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)

Plain English Summary

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 is a Phase 3 clinical trial sponsored by Rovi Pharmaceuticals Laboratories studying Advanced, Metastatic Breast Cancer. This study tests a new injectable form of letrozole (Letrozole SIE) combined with ribociclib against the standard oral form of letrozole (Femara®) also combined with ribociclib. It is for postmenopausal women with HR-positive, HER2-negative, inoperable locally advanced or metastatic breast cancer who have not received prior systemic treatment for their advanced disease. Participants will receive either the new injectable treatment or the standard oral treatment, along with ribociclib, and will be monitored for side effects and treatment effectiveness. Alternatives include other CDK4/6 inhibitors combined with hormonal therapies, or chemotherapy, depending on prior treatments and disease characteristics. The trial aims to enroll 300 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Women who are postmenopausal and have advanced or metastatic breast cancer that is HR-positive and HER2-negative can join. You must not have received any systemic treatment for your advanced cancer before, though prior chemotherapy for early-stage breast cancer is allowed if the cancer has returned. Participants should have measurable disease or bone-only disease and be generally well enough to participate (ECOG performance status 0-2). You cannot join if you have rapidly progressing cancer with life-threatening complications, uncontrolled brain metastases, active heart disease, or certain other serious medical conditions. This trial is studying Advanced, Metastatic Breast Cancer, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome, Progression Free Survival (PFS), measures how long patients live without their cancer getting worse, which is a key indicator of how well the treatment is working. The specific primary outcome measures are: Progression Free Survival (PFS) (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).). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial is important because it explores a new, potentially more convenient injectable formulation of a standard breast cancer drug, aiming to improve treatment options for women with advanced HR-p As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Advanced, Metastatic Breast Cancer, where improved treatment options are needed.

Investor Insight

This trial addresses a significant market for advanced breast cancer treatments, comparing a novel drug delivery method against an established regimen, with potential for improved patient compliance a Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about the potential benefits and risks of both the injectable and oral treatments, and how they might fit your specific situation. Understand that participation involves regular clinic visits for treatment, monitoring, and tests, which may include blood work, scans, and physical exams. Be prepared for potential side effects and discuss any new or worsening symptoms with your healthcare team promptly. The trial is being conducted at multiple sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: QUADRUPLE
• Enrollment: 300 participants

Interventions

• DRUG: Letrozole SIE + Ribociclib + Oral placebo — Letrozole SIE quarterly (injectable) + Ribociclib once daily (oral) + placebo once daily (oral)
• DRUG: Oral Femara® + Ribociclib + Injectable placebo — Femara® 2.5 mg/day (oral) + Ribociclib once daily (oral) + placebo quarterly (injectable)

Primary Outcomes

• Progression Free Survival (PFS) (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

• Overall Survival (OS): Primary analysis (From the date of randomization to date of death from any cause (up to approximately 30 months).)
• Overall Survival (OS): Final analysis (From the date of randomization to date of death from any cause (up to approximately 88 months).)
• Objective Response Rate (ORR) (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 (From the date of the first dose of study intervention to the post-discontinuation visit (up to approximately 30 months).)
• Time to Response (TTR) (From the date of randomization to the date of the first documented evidence of complete response or partial response (up to approximately 30 months).)

Full Eligibility Criteria

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.

Frequently Asked Questions

Related Conditions

• Breast Cancer
• Metastatic Breast Cancer
• Locally Advanced Breast Cancer
• Hormone Receptor-Positive Breast Cancer
• HER2-Negative Breast Cancer
• Postmenopausal Breast Cancer
• Endocrine Therapy Resistance
• Targeted Therapy
• Oncology
• Cancer Treatment

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