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

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

The objective of this study is to assess the pharmacokinetic profile of a single ascending doses of Letrozole ISM® (Rovi), and secondly, to evaluate safety and tolerability of single ascending doses of Letrozole ISM, measure estrogen levels, and characterize oral letrozole pharmacokinetic profile to be used in subsequent comparison to Letrozole ISM.

The study will be carried out in healthy post-menopausal women who satisfy inclusion and exclusion criteria.

The study consists of 3 treatment periods (TP) (TP1, TP2 and TP3) preceding by 2 Screening Periods (one for TP1 and one for TP3). In TP1, each subject will sequentially receive 1 dose daily of oral Femara (EU sourced) over a period of 14 days followed by a single intramuscular (IM) dose of Letrozole ISM (after a washout period) in TP2. Ascending doses of Letrozole ISM will be given sequentially to four Cohorts (1, 2, 3, and 4) \[NOTE: Cohorts 3 and 4 were not finally performed because the Safety Review Committee considered it was not necessary for the achieving the objectives of the study\] . All subjects who will finalize TP2 and fulfil the eligibility criteria will be offered to participate in TP3. The purpose is to have, at least, a minimum of 12 subjects receiving one oral daily dose of Femara (US sourced) 2.5 mg QD for a period of 14 days, to provide a complete pharmacokinetic (PK)/pharmacodynamic (PD) face-to-face comparison.

Eligibility Criteria:
Inclusion Criteria:

1. 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.
2. 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.
3. 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.
4. Weight of ≥ 50 kg and a BMI ≥ 19 and ≤ 39 kg/m2.
5. 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.
6. Subjects who have not had a mammogram within the last 12 months (documentation required) must be willing to have one performed.
7. 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.
8. Subjects will have given their written informed consent to participate in the study and to abide by the study restrictions.
9. Subjects should be able to communicate with clinic staff.

Exclusion Criteria:

1. Subjects who have a history of allergy or hypersensitivity to letrozole or any of the inactive ingredients in the last 3 months.
2. Subjects who have a history of galactose intolerance, severe hereditary lactase deficiency glucose-galactose malabsorption.
3. 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.
4. 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).

   4.1. 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.
5. Subjects who have used:

   5.1. 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).

   5.2. 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.
6. 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.
7. 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.
8. 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.

   8.1. Subjects who are not on a stable dose of long- or short-acting bisphosphonates therapy for at least 3 months prior to Screening.

   8.2. Subjects who are on raloxifene therapy.
9. 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.
10. 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.
11. Subjects who have any clinically significant abnormal physical examination finding.
12. Subjects who have any clinically significant abnormal laboratory safety findings at Screening or Check-in, upon repeat testing, as determined by the investigator (1 repeat assessment is acceptable).

    12.1. Subjects who have ALT or AST \>1.5 × ULN. For subjects with elevated total bilirubin, direct and indirect bilirubin will be evaluated.

    12.2. Subjects with elevated cholesterol or triglyceride levels above the ULN must be determined by the Investigator to be not clinically significant.
13. Subjects who have relevant diseases or clinically significant abnormal relevant findings at Screening, as determined by medical history, physical examination, laboratory, ECG, DEXA, and breast and pelvic examination.
14. Subjects who have history of any significant chronic disease, such as but not limited to: thrombotic disorders, coronary artery or cerebrovascular disease, liver, kidney or gallbladder dysfunction/disorder(s), diabetes or any other endocrine disease, estrogen dependent neoplasia, post-menopausal uterine bleeding, or endometrial hyperplasia. Subjects with cholecystectomy will be permitted if no medical sequelae post-surgery.
15. History of cancer within the past 5 years with the exception of non-melanoma skin cancer.
16. Subjects who have a history of drug-dependence, and recent history of alcoholism or abuse of alcohol.
17. Subjects who have a positive result for hepatitis B surface antigen (HBsAg), hepatitis B core antibody, hepatitis C antibody, or human immunodeficiency virus (HIV) antibodies.
18. Subjects with a positive drugs of abuse screen or alcohol breath test at Screening (urine will be screened for the presence of the following: amphetamine, barbiturates, benzodiazepines, cannabinoid, cocaine, opiates, phencyclidine, and methadone).
19. Subjects with a history of, or difficulty of, access to veins for venipuncture.
20. Subjects who have donated blood in the 30 days prior to first dose (Treatment Period 1).
21. Subjects who have received blood products within 2 months prior to Screening.
22. Subjects who have received a drug in research or have participated in other clinical trials within 30 days, or 5 half-lives (whichever is longer) prior to dosing (Treatment Period 1).
23. Subjects who have previously taken part in or have withdrawn from this study. (Subjects who have been screened for but not included in a cohort or subjects who dropped out from screening in a previous cohort for non-medical reasons may be eligible to be included in subsequent cohorts.)
24. Any other unspecified reason that, in the opinion of the investigator (or designee) or Sponsor, makes the subject unsuitable for enrollment.