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Advanced, Metastatic Breast CancerPhase 3SIE-3NCT07340658

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

A Phase 3 study of Advanced, Metastatic Breast Cancer, run by Rovi Pharmaceuticals Laboratories.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Advanced, Metastatic Breast Cancer
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
300 participants
Where
No sites listed yet
Study dates
Aug 2026to Dec 2033
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

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

Trial locations and contacts

No sites are listed yet. Contact the study team or a site near you to ask about taking part.

Clinical Operations. Laboratorios Farmacéuticos ROVI contact

+34 913756230

departamento.medico@rovi.es

About this study

Official title: 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.

Read the 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.

Being tested
Letrozole SIE + Ribociclib + Oral placebo, Oral Femara® + Ribociclib + Injectable placebo
Keywords
Letrozole SIE, Advanced breast cancer, Metastatic breast cancer, Endocrine therapy, Efficacy, Safety, Injectable, Ribociclib
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Letrozole SIE + Ribociclib + Oral placeboDrug

    Letrozole SIE quarterly (injectable) + Ribociclib once daily (oral) + placebo once daily (oral)

  • Oral Femara® + Ribociclib + Injectable placeboDrug

    Femara® 2.5 mg/day (oral) + Ribociclib once daily (oral) + placebo quarterly (injectable)

Study groups in NCT07340658
Study groupRoleWhat they receive
Letrozole SIEExperimentalNot described
Receives: Drug: Letrozole SIE + Ribociclib + Oral placebo
Femara® 2.5 mgActive comparatorNot described
Receives: Drug: Oral Femara® + Ribociclib + Injectable placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression Free Survival (PFS)

    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.

    Measured: 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 outcomes (26)
  1. Overall Survival (OS): Primary analysis

    OS, defined as the time from the date of randomization to date of death from any cause.

    Measured: From the date of randomization to date of death from any cause (up to approximately 30 months).

  2. Overall Survival (OS): Final analysis

    OS, defined as the time from the date of randomization to date of death from any cause.

    Measured: From the date of randomization to date of death from any cause (up to approximately 88 months).

  3. Objective Response Rate (ORR)

    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.

    Measured: 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).

  4. Incidence of arthralgias/arthritis and/or myalgias

    To compare the incidence rate of a combined event of arthralgias/arthritis and/or myalgias between Letrozole SIE and Femara®

    Measured: From the date of the first dose of study intervention to the post-discontinuation visit (up to approximately 30 months).

  5. Time to Response (TTR)

    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.

    Measured: From the date of randomization to the date of the first documented evidence of complete response or partial response (up to approximately 30 months).

  6. Duration of response (DOR)

    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.

    Measured: 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).

  7. Clinical benefit rate (CBR)

    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.

    Measured: 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).

  8. Time to treatment failure (TTF)

    TTF, defined as the time from randomization to study intervention discontinuation for any reason.

    Measured: From date of randomization to study intervention discontinuation for any reason (up to approximately 30 months).

  9. Change from baseline in the FACT-G total score

    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.

    Measured: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

  10. Change from baseline in the FACT-G Physical well-being subscale score

    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.

    Measured: From the date of randomization to the time of disease progression (up to approximately 30 months).

  11. Change from baseline in the FACT-G Social/Familiy well-being subscale score

    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.

    Measured: From the date of randomization to the time of disease progression (up to approximately 30 months).

  12. Change from baseline in the FACT-G Emotional well-being subscale score

    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.

    Measured: From the date of randomization to the time of disease progression (up to approximately 30 months).

  13. Change from baseline in the FACT-G Functional well-being subscale score

    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.

    Measured: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

  14. Change from baseline in the FACT-B total score

    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.

    Measured: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

  15. Change from baseline in the FACT-B Breast Cancer subscale score

    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.

    Measured: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

  16. Change from baseline in the FACT-ES total score

    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.

    Measured: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

  17. Change from baseline in the FACT-ES Endocrine Symptoms subscale score

    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.

    Measured: From the date of randomization to the post-discontinuation visit (up to approximately 30 months).

  18. Time to deterioration in the FACT-G total score

    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.

    Measured: 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).

  19. Time to deterioration in the FACT-B total score

    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.

    Measured: 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).

  20. Time to deterioration in the FACT-ES total score

    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.

    Measured: 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).

  21. ESR1 mutation status

    Percentage of participants with ESR1 mutations at the time of disease progression among those without ESR1 mutations at baseline.

    Measured: From the date of randomization to the time of disease progression (up to approximately 30 months).

  22. ESR1 mutant allele frequency

    ESR1 mutant allele frequency at the time of disease progression.

    Measured: At the time of disease progression (up to approximately 30 months).

  23. Incidence of Adverse Events (AEs)

    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.

    Measured: From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 88 months).

  24. Incidence of injection site reactions

    Injection site redness, swelling, and induration will be evaluated before and after Letrozole SIE or injectable placebo administration.

    Measured: From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 88 months).

  25. Changes in injection-related pain score

    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).

    Measured: From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 88 months).

  26. Change from baseline in Bone mineral density (BMD)

    Change from baseline in BMD assessed by DXA

    Measured: From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 30 months).

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jan 2026
  2. Study startAug 2026 (estimated)
  3. Primary completionFeb 2029 (estimated)
  4. Study completionDec 2033 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
300 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07340658
Sponsor's protocol ID
ROV-SIE-2025-02
Other IDs
2025-524846-85-00, 2025
Acronym
SIE-3
Status last verified
Mar 2026
First submitted
9 Jan 2026
Last updated
2 Apr 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study of Advanced, Metastatic Breast Cancer, run by Rovi Pharmaceuticals Laboratories.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 2 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Clinical Operations. Laboratorios Farmacéuticos ROVI (+34 913756230, departamento.medico@rovi.es), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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).). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Apr 2026.

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