Denosumab for the Treatment of Adult LCH

Study Purpose

This study is aiming to evaluate the efficacy of denosumab among adult patients suffering from Langerhans Cell Histiocytosis (LCH).

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - Adults (>18 years of age) - Definitive diagnosis of LCH [Based on clinic-pathological evidence with microscopic examination and at least one of the following immunological staining: Langerin (CD 207) positivity, Cluster of Differentiation 1a (CD1a) positivity, Presence of Birbeck granules on electronic microscopy] - Mild symptoms (symptoms of low intensity; no need for hospitalization) and low risk disease needing first line systemic therapy for LCH because of: - single system disease with multifocal lesions, or - single system disease with "special site" lesions (vertebral lesions with intraspinal extension, craniofacial bone lesions with soft tissue extension), or - multi-system disease without involvement of risk organs [hematopoietic system, spleen, liver, tumorous central nervous system (CNS)].
  • - Have signed the informed consent form (consent should be taken before any study-specific procedure is performed).
  • - A patient should undergo a PET-CT imaging test, in order for him to be deemed suitable for the study.
The initial PET-CT either may have been carried out, within 3 months prior to visit 1, regardless of the diagnostic center or the type of the device, which has been used for, or may take place in the context of visit 2, at the diagnostic center(s) specialized on Nuclear Medicine, which have been partnered with the Sponsor. Whichever is the case, the initial PET-CT report should be legible and accurate, so that to be assessed by the qualified physician, responsible for the PET-CT test at the partnered diagnostic center(s).

Exclusion Criteria:

  • - Symptomatic multi system LCH - no risk organs involved.
  • - Multi-system LCH (with or without symptoms) - risk organs involved.
  • - Isolated pulmonary LCH disease - Previous administration of denosumab from clinical trials or other use (e.g. commercial use).
  • - Current participation in another clinical trial or having received any investigational product within the last 3 months.
  • - Impaired renal function as determined by an estimated glomerular filtration rate (eGFR) of ≤ 30 mL/min/1,73m2 [using the Chronic Kidney Disease-Epidemiology, (CKD-EPI) formula].
  • - Patients that have received oral bisphosphonates within 6 months of study enrollment or intravenous bisphosphonates, fluoride and strontium ranelate within 1 year of study enrollment.
  • - Treatment with immune suppressive agents within 4 weeks from baseline evaluation.
  • - Patients with severe impairment of clinical condition including: severely impaired pulmonary function [for example total lung capacity (TLC)<60%, forced expiratory volume 1 (FEV1)<30%, diffusing capacity of the lungs for carbon monoxide (DLCO)<30%, partial pressure of oxygen (PaO2)<55 mmHg), long term oxygen therapy or cor pulmonale.
  • - Known to have a liver failure or chronic hepatic disease e.g. cirrhosis, chronic hepatitis; or elevated transaminases defined as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 fold the upper limit of normal laboratory range.
  • - Heart failure [New York Heart Association (NYHA) Functional Classification above 2].
  • - Patients with life expectancy of less than one year.
  • - Female subjects of childbearing potential who refuse to use a reliable contraceptive method throughout the study, defined as use of 2 highly effective forms of contraception and continuation of use for 7 months after last administration of study drug.
Birth control methods that can achieve a failure rate of less than 1% per year, when used consistently and correctly, are considered as highly effective.
  • - Pregnancy, planning a pregnancy or currently lactating - Severe concurrent illness which in the investigator's opinion may confound patient evaluation, e.g. malignancy (except basal cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years.
  • - Known alcohol or drug abuse.
  • - Parathyroid hormone (PTH), PTH derivatives, teriparatide, odanacatib, anabolic steroids, testosterone, glucocorticosteroids (> 5 mg/day of prednisone equivalent for > 10 days), systemic hormone-replacement therapy, selective estrogen receptor modulators (SERMs), raloxifene, tibolone, calcitonin use within the last 6 weeks.
  • - Evidence of hyper- or hypothyroidism; patients with an abnormal thyroid stimulate hormone (TSH) level on thyroid treatment (patients on stable thyroid treatment with a normal TSH allowed); current hyper- or hypoparathyroidism; current hyper or hypocalcemia (hypercalcemia based on albumin adjusted serum calcium > 10.40 mg/dL; hypocalcemia based on albumin adjusted serum calcium < 8.5 mg/dL); vitamin D deficiency (25-hydroxy vitamin D level < 20 ng/mL; if the resulted value of the retest is 20 ≥ ng/Ml, after repletion with 50,000 - 100,000 IU of cholecalciferol, subject will be allowed.
The retest should be carried out within 30 days post to visit 1(screening)); rheumatoid arthritis; Paget's disease; any known bone disease with osteolytic and/or osteoblastic lesions that would interfere with interpretation of findings.
  • - Known sensitivity to mammalian cells, denosumab or any components of denosumab 120mg, or any of the products to be administered during the study (e.g., calcium or vitamin D).
  • - History of any Solid Organ or Bone Marrow Transplant.
  • - History of osteonecrosis of the jaw, and/or recent tooth extraction or other dental surgery; or planned invasive dental work during the study.
  • - Intolerance to calcium supplements.
  • - Malabsorption syndrome; severe malabsorption including Celiac disease, Short Bowel Syndrome, Crohn's disease, Previous Gastric Bypass.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT03270020
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Hellenic Society for the Study of Bone Metabolism
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Polyzois Makras, MD, PhD
Principal Investigator Affiliation Dpt of Endocrinology & Diabetes, 251 Hellenic AirForce & VA General Hospital, Athens, Greece
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Recruiting
Countries Greece
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Langerhans Cell Histiocytosis
Additional Details

The majority and diversity of clinical manifestations in LCH are attributed to immunological dysfunction resulting from langerhans cell (LC) derived cytokine secretion both at the lesional and systemic level. In a recent study, Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) was found to be abundantly expressed in cells within diverse LCH lesions from adult patients, especially in inflammatory infiltrates, a finding in line with a previously reported high osteoprotegerin (OPG) and low RANKL levels in the serum of patients with or without bone involvement. RANKL expression was associated with concomitant p65 Nuclear Factor Kappa-B (NFκB) nuclear staining, the main downstream effector of RANKL signaling, suggesting that lesional cell activation may be triggered locally by RANKL. Combining the serum and the lesional results, it can be inferred that there is an ongoing process of countervailing OPG production against lesional RANKL, which could be one of the self defense mechanisms among LCH patients. Therefore, the use of denosumab seems a rational treatment option in LCH in order to support and enhance the defensive OPG action and hopefully control or even interrupt the lesional immunological process. The primary study objective is to assess the therapeutic efficacy of denosumab 120 mg every 8 weeks (Q8W) sc in adult LCH patients. Secondary Objectives: 1. To define an uniform treatment approach for LCH patients with mild symptoms and low risk disease. 2. To explore the efficacy of denosumab 120 mg Q8W sc in reducing disease reactivations after treatment completion. 3. To illustrate the safety profile of denosumab in LCH patients. The primary efficacy endpoint is defined as the percentage of patients with progression of disease at Month 8.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Athens, Attiki, Greece

Status

Recruiting

Address

251 Hellenic AirForce & VA General Hospital, Dpt of Endocrinology

Athens, Attiki, 11525

Site Contact

Polyzois Makras, MD, PhD

pmakras@gmail.com

+306944549654

Terms of Service

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