Evaluation of IM Letrozole ISM® Pharmacokinetics, Safety, and Tolerability in Healthy Post-menopausal Women (LISA-1)

NCT03401320 | Completed Phase 1 DMC

• 2 other identifiers: ROV-LET-2017-01LISA-1
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I, open label, dose escalation study designed to evaluate the pharmacokinetics, safety, and tolerability of single intramuscular injections of Letrozole ISM® at different strengths in voluntary healthy post menopausal women

Conditions

Healthy

Keywords

pharmacokinetics; letrozole

Outcome Measures

Primary Outcomes (12)

• λz

  Terminal phase elimination rate constant

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• Cmax

  Maximum observed plasma concentration

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• Cmax/D

  Dose-normalized Maximum observed plasma concentration

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• tmax

  Time to maximum observed concentration

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• tlag

  Lag time before observation of quantifiable concentrations in plasma

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• t½

  Terminal elimination half life

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• AUC∞

  Area under the concentration time curve from time zero extrapolated to infinity

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• AUC∞/D

  Dose-normalized AUC∞

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• AUCextrap

  Percentage of AUC∞ obtained by extrapolation

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• AUClast

  Area under the concentration time curve from time zero up to the last quantifiable concentration

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• Vz/F

  Apparent volume of distribution during terminal phase after extravascular dosing

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

• CL/F

  Apparent systemic clearance after extravascular dosing

  Following single intramuscular administration of Letrozole ISM (Period 2, Day 1)

Secondary Outcomes (11)

• λz

  Following multiple oral administrations of Femara (Period 1, Day 14)

• Cav

  Following multiple oral administrations of Femara (Period 1, Day 14)

• Cmin,ss

  Following multiple oral administrations of Femara (Period 1, Day 14)

• Cmax,ss

  Following multiple oral administrations of Femara (Period 1, Day 14)

• tmax

  Following multiple oral administrations of Femara (Period 1, Day 14)

Study Arms (4)

Cohort 1: Letrozole ISM 50 mg

EXPERIMENTAL

14 oral doses of 2.5 mg Femara (once daily) + single IM injection of 50 mg Letrozole ISM

Drug: Letrozole ISM

Cohort 2: Letrozole ISM 100 mg

EXPERIMENTAL

14 oral doses of 2.5 mg Femara (once daily) + single IM injection of 100 mg Letrozole ISM

Drug: Letrozole ISM

Cohort 3: Letrozole ISM 200 mg

EXPERIMENTAL

14 oral doses of 2.5 mg Femara (once daily) + single IM injection of 200 mg Letrozole ISM

Drug: Letrozole ISM

Cohort 4: Letrozole ISM 400 mg

EXPERIMENTAL

14 oral doses of 2.5 mg Femara (once daily) + single IM injection of 400 mg Letrozole ISM

Drug: Letrozole ISM

Interventions

Letrozole ISM DRUG

2.5 mg Femara + single IM injection of 50-400 mg Letrozole ISM

Also known as: Femara, 4,4'-(1H- 1,2,4-Triazol-1-ylmethylene)dibenzonitrile

Cohort 1: Letrozole ISM 50 mg; Cohort 2: Letrozole ISM 100 mg; Cohort 3: Letrozole ISM 200 mg; Cohort 4: Letrozole ISM 400 mg

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy post-menopausal women, ≥ 18 and ≤ 75 years of age, who have achieved complete menopause, either natural or surgical, and amenorrhea, and have not been on hormone replacement therapy in the last 3 months.
• Post-menopausal subjects should have absence of menses for 1 year, and oophorectomized subjects should have absence of menses for at least 6 weeks. For oophorectomized subjects and subjects who have had a hysterectomy, a surgical pathology report documenting the absence of malignant disease is required. In addition, for oophorectomized subjects an operative report documenting bilateral oophorectomy is required.
• Baseline follicle-stimulating hormone (FSH) and 17β-estradiol plasma levels should be consistent with the post-menopausal status of the subject (FSH ≥ 40 mIU/mL; 17β-estradiol ≤ 31 pg/mL), confirmed at least 48 hours prior to dosing.
• Weight of ≥ 50 kg and a BMI ≥ 19 and ≤ 39 kg/m2.
• Subjects will be in good health, as determined by medical history, physical examination, vital signs assessments (pulse rate, systolic and diastolic blood pressure, and temperature), clinical laboratory evaluations, and 12-lead ECG. Minor deviations outside the reference ranges will be acceptable, if deemed not clinically significant by the investigator.
• Subjects who have not had a mammogram within the last 12 months (documentation required) must be willing to have one performed.
• Subjects with an intact uterus and cervix who have not had a Papanicolaou (pap) smear test within the last 6 months (documentation required) must be willing to have one performed.
• Subjects will have given their written informed consent to participate in the study and to abide by the study restrictions.
• Subjects should be able to communicate with clinic staff.

You may not qualify if:

• Subjects who have a history of allergy or hypersensitivity to letrozole or any of the inactive ingredients in the last 3 months.
• Subjects who have a history of galactose intolerance, severe hereditary lactase deficiency glucose-galactose malabsorption.
• Subjects who have used estrogen or progesterone hormone replacement therapy, thyroid replacement therapy, oral contraceptives, androgens, luteinizing hormone (LH) releasing hormone analogs, prolactin inhibitors, or antiandrogens within 3 months prior to Screening.
• Subjects who have regularly taken foods or food supplements that contain high levels of Isoflavinoids, including soybean, soymilk, soynuts, chickpeas, alfalfa, fava beans, kudzu, miso and tofu in the 14 days prior to dosing (Treatment Period 1).
• The investigator and medical monitor will determine on a case-by-case basis if a subject who intakes food or food supplements containing Isoflavinoids is eligible to participate in the study.
• Subjects who have used:
• Any medications including St. John's wort, known to be potent or moderate inducers of CYP P450 3A4 in the 3 weeks prior to dosing (Treatment Period 1).
• Any medications or products known to be potent or moderate inhibitors of CYP P450 3A4 (e.g. grapefruit juice) in the 7 days prior to dosing on Treatment Period 1.
• Any prescribed preparations within 14 days prior to dosing (Treatment Period 1), unless in the opinion of the investigator (or designee) the medication will not interfere with the study procedures or compromise safety.
• Any non-prescribed systemic or topical medications within 7 days of dosing (Treatment Period 1) unless in the opinion of the investigator (or designee) the medication will not interfere with the study procedures or compromise safety. Vitamins and minerals including the use of calcium and/or vitamin D for osteoporosis prevention are allowed.
• Subjects who have been diagnosed with osteoporosis (previously or results from screening DEXA for this study with a T score \< -2.5). Subjects with osteopenia (with the T-score between -1 and -2.5) will be allowed to participate in this study.
• Subjects who are not on a stable dose of long- or short-acting bisphosphonates therapy for at least 3 months prior to Screening.
• Subjects who are on raloxifene therapy.
• Subjects who have an abnormality in heart rate, blood pressure, or temperature at Screening and prior to first dose (Treatment Period 1) that in the opinion of the investigator increases the risk of participating in the study. Resting SBP must be ≤ 150mmHg and resting DBP ≤ 95 mmHg.
• Subjects who have an abnormality in the 12-lead ECG at Screening and prior to first dose (Treatment Period 1) that in the opinion of the Investigator increases the risk of participating in the study.

Sponsors & Collaborators

• Rovi Pharmaceuticals Laboratories: lead

Study Sites (1)

Investigational Site Number 42001

Prague, Czech Republic, 10, Czechia

Location

MeSH Terms

Interventions

Letrozole

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Javier Martínez, MD

  Laboratorios Farmaceuticos Rovi, S.A.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Phase I, open label, sequential, single ascending dose

Study Record Dates

• First Submitted: January 8, 2018
• First Posted: January 17, 2018
• Study Start: November 6, 2017
• Primary Completion: May 17, 2024
• Study Completion: May 17, 2024
• Last Updated: December 4, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (1)