Exploratory study to evaluate the safety and tolerability of tamoxifen citrate in the treatment of cystic fibrosis in patients without mutations currently eligible for therapy with CFTR modulator drugs

Prior treatment

• Patients on any CFTR modulator therapy
• Participation in a clinical study where an investigational drug was administered within 30 days prior to enrollment in the study or 5 half-lives of the study drug, whichever is longer
• Female patients of childbearing potential who do not use adequate contraception. A woman is considered of childbearing potential (WOCBP), i.e., fertile, after menarche and until reaching post-menopause, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as the absence of menstruation for 12 months without an alternative medical cause. An elevated follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of menstrual cycle, a single FSH measurement is not sufficient.
• Pulmonary exacerbations within 3 weeks before Day 1 (first dose of study drug)
• Changes in therapy for lung disease within 3 weeks before Day 1 (first dose of study drug).

Other illness

• Any surgical or medical condition that may significantly alter the absorption, distribution, metabolism, or excretion of drugs, or that may jeopardize the subject in case of participation in the study.
• History of immunodeficiency diseases
• History of drug or alcohol abuse
• History of any disease or condition that, in the investigator’s opinion, could confound the study results.
• Family and/or personal history of thromboembolism and thromboembolic conditions up to 1st-degree relatives
• History of solid organ or hematopoietic transplant
• History of hypersensitivity to the study drug or drugs of similar chemical classes or any excipients
• History of malignancy in any organ system (other than localized basal cell carcinoma of the skin) in the last 5 years

Lab values

• Hemoglobin levels < 9.0 g/dl
• Abnormal liver function, defined as ≥ 3 times the upper limit of normal (ULN) for any of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), total bilirubin
• History or presence of prolonged QT interval (QTcB > 450 msec)

Other

• Presence at baseline visit of endometrial polyps or vaginal symptoms (e.g., blood discharge, spotting, staining).
• Female patients who are pregnant or breastfeeding or who wish to become pregnant during the clinical study period and within one month after the end of the study.
• Documented hereditary thrombophilia (hypercoagulability), e.g., protein C, protein S, and antithrombin deficiency; factor V G169A Leiden, prothrombin G20210A (PT20210A), elevated factor VIII levels, hereditary dysfibrinogenemia.

• Subjects of both sexes, affected by cystic fibrosis, attending the CF Center in Verona
• Subjects able to perform reliable and reproducible pulmonary function test maneuvers
• Subjects able to communicate well with the investigator, understand, and comply with the study requirements
• Female subjects must have a negative serum pregnancy test
• Sexually active subjects able to follow the contraceptive methods defined within the protocol (non-hormonal contraception) during the study and for 2 months after study discontinuation
• Signed informed consent for participation in the study and for the processing of personal data
• Patients who do not have mutations currently eligible for therapy with CFTR modulator drugs
• Age 18 years or older
• Predicted forced expiratory volume in 1 second (ppFEV1) ≥ 40% and ≤ 90% (of the predicted value for people of their age, sex, and height) before bronchodilator administration
• Stable routine CF therapy in terms of dose and medication (inhaled antibiotic cycles, bronchodilator, anti-inflammatory, inhaled corticosteroid, physiotherapy technique/schedule) within 28 days prior to Day 1
• Clinically stable respiratory disease within 3 weeks before Day 1 (first dose of study drug)