-dose and high-dose reported that significantly greater Ki67 and ER downregulation was achieved with the high-dose compared with the low-dose regimen and that both doses were well tolerated. A recent randomized trial also showed superior outcome of high-dose fulvestrant than AI.

Based on this rationale, we introduced high-dose fulvestrant with LHRH agonist as a randomized trial comparing with AI plus LHRH agonist and LHRH alone in premenopausal metastatic breast cancer patients who failed to tamoxifen treatment.

• Detailed Description: This randomized phase II trial is studying fulvestrant with goserelin for ovarian suppression by goserelin to see how well it works compared to anastrozole with goserelin and goserelin alone in recurrent or metastatic ER-positive breast cancer.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Breast Cancer
• Estrogen Receptor Positive Tumor
• Breast Cancer Nos Premenopausal

Intervention

• Drug: Fulvestrant plus Goserelin
  Fulvestrant s.c. plus Goserelin s.c.
  Other Name: Anastrozole plus Goserelin
• Drug: Anastrozole plus Goserelin
  Anastrozole 1 mg p.o. plus Goserelin s.c.
  Other Name: Fulvestrant plus Goserelin
• Drug: Goserelin
  Goserelin s.c.
  Other Names:

  • Fulvestrant plus Goserelin
  • Anastrozole plus Goserelin

Study Arms

• Experimental: Fulvestrant plus Goserelin
  Interventions:

  • Drug: Fulvestrant plus Goserelin
  • Drug: Anastrozole plus Goserelin
  • Drug: Goserelin
• Experimental: Anastrozole plus Goserelin
  Interventions:

  • Drug: Fulvestrant plus Goserelin
  • Drug: Anastrozole plus Goserelin
  • Drug: Goserelin
• Active Comparator: Goserelin alone
  Interventions:

  • Drug: Fulvestrant plus Goserelin
  • Drug: Anastrozole plus Goserelin
  • Drug: Goserelin

• Publications *: Kim JY, Im SA, Jung KH, Ro J, Sohn J, Kim JH, Park YH, Kim TY, Kim SB, Lee KS, Kim GM, Kim SH, Kim S, Ahn JS, Lee KH, Ahn JH, Park IH, Im YH; breast cancer committee of Korean Cancer Study Group (KCSG). Fulvestrant plus goserelin versus anastrozole plus goserelin versus goserelin alone for hormone receptor-positive, HER2-negative tamoxifen-pretreated premenopausal women with recurrent or metastatic breast cancer (KCSG BR10-04): a multicentre, open-label, three-arm, randomised phase II trial (FLAG study). Eur J Cancer. 2018 Nov;103:127-136. doi: 10.1016/j.ejca.2018.08.004. Epub 2018 Sep 14.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: December 22, 2010): 147
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2019
• Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 1) All patients must be female and premenopausal. Premenopausal is defined as either: ① last menstrual period within 3 months, or ② post-hysterectomy without bilateral oophorectomy and with FSH in the premenopausal range (≤ 30 mIU/mL), or, ③ if on tamoxifen within the past 3 months, a plasma estradiol in the premenopausal range (≥20 pg/mL), ④ if in case of chemotherapy induced amenorrhea, a plasma estradiol in the premenopausal range (≥20 pg/mL).

  2) Patients must have either positive estrogen and/or progesterone receptor determination by IHC or competitive binding assay on metastatic disease, or if not performed on their metastatic disease a positive result on their primary breast cancer specimen.

  3) No HER2 overexpressing breast cancer by IHC 3+ or FISH. 4) Patients who showed progressive disease on tamoxifen treatment as a palliative hormonal therapy or an adjuvant endocrine treatment 5) Patients who recurred after 5 years of tamoxifen use and could not be considered for resume to tamoxifen treatment.

  6) No prior treatment with an aromatase inhibitor or inactivator or fulvestrant 7) No prior treatment with an LH/RH agonist/antagonist except the use for ovarian protection for 6 months during adjuvant chemotherapy.

  8) No adjuvant chemotherapy within 1 year of study entry. 9) Patients must have an ECOG performance status of 0, 1, or 2. 10) Patients must have adequate bone marrow, hepatic, and renal function 11) Patients must not have received chemotherapy or hormonal therapy for at least 4 weeks prior to enrollment.

  12) Patients may receive irradiation to any bony sites of disease for pain control or for prevention of fracture.

  13) Patients may continue on bisphosphonates who already established on bisphosphonate therapy for at least 3 months.

  14) Patients who are pregnant or lactating are ineligible. Must be using effective contraception or not be of childbearing potential.

  15) Patients must not have had an active malignancy other than breast cancer, in situ carcinoma of the cervix, or non-melanomatous skin cancers in the past 5 years.

  16) No active, unresolved infection. 17) All patients must give signed written informed consent

Exclusion Criteria:

1. Patients who had received previous treatment for metastatic disease (including systemic cytostatic or hormonal treatment) other than tamoxifen.
2. Lymphangitic pulmonary metastases
3. Multiple or diffuse hepatic metastases
4. Documented parenchymal or leptomeningeal brain metastasis
5. HER-2 overexpressing breast cancer and concomitant trastuzumab treatment is not allowed
6. Serious uncontrolled intercurrent infections
7. Serious intercurrent medical or psychiatric illness, including active cardiac disease
8. Pregnancy or breast feeding
9. Second primary malignancy (except in situ carcinoma of the cervix or resected papillary thyroid carcinoma or adequately treated nonmelanomatous carcinoma of the skin or other malignancy treated at least 5 years previously with no evidence of recurrence)

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: up to 55 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Korea, Republic of

Administrative Information

• NCT Number: NCT01266213
• Other Study ID Numbers: 2010-04-001
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Young-Hyuck Im, Samsung Medical Center
• Original Responsible Party: Young-Hyuck Im/Professor, Samsung Medical Center
• Current Study Sponsor: Samsung Medical Center
• Original Study Sponsor: Same as current

Collaborators

• Asan Medical Center
• Seoul National University Hospital
• Severance Hospital
• Ulsan University Hospital
• Kosin University Gospel Hospital
• Korea University Guro Hospital
• Korea University Anam Hospital

Investigators

• Principal Investigator: Young-Hyuck Im, M.D., Ph.D.; Samsung Medical Center

• PRS Account: Samsung Medical Center
• Verification Date: April 2017