Letrozole in Preventing Cancer in Postmenopausal Women Who Have Received 4-6 Years of Hormone Therapy for Hormone Receptor-Positive, Lymph Node-Positive, Early-Stage Breast Cancer (SOLE)

• ClinicalTrials.gov Identifier: NCT00553410
• Recruitment Status: Completed
• First Posted: November 4, 2007
• Results First Posted: January 29, 2019
• Last Update Posted: March 11, 2020
• Sponsor: ETOP IBCSG Partners Foundation
• Collaborator: Breast International Group
• Information provided by (Responsible Party): ETOP IBCSG Partners Foundation

Tracking Information

• First Submitted Date: November 2, 2007
• First Posted Date: November 4, 2007
• Results First Submitted Date: January 4, 2019
• Results First Posted Date: January 29, 2019
• Last Update Posted Date: March 11, 2020
• Study Start Date: August 2007
• Actual Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 4, 2019)

Disease-free Survival (DFS) [ Time Frame: 5-year estimates, reported at a median follow-up of 60 months ]

Duration of time from randomization to the first indication of the following events: invasive recurrence at local (including recurrence restricted to the breast after breast conserving treatment), regional or distant sites; a new invasive cancer in the contralateral breast; any second (non-breast) invasive malignancy; or a death without prior cancer event. Appearance of DCIS or LCIS either in the ipsilateral or in the contralateral breast was not be considered as an event for DFS. In the absence of an event, DFS was censored at the date of last follow-up visit.

• Original Primary Outcome Measures (submitted: November 2, 2007): Disease-free survival (DFS)

Current Secondary Outcome Measures (submitted: January 4, 2019)

• Overall Survival [ Time Frame: 5-year estimates, reported at a median follow-up of 60 months ]
  Duration of time from randomization to death from any cause, or was censored at the date last known alive. (Note, for patients who withdrew consent or were lost to follow-up but follow-up for survival was possible through hospital or registry records, OS was censored at the date last known alive rather than date of last follow-up/withdrawn consent).
• Distant Recurrence-free Interval (DRFI) [ Time Frame: 5-year estimates, reported at a median follow-up of 60 months ]
  Duration of time from randomization to the first indication of invasive breast recurrence at a distant site. In the absence of an event, DRFI was censored at the date of last follow-up visit or date or death without distant recurrence.* *This endpoint replaced DDFS, which was specified in the protocol
• Breast Cancer-free Interval [ Time Frame: 5-year estimates, reported at a median follow-up of 60 months ]
  Duration of time from randomization to the first indication of the following events: invasive breast recurrence at local, regional or distant sites; a new invasive cancer in the contralateral breast (second non-breast malignancies are ignored). In the absence of an event, BCFI was censored at the date of last follow-up visit or date of death without prior breast cancer event.

Original Secondary Outcome Measures (submitted: November 2, 2007)

• Overall survival
• Distant DFS
• Breast cancer-free interval
• Sites of first DFS failure
• Second (nonbreast) malignancies
• Deaths without prior cancer events
• Adverse events

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

Descriptive Information

• Brief Title: Letrozole in Preventing Cancer in Postmenopausal Women Who Have Received 4-6 Years of Hormone Therapy for Hormone Receptor-Positive, Lymph Node-Positive, Early-Stage Breast Cancer
• Official Title: SOLE, Study of Letrozole Extension, A Phase III Trial Evaluating the Role of Continuous Letrozole Versus Intermittent Letrozole Following 4 to 6 Years of Prior Adjuvant Endocrine Therapy for Postmenopausal Women With Hormone-Receptor Positive, Node Positive Early Stage Breast Cancer

Brief Summary

RATIONALE: Estrogen can cause the growth of breast cancer cells. Letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known which regimen of letrozole is more effective in postmenopausal women who have received hormone therapy for early-stage breast cancer.

PURPOSE: This randomized phase III trial is comparing two different regimens of letrozole in preventing cancer in postmenopausal women who have received 4-6 years of hormone therapy for hormone receptor-positive, lymph node-positive, early-stage breast cancer.

Detailed Description

OBJECTIVES:

Primary

• Compare the disease-free survival (DFS) of postmenopausal women treated with continuous letrozole for 5 years vs intermittent letrozole over a 5-year period.

Secondary

• Compare overall survival of patients treated with these two regimens.
• Compare distant DFS of these patients.
• Compare breast cancer-free interval of these patients.
• Compare sites of first DFS failure in these patients.
• Compare second (nonbreast) malignancies in these patients.
• Compare deaths without prior cancer events in these patients.
• Compare adverse events resulting from these two regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to treatment center and type of prior endocrine therapy (selective estrogen receptor modulators [SERMs] alone vs aromatase inhibitors [AIs] alone vs both SERMs and AIs each for at least 1 month). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral letrozole daily for 5 years.
• Arm II: Patients receive oral letrozole daily for the first 9 months of years 1 through 4, followed by 12 months in year 5.

After completion of study therapy, patients are followed annually.

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

Intervention

• Drug: Letrozole
  Film-coated tablet, oral use, 2.5 mg Letrozole daily for 5 years continuously
• Drug: Letrozole
  Film-coated tablet, oral use, 2.5 mg daily, 48 months over 5 yrs: 4 x 9 months (9 mo followed by 3 mo treatment-free interval in yrs 1-4, -> 36 mo) plus 1 x 12 mo in yr 5 -> 48 months

Study Arms

• Active Comparator: Continuous letrozole
  Continuous letrozole: 5 years continuously (2.5 mg Letrozole daily)
  Intervention: Drug: Letrozole
• Experimental: Intermittent letrozole
  Intermittent letrozole: 48 months over 5 yrs: 4 x 9 months (9 mo followed by 3 mo treatment-free interval in yrs 1-4, -> 36 mo) plus 1 x 12 mo in yr 5 -> 48 months
  Intervention: Drug: Letrozole

Publications *

• Guerini-Rocco E, Gray KP, Fumagalli C, Reforgiato MR, Leone I, Rafaniello Raviele P, Munzone E, Kammler R, Neven P, Hitre E, Jerusalem G, Simoncini E, Gombos A, Deleu I, Karlsson P, Aebi S, Chirgwin J, Di Lauro V, Thompson A, Graas MP, Barber M, Fontaine C, Loibl S, Gavila J, Kuroi K, Muller B, O'Reilly S, Di Leo A, Goldhirsch A, Viale G, Barberis M, Regan MM, Colleoni M. Genomic Aberrations and Late Recurrence in Postmenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the SOLE Trial. Clin Cancer Res. 2021 Jan 15;27(2):504-512. doi: 10.1158/1078-0432.CCR-20-0126. Epub 2020 Oct 20.
• Colleoni M, Luo W, Karlsson P, Chirgwin J, Aebi S, Jerusalem G, Neven P, Hitre E, Graas MP, Simoncini E, Kamby C, Thompson A, Loibl S, Gavila J, Kuroi K, Marth C, Muller B, O'Reilly S, Di Lauro V, Gombos A, Ruhstaller T, Burstein H, Ribi K, Bernhard J, Viale G, Maibach R, Rabaglio-Poretti M, Gelber RD, Coates AS, Di Leo A, Regan MM, Goldhirsch A; SOLE Investigators. Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):127-138. doi: 10.1016/S1470-2045(17)30715-5. Epub 2017 Nov 17.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 13, 2015): 4884
• Original Enrollment (submitted: November 2, 2007): 4800
• Actual Study Completion Date: May 15, 2019
• Actual Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Confirmed diagnosis of prior operable, noninflammatory breast cancer meeting the following criteria:

  • Steroid hormone receptor-positive tumors (estrogen receptor and/or progesterone receptor), determined by immunohistochemistry, after primary surgery and before commencement of prior endocrine therapy
  • Prior local treatment including surgery with or without radiotherapy for primary breast cancer with no known clinical residual loco-regional disease
  • Following primary surgery, eligible patients must have had evidence of lymph node involvement either in the axillary or internal mammary nodes, but not supraclavicular nodes
  • Clinically disease-free

• Must have completed 4-6 years of prior adjuvant selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or a sequential combination of both

  • When calculating 4-6 years, neoadjuvant endocrine therapy should not be included
• No evidence of recurrent disease or distant metastatic disease
• No prior bilateral breast cancer

PATIENT CHARACTERISTICS:

• Female

• Must be postmenopausal by any of the following criteria:

  • Patients of any age who have had a bilateral oophorectomy (including radiation castration AND amenorrheic for > 3 months)
  • Patients 56 years old or older with any evidence of ovarian function must have biochemical evidence of definite postmenopausal status (defined as estradiol, luteinizing hormone [LH], and follicle-stimulating hormone [FSH] in the postmenopausal range)

  • Patients 55 years old or younger must have biochemical evidence of definite postmenopausal status (defined as estradiol, LH, and FSH in the postmenopausal range)

    • Patients who have received prior luteinizing-hormone releasing-hormone (LHRH) analogues within the last year are eligible if they have definite evidence of postmenopausal status as defined above
• Clinically adequate hepatic function
• No bone fracture due to osteoporosis at any time during the 4-6 years of prior therapy
• No prior or current malignancy except adequately treated basal cell or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, or contra- or ipsilateral in situ breast carcinoma
• No other nonmalignant systemic diseases (cardiovascular, renal, lung, etc.) that would prevent prolonged follow-up
• No psychiatric, addictive, or any other disorder that compromises compliance with protocol requirements

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 12 months since prior and no other concurrent endocrine SERM/AI therapy

• Any type of prior adjuvant therapy allowed including, but not limited to, any of the following:

  • Neoadjuvant chemotherapy
  • Neoadjuvant endocrine therapy
  • Adjuvant chemotherapy
  • Trastuzumab (Herceptin®)
  • Ovarian ablation
  • Gonadotropin releasing hormone analogues
  • Lapatinib ditosylate
• No concurrent hormone-replacement therapy, bisphosphonates (except for treatment of bone loss), or any other investigational agent

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 120 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Chile, Denmark, France, Germany, Hungary, India, Italy, Japan, New Zealand, Peru, Russian Federation, South Africa, Spain, Sweden, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT00553410
• Other Study ID Numbers: IBCSG 35-07 / BIG 1-07; 2007-001370-88 ( EudraCT Number ); CDR0000574249 ( Registry Identifier: CT.gov )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: ETOP IBCSG Partners Foundation
• Original Responsible Party: Not Provided
• Current Study Sponsor: ETOP IBCSG Partners Foundation
• Original Study Sponsor: Same as current
• Collaborators: Breast International Group

Investigators

• Study Chair: Marco Colleoni, MD; European Institute of Oncology

• PRS Account: ETOP IBCSG Partners Foundation
• Verification Date: May 2019