A Study to Investigate the Efficacy and Safety of Letrozole SIE Compared With Femara® (Both Combined With the CDK4/6 Inhibitor Ribociclib) in Postmenopausal Women With HR-Positive, HER2-Negative, Inoperable Locally Advanced or Metastatic Breast Cancer (SIE-3)

March 27, 2026 updated by: Rovi Pharmaceuticals Laboratories

A Multicenter, Randomized, Double-Blind, Double-Dummy, Phase III Study to Evaluate the Efficacy and Safety of Letrozole SIE Compared to Femara® (Both in Combination With the CDK4/6 Inhibitor Ribociclib) in Postmenopausal Women With HR-Positive, HER2-Negative, Inoperable Locally Advanced or Metastatic Breast Cancer (SIE-3)

The purpose of this study is to evaluate the efficacy and safety of Letrozole SIE (injectable) compared to Femara® (oral tablet), both given together with ribociclib, for the first-line treatment of postmenopausal women with HR-positive, HER2-negative, inoperable locally advanced or metastatic breast cancer.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a multicenter, randomized, double-blind, double-dummy, active-controlled Phase III study comparing Letrozole SIE with Femara® (both in combination with the CDK4/6 inhibitor ribociclib) in postmenopausal women with HR-positive, HER2-negative, inoperable locally advanced or metastatic breast cancer. The study employs double-blinding with matching placebos (double-dummy technique) to minimize bias on the part of participants, investigators, and analysts. Participants will be randomized in a 1:1 ratio to receive either Letrozole SIE (experimental use) or Femara® (active comparator), both in combination with the CDK4/6 inhibitor ribociclib. Randomization occurs after Screening and confirmation of eligibility and will be stratified by visceral metastasis (Yes/No) and prior adjuvant endocrine therapy (Yes/No).

The Treatment Period will last from Cycle 1 Day 1 (C1D1) until study intervention discontinuation due to disease progression, symptomatic deterioration, unacceptable toxicity, withdrawal of consent, loss to follow-up, participant's death, or end of study, whichever occurs first. After study intervention discontinuation, a post-discontinuation visit will be performed. Then, participants will be followed until withdrawal of consent, loss to follow-up, the participant's death, or end of study, whichever occurs first.

Study Type

Interventional

Enrollment (Estimated)

300

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Female participants with inoperable locally advanced or metastatic breast cancer.
  • Confirmed diagnosis of HR-positive/HER2-negative breast cancer.
  • Postmenopausal woman.
  • Previously untreated with any systemic anticancer therapy for their locoregionally recurrent or metastatic HR-positive disease. Participants may have received cytotoxic chemotherapy within (neo) adjuvant previous treatment of breast cancer but must show progressive disease prior to enrollment.
  • Have either measurable disease or non-measurable bone-only disease.
  • ECOG performance status 0-2.
  • Adequate organ and marrow function.
  • Resolution of all acute toxic effects of prior anticancer therapy or surgical procedures to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the participant at the investigator's discretion).
  • BMI ≥ 19 and ≤ 39 kg/m2.

Exclusion Criteria:

  • Participants with advanced, symptomatic, visceral spread who are at risk of life-threatening complications in the short term.
  • Participants with inflammatory breast cancer.
  • Known uncontrolled or symptomatic central nervous system (CNS) metastases.
  • Concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer.
  • Active cardiac disease or documented history of cardiac dysfunction.
  • Uncontrolled hypertension.
  • History of symptomatic vertebral fragility fracture or any fragility fracture of the hip, pelvis, wrist, or other location (defined as any fracture without a history of trauma or because of a fall from standing height or less, excluding fingers, toes, face and skull).
  • Presence of medical conditions associated with low bone mass.
  • History of ILD/pneumonitis.
  • Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation/behavior, or laboratory or ECG abnormalities that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
  • Presence of detectable viral infection, including HBV, HCV, and HIV. Screening is not required for enrollment. Note: Participants who have been effectively treated and have a sustained virologic response are eligible for enrollment.
  • Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anticancer therapy within 14 days (2 weeks) before randomization. Participants who received prior radiotherapy to > 25% of bone marrow are not eligible independent of when it was received.
  • Bisphosphonates or receptor activator of nuclear factor kappa-β ligand (RANKL) inhibitors initiated or have their dose changed within 14 days prior to randomization, i.e., participants should be on stable dose treatment for at least 14 days prior to randomization.
  • Hormonal medications or medications or products known to affect serum LH, FSH (except spironolactone which is allowed if medically indicated), or estrogen/E2 levels within 3 months prior to randomization. This includes, but is not limited to, estrogen or progesterone hormone replacement therapy, oral contraceptives, androgens, LHRH analogs, prolactin inhibitors, or antiandrogens and other medications, herbal remedies, and/or supplements for the treatment of vasomotor hot flush symptoms administered via any route, including topical or intravaginal administration.

  • Use of the following medications within the 3 previous days or a period of 5 half-lives, (whichever is longer) prior to randomization:

    1. Any medications or products including St. John's wort, known to be strong inducers of CYP3A.
    2. Any medications or products known to be strong inhibitors of CYP3A (e.g., grapefruit or grapefruit juice).
    3. Any medications known to be inducers of CYP2A6.
    4. Any medications known to be inhibitors of CYP2A6.
  • Concurrently use of other anticancer therapy.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Letrozole SIE
Drug: Letrozole SIE + Ribociclib + Oral placebo
Letrozole SIE quarterly (injectable) + Ribociclib once daily (oral) + placebo once daily (oral)
Active Comparator: Femara® 2.5 mg
Drug: Oral Femara® + Ribociclib + Injectable placebo
Femara® 2.5 mg/day (oral) + Ribociclib once daily (oral) + placebo quarterly (injectable)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 30 months).
PFS per Investigator assessment, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a local radiology assessment according to RECIST v1.1. PFS as assessed through a blinded independent central review will be used for supportive evidence of the primary efficacy endpoint.
From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 30 months).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS): Primary analysis
Time Frame: From the date of randomization to date of death from any cause (up to approximately 30 months).
OS, defined as the time from the date of randomization to date of death from any cause.
From the date of randomization to date of death from any cause (up to approximately 30 months).
Overall Survival (OS): Final analysis
Time Frame: From the date of randomization to date of death from any cause (up to approximately 88 months).
OS, defined as the time from the date of randomization to date of death from any cause.
From the date of randomization to date of death from any cause (up to approximately 88 months).
Objective Response Rate (ORR)
Time Frame: From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 30 months).
ORR, defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) by Investigator assessment per RECIST v1.1 criteria.
From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 30 months).
Incidence of arthralgias/arthritis and/or myalgias
Time Frame: From the date of the first dose of study intervention to the post-discontinuation visit (up to approximately 30 months).
To compare the incidence rate of a combined event of arthralgias/arthritis and/or myalgias between Letrozole SIE and Femara®
From the date of the first dose of study intervention to the post-discontinuation visit (up to approximately 30 months).
Time to Response (TTR)
Time Frame: From the date of randomization to the date of the first documented evidence of complete response or partial response (up to approximately 30 months).
TTR, defined for participants with complete response or partial response defined by Investigator assessment per RECIST v1.1 criteria as the interval between randomization and the earliest documentation of response.
From the date of randomization to the date of the first documented evidence of complete response or partial response (up to approximately 30 months).
Duration of response (DOR)
Time Frame: From first documented evidence of complete response (CR) or partial response (PR) until disease progression or death from any cause, whichever occurs first (up to approximately 30 months).
DOR, defined for those participants with complete response (CR) or partial response (PR) as the time from first documented evidence of CR or PR until disease progression by Investigator assessment per RECIST v1.1 criteria, or death from any cause, whichever occurs first.
From first documented evidence of complete response (CR) or partial response (PR) until disease progression or death from any cause, whichever occurs first (up to approximately 30 months).
Clinical benefit rate (CBR)
Time Frame: From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 30 months).
CBR, defined as the proportion of participants with complete response (CR), partial response (PR), or stable disease (SD) ≥ 6 months according to Investigator assessment per RECIST v1.1 criteria.
From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 30 months).
Time to treatment failure (TTF)
Time Frame: From date of randomization to study intervention discontinuation for any reason (up to approximately 30 months).
TTF, defined as the time from randomization to study intervention discontinuation for any reason.
From date of randomization to study intervention discontinuation for any reason (up to approximately 30 months).
Change from baseline in the FACT-G total score
Time Frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G questionnaire. FACT is a modular approach to assess participant health-related quality of life using a 'core' set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. For all questions, participants are asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much.
From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
Change from baseline in the FACT-G Physical well-being subscale score
Time Frame: From the date of randomization to the time of disease progression (up to approximately 30 months).
To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G subscales.
From the date of randomization to the time of disease progression (up to approximately 30 months).
Change from baseline in the FACT-G Social/Familiy well-being subscale score
Time Frame: From the date of randomization to the time of disease progression (up to approximately 30 months).
To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G subscales.
From the date of randomization to the time of disease progression (up to approximately 30 months).
Change from baseline in the FACT-G Emotional well-being subscale score
Time Frame: From the date of randomization to the time of disease progression (up to approximately 30 months).
To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G subscales.
From the date of randomization to the time of disease progression (up to approximately 30 months).
Change from baseline in the FACT-G Functional well-being subscale score
Time Frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-G subscales.
From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
Change from baseline in the FACT-B total score
Time Frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using FACT-B questionnaire. FACT is a modular approach to assess participant health-related quality of life using a 'core' set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. The FACT-B consists of the FACT-G and a breast-specific module: a 10-item instrument designed to assess participant concerns relating to breast cancer. For all questions, participants were asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much.
From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
Change from baseline in the FACT-B Breast Cancer subscale score
Time Frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using the FACT-B questionnaire.
From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
Change from baseline in the FACT-ES total score
Time Frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using the FACT-ES questionnaire. FACT is a modular approach to assess participant health-related quality of life using a 'core' set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. FACT-ES incorporates 19 additional items that assess endocrine related symptoms in addition to the FACT-G core items. For all questions, participants were asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much.
From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
Change from baseline in the FACT-ES Endocrine Symptoms subscale score
Time Frame: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
To compare the health-related quality of life between Letrozole SIE and Femara® (both in combination with the CDK4/6 inhibitor ribociclib) using the FACT-ES questionnaire.
From the date of randomization to the post-discontinuation visit (up to approximately 30 months).
Time to deterioration in the FACT-G total score
Time Frame: From the date of randomization to to the first occurrence of a decrease from baseline of at least 5 points for FACT-G (up to approximately 30 months).
Deterioration will be defined as the time from the date of randomization to the first occurrence of a decrease from baseline of at least 5 points for FACT-G total score.
From the date of randomization to to the first occurrence of a decrease from baseline of at least 5 points for FACT-G (up to approximately 30 months).
Time to deterioration in the FACT-B total score
Time Frame: From the date of randomization to to the first occurrence of a decrease from baseline of at least 7 points for FACT-B (up to approximately 30 months).
Deterioration will be defined as the time from the date of randomization to the first occurrence of a decrease from baseline of at least 7 points for FACT-B total score.
From the date of randomization to to the first occurrence of a decrease from baseline of at least 7 points for FACT-B (up to approximately 30 months).
Time to deterioration in the FACT-ES total score
Time Frame: From the date of randomization to to the first occurrence of a decrease from baseline of at least 7 points for FACT-ES (up to approximately 30 months).
Deterioration will be defined as the time from the date of randomization to the first occurrence of a decrease from baseline of at least 7 points for FACT-ES total score.
From the date of randomization to to the first occurrence of a decrease from baseline of at least 7 points for FACT-ES (up to approximately 30 months).
ESR1 mutation status
Time Frame: From the date of randomization to the time of disease progression (up to approximately 30 months).
Percentage of participants with ESR1 mutations at the time of disease progression among those without ESR1 mutations at baseline.
From the date of randomization to the time of disease progression (up to approximately 30 months).
ESR1 mutant allele frequency
Time Frame: At the time of disease progression (up to approximately 30 months).
ESR1 mutant allele frequency at the time of disease progression.
At the time of disease progression (up to approximately 30 months).
Incidence of Adverse Events (AEs)
Time Frame: From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 88 months).
AEs type, severity, seriousness, and relationship to study intervention, including the incidence of TEAEs, the incidence of serious TEAEs, and the incidence of TEAEs leading to study intervention discontinuation.
From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 88 months).
Incidence of injection site reactions
Time Frame: From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 88 months).
Injection site redness, swelling, and induration will be evaluated before and after Letrozole SIE or injectable placebo administration.
From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 88 months).
Changes in injection-related pain score
Time Frame: From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 88 months).
Injection site pain, self-assessed by participants using an numeric rating scale (NRS) at the time of Letrozole SIE or injectable placebo administration and for a longer period of time if necessary. The numeric rating scale (NRS) evaluates the intensity of injection-related pain experienced at the time of Letrozole SIE/injectable placebo administration. It is scored from 0 to 10 (0 meaning no pain and 10 meaning the worst possible pain).
From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 88 months).
Change from baseline in Bone mineral density (BMD)
Time Frame: From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 30 months).
Change from baseline in BMD assessed by DXA
From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 30 months).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rovi Pharmaceuticals Laboratories

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

August 1, 2026

Primary Completion (Estimated)

February 1, 2029

Study Completion (Estimated)

December 1, 2033

Study Registration Dates

First Submitted

January 9, 2026

First Submitted That Met QC Criteria

January 13, 2026

First Posted (Actual)

January 14, 2026

Study Record Updates

Last Update Posted (Actual)

April 2, 2026

Last Update Submitted That Met QC Criteria

March 27, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ROV-SIE-2025-02
  • 2025-524846-85-00 (Ctis)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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