Pilot Study of Tocilizumab in Patients With Erdheim-Chester Disease - Full Text View

Purpose

The study we propose is a pilot phase II, interventional, treatment, open-label, single-arm, efficacy/safety clinical trial of a 6-month treatment with tocilizumab (8 mg/kg once monthly) in adult patients with extraskeletal Erdheim-Chester disease (ECD). Efficacy will be assessed as the effect of the treatment on the size of the measurable lesions, as evaluated by bidimensional measurements, and by the impact of the treatment on symptom control and on patient quality of life. Safety of the treatment will be determined by the analysis of adverse events and of the relevant safety laboratory parameters.

Secondary objectives of the study will be:

to better characterize the mechanisms underlying such disease and the possible response to the treatment. In particular: i) we will investigate the immunophenotypic and histomorphologic features of ECD histiocytes; ii) we will gather gene expression data from peripheral blood immune cells to better characterize their functional status, to define their transcriptional fingerprints and their possible modulation as a result of tocilizumab treatment; iii) we will assess the production of soluble mediators and the expression of activation molecules by monocytes derived from ECD patients, as well as after stimulation with selected inflammatory cytokines; iv) we will investigate the ex vivo and in vitro impact of tocilizumab treatment on those markers, for possible use as a predictor or indicator of response to treatment.
to investigate the metabolic pattern in ECD patients before and after tocilizumab treatment as evaluated by fluoro-d-glucose positron emission tomography (FDG-PET) and to verify if it can be an indicator of ECD activity.

Condition	Intervention	Phase
Erdheim-Chester Disease	Drug: Tocilizumab	Phase 2


Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Open-label, Single-arm, Phase II, Prospective, Pilot Study of Tocilizumab in Patients With Erdheim-Chester Disease

Resource links provided by NLM:

Genetics Home Reference related topics: Erdheim-Chester disease

Drug Information available for: Tocilizumab

Genetic and Rare Diseases Information Center resources: Lipogranulomatosis Erdheim-Chester Disease

U.S. FDA Resources

Further study details as provided by Lorenzo Dagna, Ospedale San Raffaele:

Primary Outcome Measures:

Reduction in the dimensions of measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria [ Time Frame: 6 months ]
Functional improvement in measurable indexes [ Time Frame: 6 months ]
Improvement in renal, hypophyseal, and respiratory function or of bone turnover, when altered at baseline
Variations of patient quality of life [ Time Frame: 6 months ]
As evaluated by standard questionnaires (HAQ, Short Form (SF)-36)
Analysis of the adverse events and of the relevant safety laboratory parameters [ Time Frame: 6 months ]
Monitoring of adverse events, variations in biochemical and hematological tests (full blood count, liver and renal function tests, lipid profile)
Variations in disease activity as evaluated by FDG-PET imaging [ Time Frame: 0, 2 and 6 months ]

Secondary Outcome Measures:

Evaluation of soluble factors, receptors and activation molecules involved the accumulation, activation and entrapment of histiocytes possibly associated to a response to the experimental treatment [ Time Frame: 6 months ]
- the levels of circulating cytokines and chemokines before, during and after tocilizumab treatment;
- the immunophenotype and the transcriptional fingerprints of circulating immune cells from ECD patients and their possible modulation as a result of tocilizumab treatment;
- the pathways involved in the production of interleukin (IL)-6 and IL-6-induced cytokines and chemokines by mononuclear cells obtained from ECD patients;
- the interference of tocilizumab in vitro on monocyte activation and ex vivo from treated patients, also to evaluate its effect on the profile of circulating cytokines and on the secretory potential of patient-derived monocytes


Enrollment:	3
Study Start Date:	November 2012
Study Completion Date:	December 2015
Primary Completion Date:	February 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Tocilizumab Tocilizumab 8 mg/kg intravenously every month for six months	Drug: Tocilizumab Other Names: Ro-Actemra Actemra

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

patients >= 18 years of age able to understand and sign an informed consent;
histologically proven diagnosis of Erdheim-Chester disease ;
an advanced disease not limited to the skeleton, with at least one measurable lesion;
if females of childbearing potential, a negative pregnancy test and willingness to adhere to a highly effective contraceptive method of birth control for the duration of the study;

Exclusion Criteria:

history of hypersensitivity to tocilizumab or to any of the excipients;

- severe infections requiring hospitalization or antibiotic therapy in the 30 days before the enrollment in the study;
active tuberculosis, listeriosis, histoplasmosis, sepsis, abscesses, opportunistic infections; active hepatitis B or C virus infection;
past history of tuberculosis (as documented by a positive purified protein derivative (PPD) skin test and/or a positive Quantiferon test and/or a chest X- ray), in the absence of a documented and appropriate administration of a specific treatment for latent tuberculosis;
history of human immunodeficiency virus (HIV) infection;
past history (< 5 years before enrollment) of a lymphoproliferative disorder or of a solid cancer (excluding cured basal cell or squamous cell carcinoma of the skin);
moderate or severe heart failure (NYHA class III/IV), uncontrolled diabetes mellitus or other diseases that -according to the physician in charge of the protocol- may be of harm to the patient, if he/she would enroll in the study;
history of alcohol and/or drug abuse;
prior treatment with alkylating drugs (chlorambucil, cyclophosphamide);
serum creatinine > 1.6 mg/dL in female patients or > 1.9 mg/dL in male patients, aspartate aminotransferase and/or alanine aminotransferase > 3 x upper limit of normal ; platelet < 100.000/fL; hemoglobin < 8.5 g/dL; white blood cell count < 1000/fL; lymphocyte < 500/fL; total bilirubin > 2.0 mg/dL

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01727206

Locations


Italy
San Raffaele Hospital
Milano, Italy, 20132

Sponsors and Collaborators

Ospedale San Raffaele

Investigators


Principal Investigator:	Lorenzo Dagna, MD	San Raffaele Scientific Institute

More Information


Responsible Party:	Lorenzo Dagna, Professor, Ospedale San Raffaele
ClinicalTrials.gov Identifier:	NCT01727206 History of Changes
Other Study ID Numbers:	ECD-TCZ-01 2012-003151-11 ( EudraCT Number ) GR-2009-1594586 ( Other Grant/Funding Number: Italian Ministry of Health )
Study First Received:	November 12, 2012
Last Updated:	February 9, 2016

Keywords provided by Lorenzo Dagna, Ospedale San Raffaele:


Erdheim-Chester disease Tocilizumab Treatment Phase II

Additional relevant MeSH terms:


Erdheim-Chester Disease Histiocytosis, Non-Langerhans-Cell Histiocytosis Lymphatic Diseases

ClinicalTrials.gov processed this record on July 14, 2017