A Study to Compare the Steady-State Bioavailability of Injectable Letrozole SIE and Oral Letrozole in Post-Menopausal Women With Hormone Receptor Positive Early Breast Cancer (SIE-1)

An Open-Label, One-Sequence Study to Evaluate the Steady-State Comparative Bioavailability of Quarterly Letrozole SIE and Once Daily 2.5 mg Oral Letrozole (Femara®) in Post-Menopausal Women Treated With Endocrine Therapy for Hormone Receptor-Positive Early Breast Cancer. (SIE-1)

The study aims to compare the amount of the drug letrozole that gets into the bloodstream after multiple doses of the quarterly injection Letrozole SIE, versus multiple doses of the standard oral daily tablet of letrozole (Femara®), in women who have gone through menopause and have received treatment for hormone receptor-positive early breast cancer. Participants must have completed at least five years of hormone therapy with at least two of those years with letrozole before starting their participation in the study. Women who have completed four years of hormone therapy are also eligible if their doctor considers them at low risk of cancer returning.

Study Overview

• Status: Not yet recruiting
• Conditions: Hormone Receptor Positive Early Breast Cancer
• Intervention / Treatment: Drug: US-sourced oral Femara® + Letrozole SIE; Drug: EU sourced oral Femara® + Letrozole SIE

Detailed Description

The primary objective of the study is to evaluate the steady-state comparative bioavailability of quarterly injectable Letrozole SIE compared to United States (US)-sourced oral Femara® in the US-sourced arm and of quarterly injectable Letrozole SIE compared to European Union (EU)-sourced oral Femara® in the EU-sourced arm, in post-menopausal women treated with endocrine therapy for hormone-receptor positive (HR+) early breast cancer (EBC). The study also aims to characterize the elimination phase of Letrozole SIE after multiple doses.

The study consists of four periods: Screening, Treatment Period 1 (TP1), Treatment Period 2 (TP2) and Extension Period. After the Screening Period, participants will be randomized to two different arms: US-sourced oral Femara® or EU-sourced oral Femara® for 14 days to achieve the steady-state concentrations of letrozole in TP1. After receiving the latest oral letrozole dose, participants from both arms will start TP2. In TP2, quarterly injectable Letrozole SIE will be administered to achieve steady-state. After TP2, a subset of participants (up to 60 participants, regardless of which study arm they belong to) will continue in the study for the assessment of the elimination phase of Letrozole SIE after multiple doses during the Extension Period.

It is estimated that approximately 120 subjects should be randomized.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Operations. Laboratorios Farmacéuticos ROVI; Phone Number: +34913756230; Email: departamento.medico@rovi.es

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women with weight of ≥50 kg and a Body Mass Index (BMI) ≥19 kg/m2 and ≤39 kg/m2
• Postmenopausal women.
• Women with confirmed diagnosis of HR+/HER2- or HR+/HER2+ early stage breast cancer who have completed at least 5 years of endocrine therapy, at least 2 years of which were with letrozole. Participants at a low risk of relapse, as assessed by the investigator, can also be eligible after completing 4 years of adjuvant endocrine therapy, at least 2 of which were with letrozole.
• Women in good health.
• Women who have undergone breast imaging per applicable guidelines (e.g., mammogram) within the last 12 months with no evidence of malignancy (documentation required), and if not done, must be willing to have 1 performed prior to baseline.

Exclusion Criteria:

• Presence of an uncontrolled, unstable, clinically significant medical condition.
• Have used estrogen or progesterone systemic or topical therapy, oral contraceptives, androgens, LH-releasing hormone analogs, prolactin inhibitors, or antiandrogens within 3 months prior to screening.
• Use of inducers or inhibitors of CYP3A4 and CYP2A6.
• Diagnosed with osteoporosis.
• Preexisting cardiovascular disease
• Positive result for hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, or HIV antibodies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: US-sourced oral Femara®	Drug: US-sourced oral Femara® + Letrozole SIE; US-sourced Femara® 2.5 mg/day oral for 14 days (treatment period 1) + quarterly injectable Letrozole SIE (treatment period 2)
Experimental: EU-sourced oral Femara®	Drug: EU sourced oral Femara® + Letrozole SIE; EU-sourced oral Femara® 2.5 mg/day for 14 days (treatment period 1) + quarterly injectable Letrozole SIE (treatment period 2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the concentration-time curve within a dosing interval at Steady-State (SS AUCtau)	Individual and mean area under the concentration-time curve within a dosing interval at steady-state	After multiple doses of Letrozole SIE until Day 281 TP2 and after multiple doses of US-sourced oral Femara® or EU-sourced oral Femara® on Day 14 TP1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Incidence of adverse events (type, severity, seriousness, and relationship to study drug), including the incidence of treatment-emergent adverse events (TEAEs), the incidence of serious TEAEs, and the incidence of TEAEs leading to treatment discontinuation.	From the time of obtaining signed informed consent until the final follow-up visit on Day 281 (or Day 421 for the subset of participants in the Extension Period)
Injection site reactions	Incidence of injection site reactions	At pre-dose and 1 hour after each Letrozole SIE administration in TP2
Injection-related pain score	Changes in injection-related pain score by numeric rating scale (NRS). The NRS evaluates the intensity of injection-related pain experienced at the time of Letrozole SIE administration. It is scored from 0 to 10 (0 meaning no pain and 10 meaning the worst possible pain).	From baseline TP2 to the follow-up visit on Day 281
Bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA)	Changes in bone mineral density BMD by DXA	From screening to Day 281 TP2
Average plasma drug concentration during a dosing interval at Steady-State (SS Cave)	Individual and mean steady-state average plasma drug concentration during a dosing interval	After multiple doses of Letrozole SIE until Day 281 TP2 and after multiple doses of US-sourced oral Femara® or EU-sourced oral Femara® at Day 14 TP1
Minimum drug concentration at steady-state (Cmin ss)	Minimum drug concentration at steady-state	After multiple doses of Letrozole SIE until Day 281 TP2 and after multiple doses of US-sourced oral Femara® or EU-sourced oral Femara® at Day 14 TP1
Maximum plasma concentration at steady-state (Cmax ss)	Maximum plasma concentration at steady-state	After multiple doses of Letrozole SIE at Day 281 TP2 and after multiple doses of US-sourced oral Femara® or EU-sourced oral Femara® at Day 14 TP1
Letrozole blood level percent fluctuation	Individual and mean letrozole blood percent fluctuation	After multiple doses of Letrozole SIE at Day 281 TP2 and after multiple doses of US-sourced oral Femara® or EU-sourced oral Femara® at Day 14 TP1
Time to peak observed concentration (Tmax)	Time to peak observed concentration	After multiple doses of Letrozole SIE until Day 281 TP2 and after multiple doses of US-sourced oral Femara® or EU-sourced oral Femara® at Day 14 TP1
Steady-State (SS)	Characterization of the steady-state	After multiple doses of Letrozole SIE until Day 281 TP2 and after multiple doses of US-sourced oral Femara® or EU-sourced oral Femara® at Day 14 TP1
Terminal rate constant (λz)	Individual and mean Terminal rate constant (λz) after multiple doses of Letrozole SIE in the subset of participants in the Extension Period	After multiple doses of Letrozole SIE in TP2 until Day 421 in the Extension Period
Terminal half-life (t1/2)	Individual and mean Terminal half-life after multiple doses of Letrozole SIE in the subset of participants in the Extension Period	After multiple doses of Letrozole SIE in TP2 until Day 421 in the Extension Period
Area under the curve extrapolated to infinity (AUC∞)	Individual and mean Area under the curve extrapolated to infinity after multiple doses of Letrozole SIE in the subset of participants in the Extension Period	After multiple doses of Letrozole SIE in TP2 until Day 421 in the Extension Period
Area under the curve that is extrapolated (AUCextrap)	Percentage of area under the curve that is extrapolated after multiple doses of Letrozole SIE in the subset of participants in the Extension Period	After multiple doses of Letrozole SIE in TP2 until Day 421 in the Extension Period

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hormone supression	Analysis of letrozole exposure and hormone suppression measuring the sex hormone estrone (E1), sulfate estrone (SE1), and estradiol (E2) plasma levels.	From screening to the final follow-up visit on Day 281 (or Day 421 for the subset of participants in the Extension Period)
CYP2A6 genotyping	Proportion of participants in each CYP2A6 metabolizer phenotype category (normal, intermediate, slow)	From screening to final follow-up visit Day 281 (or Day 421 for the subset of participants in the Extension Period)

Collaborators and Investigators

• Sponsor: Rovi Pharmaceuticals Laboratories

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: January 22, 2026
• First Submitted That Met QC Criteria: February 3, 2026
• First Posted (Actual): February 10, 2026

Study Record Updates

• Last Update Posted (Actual): February 10, 2026
• Last Update Submitted That Met QC Criteria: February 3, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Bioavailability; Endocrine therapy; Early breast cancer; Injectable; Letrozole SIE
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: ROV-SIE-2025-01; 2025-523269-31-00 (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