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

ROVI

Status and phase

Begins enrollment in 2 months

Phase 3

Conditions

Advanced, Metastatic Breast Cancer

Treatments

Drug: Letrozole SIE + Palbociclib + Oral placebo

Drug: Oral Femara® + Palbociclib + Injectable placebo

Study type

Interventional

Funder types

Industry

Identifiers

NCT07340658

ROV-SIE-2025-02

2025-524846-85-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

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 palbociclib, for the first-line treatment of postmenopausal women with HR-positive, HER2-negative, inoperable locally advanced or metastatic breast cancer.

Full 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 palbociclib) 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 palbociclib. 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.

Enrollment

300 estimated patients

Sex

Female

Ages

18+ years old

Volunteers

No Healthy Volunteers

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 enrolment.
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 5.0 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.
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 a 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.
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.
Use of estrogen or progesterone hormone replacement therapy, oral contraceptives, androgens, LHRH analogs, prolactin inhibitors, or antiandrogens within 3 months prior to randomization.
Use of the following medications within the three previous days or a period of 5 half-lives, whichever is longer prior to randomization:
1. Any medications including St. John's wort, known to be potent or moderate inducers of Cytochrome P450 (CYP) 3A.
2. Any medications or products known to be potent or moderate inhibitors of CYP3A (e.g., 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.