Hormone Receptor Positive Early Breast Cancer
Conditions
Keywords
Letrozole SIE, Early breast cancer, Pharmacokinetics, Bioavailability, Safety, Endocrine therapy, Injectable
Brief summary
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.
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.
Interventions
DRUGUS-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)
DRUGEU 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)
Sponsors
Rovi Pharmaceuticals Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area under the concentration-time curve within a dosing interval at Steady-State (SS AUCtau) | 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 | Individual and mean area under the concentration-time curve within a dosing interval at steady-state |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | 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) | 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. |
| Injection site reactions | At pre-dose and 1 hour after each Letrozole SIE administration in TP2 | Incidence of injection site reactions |
| Injection-related pain score | From baseline TP2 to the follow-up visit on Day 281 | 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). |
| Bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA) | From screening to Day 281 TP2 | Changes in bone mineral density BMD by DXA |
| Average plasma drug concentration during a dosing interval at Steady-State (SS Cave) | 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 | Individual and mean steady-state average plasma drug concentration during a dosing interval |
| Minimum drug concentration at steady-state (Cmin ss) | 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 |
| Maximum plasma concentration at steady-state (Cmax ss) | 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 | Maximum plasma concentration at steady-state |
| Letrozole blood level 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 | Individual and mean letrozole blood percent fluctuation |
| Time to peak observed concentration (Tmax) | 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 | Time to peak observed concentration |
| Steady-State (SS) | 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 | Characterization of the steady-state |
| Terminal rate constant (λz) | After multiple doses of Letrozole SIE in TP2 until Day 421 in the Extension Period | Individual and mean Terminal rate constant (λz) after multiple doses of Letrozole SIE in the subset of participants in the Extension Period |
| Terminal half-life (t1/2) | After multiple doses of Letrozole SIE in TP2 until Day 421 in the Extension Period | Individual and mean Terminal half-life after multiple doses of Letrozole SIE in the subset of participants in the Extension Period |
| Area under the curve extrapolated to infinity (AUC∞) | After multiple doses of Letrozole SIE in TP2 until Day 421 in the Extension Period | 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 |
| Area under the curve that is extrapolated (AUCextrap) | After multiple doses of Letrozole SIE in TP2 until Day 421 in the Extension Period | Percentage of area under the curve that is extrapolated after multiple doses of Letrozole SIE in the subset of participants in the Extension Period |
Countries
Serbia, Spain, United States
Contacts
CONTACTClinical Operations. Laboratorios Farmacéuticos ROVI
Outcome results
None listed