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Pilot Study of Tocilizumab in Patients With Erdheim-Chester Disease

Primary Purpose

Erdheim-Chester Disease

Status
Terminated
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Tocilizumab
Sponsored by
Ospedale San Raffaele
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Erdheim-Chester Disease focused on measuring Erdheim-Chester disease, Tocilizumab, Treatment, Phase II

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • San Raffaele Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tocilizumab

Arm Description

Tocilizumab 8 mg/kg intravenously every month for six months

Outcomes

Primary Outcome Measures

Reduction in the dimensions of measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Functional improvement in measurable indexes
Improvement in renal, hypophyseal, and respiratory function or of bone turnover, when altered at baseline
Variations of patient quality of life
As evaluated by standard questionnaires (HAQ, Short Form (SF)-36)
Analysis of the adverse events and of the relevant safety laboratory parameters
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

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
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

Full Information

First Posted
November 12, 2012
Last Updated
February 9, 2016
Sponsor
Ospedale San Raffaele
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1. Study Identification

Unique Protocol Identification Number
NCT01727206
Brief Title
Pilot Study of Tocilizumab in Patients With Erdheim-Chester Disease
Official Title
Open-label, Single-arm, Phase II, Prospective, Pilot Study of Tocilizumab in Patients With Erdheim-Chester Disease
Study Type
Interventional

2. Study Status

Record Verification Date
February 2016
Overall Recruitment Status
Terminated
Study Start Date
November 2012 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ospedale San Raffaele

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Erdheim-Chester Disease
Keywords
Erdheim-Chester disease, Tocilizumab, Treatment, Phase II

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tocilizumab
Arm Type
Experimental
Arm Description
Tocilizumab 8 mg/kg intravenously every month for six months
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
Ro-Actemra, Actemra
Primary Outcome Measure Information:
Title
Reduction in the dimensions of measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Time Frame
6 months
Title
Functional improvement in measurable indexes
Description
Improvement in renal, hypophyseal, and respiratory function or of bone turnover, when altered at baseline
Time Frame
6 months
Title
Variations of patient quality of life
Description
As evaluated by standard questionnaires (HAQ, Short Form (SF)-36)
Time Frame
6 months
Title
Analysis of the adverse events and of the relevant safety laboratory parameters
Description
Monitoring of adverse events, variations in biochemical and hematological tests (full blood count, liver and renal function tests, lipid profile)
Time Frame
6 months
Title
Variations in disease activity as evaluated by FDG-PET imaging
Time Frame
0, 2 and 6 months
Secondary Outcome Measure Information:
Title
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
Description
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
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lorenzo Dagna, MD
Organizational Affiliation
San Raffaele Scientific Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
San Raffaele Hospital
City
Milano
ZIP/Postal Code
20132
Country
Italy

12. IPD Sharing Statement

Learn more about this trial

Pilot Study of Tocilizumab in Patients With Erdheim-Chester Disease

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