Evaluating Efficacy and Safety of Danazol in Severe Hematologic or Pulmonary Disease Related to Telomeropathy (ANDROTELO)

Essai Bayésien de Phase I/II évaluant l'efficacité et la tolérance du Danazol Chez Les Patients Ayant Une Atteinte hématologique ou Pulmonaire sévère liée à Une téloméropathie - ANDROTELO

Constitutional mutations of genes involved in telomere repair and maintenance are responsible for "telomeropathy" (" Congenital Dyskeratosis "). Attrition of telomeres promotes cell senescence and genetic instability. The penetrance and severity of organ damage (pulmonary, hematological, liver, and neurological) is variable, depending on the gene involved, the generation concerned (anticipation phenomenon) and also environmental factors.

In cases of bone marrow failure, the only curative treatment is hematopoietic stem cell transplant, often limited by pulmonary and / or hepatic involvement or the absence of a suitable HLA match donor. The pulmonary phenotype is most often that of idiopathic pulmonary fibrosis. In severe forms, a lung transplant is proposed in the absence of contraindications. Anti-fibrotic treatments are not very effective or not evaluated. The observed decrease in the vital capacity of these patients is 300 ml / year, abnormally high compared to idiopathic forms. Evolution without transplant is in both situations rapidly unfavorable; the prognosis after lung or marrow transplant is also worse than that of similar transplants without telomeres disease.

Danazol has been used for over 4 decades in acquired and constitutional bone marrow failure in the absence of a therapeutic alternative. In telomeropathy, retrospective data on small cohorts indicate a haematological response rate of 60-70%. A prospective study in the United States recently showed a haematological response at 1 year in 78% of cases (10 of 12 evaluable patients) with stabilization of vital capacity. Retrospective data (unpublished) on patients treated in France have shown more side effects and more frequent treatment interruptions and eventually weaker haematological response rate. This study aim to evaluate the benefit of danazol at 12 months on the clinical response.

Study Overview

• Status: Unknown
• Conditions: Telomere Length, Mean Leukocyte; Telomere Shortening
• Intervention / Treatment: Drug: Danazol 200 MG

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Flore SICRE DE FONTBRUNE, MD PhD; Phone Number: +33 142494949; Email: flore.sicre-de-fontbrune@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• with telomeropathy defined by the existence of a deleterious constitutional mutation of a gene involved in telomere maintenance (TERT, TERC, DKC1, TINF2, RTEL1, PARN, ACD, NHP2, NOP10, NAF1, WRAP53, CTC1, ERCC6L2, USB1, POT1, DNAJC21 or a newly identified gene responsible for telomeropathy ),
• 15 years or older,
• with severe haematological involvement (platelets < 20 G/L or ANC < 0.5 G/L and/or hemoglobin < 8 g/dL and/or transfusion needs) and/or pulmonary fibrosis with parenchymal involvement greater than 10% on the CT scan.
• being able to give informed consent for patients 18 years and older,
• being able to give consent and have the consent of the holder (s) of parental authority for children over 15 years,
• being a beneficiary of social security scheme.

Exclusion Criteria:

• with HIV infection or active hepatitis B or C infection,
• with severe hepatic disease: ASAT and/or ALAT > 5N, or direct bilirubinemia > 30 μmol/L, TP <50% (except vitamin K deficiency),
• having an active or treated tumor pathology for less than 5 years with the exception of a basocellular carcinoma or a in situ carcinoma of the cervix,
• with a history of organ or hematopoietic stem cell transplantation or with an indication of hematopoietic stem cell or organ transplantation within 6 months of inclusion,
• with an absolute contraindication to treatment with danazol: active thrombosis or history of thromboembolic disease, porphyria, severe renal or cardiac insufficiency (NYHA stage III or IV), androgen-dependent tumor, uncharacterized mammary nodules, pathological genital hemorrhage of undetermined etiology,
• who have already received danazol for the treatment of telomeropathy,
• having received another androgen within a period of less than 6 months,
• receiving another experimental treatment,
• receiving another hormonal therapy,
• receiving simvastatin,
• having a pregnancy plan and not committing to effective contraception while taking the treatment,
• breastfeeding,
• under guardianship or curators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Danazol	Drug: Danazol 200 MG; DANAZOL 200 mg as capsules 800 mg/d orally, in 2 doses Duration of treatment: 12 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematological response or Pulmonary response at M12	Response at 12 months is defined according to the initial pathology. Responses is defined as a composite outcome. At least one of the following item should be validated to observe response.; For patients with bone marrow failure, the hematological response at 12 months depending on initial cytopenia(s) is defined by; 1.5 g/dL increase in hemoglobin without transfusion for 2 months; And/or increase of 20.10^9/L in platelet count without transfusion for 2 months; And/or increase of 0.5.10^9/L in neutrophils count.; For patients with pulmonary fibrosis, a decrease of less than 5% in forced vital capacity at 12 months	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		12 months
Hepatic tolerance M1	aspartate aminotransferase blood level	1 month
Hepatic tolerance M2	aspartate aminotransferase blood level	2 months
Hepatic tolerance M3	aspartate aminotransferase blood level	3 months
Hepatic tolerance M6	aspartate aminotransferase blood level	6 months
Hepatic tolerance M9	aspartate aminotransferase blood level	9 months
Hepatic tolerance M12	aspartate aminotransferase blood level	12 months
LDL cholesterol M3	Low-density lipoprotein (LDL) cholesterol blood level in mmol/l	3 months
LDL cholesterol M6	Low-density lipoprotein (LDL) cholesterol blood level in mmol/l	6 months
LDL cholesterol M9	Low-density lipoprotein (LDL) cholesterol blood level in mmol/l	9 months
LDL cholesterol M12	Low-density lipoprotein (LDL) cholesterol blood level in mmol/l	12 months
HDL cholesterol M3	High-density lipoprotein (LDL) cholesterol blood level in mmol/l	3 months
HDL cholesterol M6	High-density lipoprotein (LDL) cholesterol blood level in mmol/l	6 months
HDL cholesterol M9	High-density lipoprotein (LDL) cholesterol blood level in mmol/l	9 months
HDL cholesterol M12	High-density lipoprotein (LDL) cholesterol blood level in mmol/l	12 months
TG M3	triglycerides blood level in mmol/l	3 months
TG M6	triglycerides blood level in mmol/l	6 months
TG M9	triglycerides blood level in mmol/l	9 months
TG M12	triglycerides blood level in mmol/l	12 months
PSA M3	Prostate-specific antigen (PSA) blood level for men	3 months
PSA M6	Prostate-specific antigen (PSA) blood level for men	6 months
PSA M12	Prostate-specific antigen (PSA) blood level for men	12 months
Pulmonary parenchymal abnormalities M6	Evolution of pulmonary parenchymal abnormalities at CT scan	6 months
Pulmonary parenchymal abnormalities M12	Evolution of pulmonary parenchymal abnormalities at CT scan	12 months
Telomere length	Evolution of the telomere length by Flow Fish	12 months
cytological and cytogenetic abnormalities	Appearance of cytological and cytogenetic abnormalities (bone marrow aspiration with cytogenetic)	12 months
Quality of life evaluation M3	European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients questionnaire (EORTC QLQ-C30, v3.0). The scale range from to 30 to 126 (30 represents the worse quality of life and 126 the best quality of life). http://www.eortc.be/qol/files/C30/QLQ-C30%20English.pdf	3 months
Quality of life evaluation M6	European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients questionnaire (EORTC QLQ-C30, v3.0). The scale range from to 30 to 126 (30 represents the worse quality of life and 126 the best quality of life). http://www.eortc.be/qol/files/C30/QLQ-C30%20English.pdf	6 months
Quality of life evaluation M12	European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients questionnaire (EORTC QLQ-C30, v3.0). The scale range from to 30 to 126 (30 represents the worse quality of life and 126 the best quality of life). http://www.eortc.be/qol/files/C30/QLQ-C30%20English.pdf	12 months
DLCO M3	Diffusing capacity of the lung for carbon monoxide (DLCO)	3 months
DLCO M6	Diffusing capacity of the lung for carbon monoxide (DLCO)	6 months
DLCO M9	Diffusing capacity of the lung for carbon monoxide (DLCO)	9 months
DLCO M12	Diffusing capacity of the lung for carbon monoxide (DLCO)	12 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Anticipated): October 20, 2018
• Primary Completion (Anticipated): October 20, 2021
• Study Completion (Anticipated): October 20, 2022

Study Registration Dates

• First Submitted: October 10, 2018
• First Submitted That Met QC Criteria: October 15, 2018
• First Posted (Actual): October 18, 2018

Study Record Updates

• Last Update Posted (Actual): October 18, 2018
• Last Update Submitted That Met QC Criteria: October 15, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Estrogen Antagonists; Danazol
• Other Study ID Numbers: P170925J; 2018-001686-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No