Langerhans cell histiocytosis
Conditions
Interventions
Trade Name: Indocid 25mg-Kapseln
Product Name: Indocid
Pharmaceutical Form: Capsule
INN or Proposed INN: INDOMETACIN
CAS Number: 53-86-1
Concentration unit: mg milligram(s)
Concentration number: 25-
Sponsors
St. Anna Kinderkrebsforschung
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: •Stratum I: Patients must be less than 18 years of age at the time of diagnosis, Patients must have histological verification of the diagnosis of Langerhans cell histiocytosis, No prior systemic therapy for LCH, except systemic steroids given up to one week Signed informed consent , •Stratum II Patients of Stratum I who have proressive disease (AD worse) in non-risk organs after Initial Course 1, AD intermediate or worse in non-risk organs or AD better in risk organs after Initial Course 2, AD intermediate or worse, who do not meet organ dysfunction eligibility criteria (acc table XI) at any time of stratum I treatment Disease progression (AD worse) in non-risk organs at any time during continuation treatment, Active disease at the end of Stratum I treatment, Disease reactivation in non-risk organs at any time after completion of Stratum I treatment, Disease reactivation in risk organs, who do not meet organ dysfunction criteria (acc table XI) at any time or after completion of Stratum I treatment Signed informed consent, •Stratum III Patients from Stratum I who fulfill the following criteria: AD intermediate or worse in risk organs after after Initial Course 1, or AD worse or AD intermediate in risk organs after Initial Course 2, Presence of unequivocally severe organ dysfunction (hematological dysfunction, liver dysfunction, or both of them), Signed informed consent, •Stratium IV Patients from Stratum I or Stratum III who fulfill the following criteria: AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after after Initial Course 2 of Stratum I, or AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD intermediate after the 4th 2-CdA/Ara-C course of Stratum III, and Presence of unequivocally severe organ dysfunction, Informed consent available, Adequate organ function •Stratum V All patients with verified diagnosis of LCH and MRI findings consistent with neurodegenerative (ND) CNS-LCH irrespective of previous treatments, Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion in the hypothalamus-pituitary axis), Signed informed consent •Stratum VI Patients with newly diagnosed single-system LCH (other than mfb, isolated tumorous CNS-LCH, or isolated CNS-risk lesion, Signed informed consent, •Stratum VII All patients registered in LCH IV as long as consent for long-term follow-up has not been witheld Are the trial subjects under 18? yes Number of subjects for this age range: 1400 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: •Stratum I Pregancy (patients of child-bearing age must be appropriately tested before chemotherapy), LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis, lung fibrosis, etc.) in the absence of active disease, Prior systemic therapy, except systemic steroids given up to one week •Stratum II Patients with progressive disease in risk organs, Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without evidence of active LCH in the same organ or in any other locations, No written consent of the patient or his/her parents or legal guardian •Stratum III Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of risk organ involvement, Inadequate renal function as defined by serum creatinine > 3x normal for age •Stratum IV Pulmonary failure (requiring mechanical ventilation) not due to active LCH, Isolated liver sclerosis or pulmonary fibrosis, without active LCH, Uncontrolled active life-threatening infection. Decreased renal function with a GFR of less than 50ml/1.73m2/min, Pregnancy or active breast feeding, Failure to provide signed informed consent •Stratum V Patients without any evidence of isolated tumorous CNS-LCH lesions or ND-CNS lesions •Stratum VI Patients with single-system LCH who have an isolated tumorous CNS lesion (eligible for Stratum V), Patients with isolated CNS-risk or mfb lesion (eligible for Stratum I, Group 2) •Stratum VII no consent for long-term follow up available
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •Reduction of mortality in multi-system (ms)-LCH by early switch to salvage treatment of pat. with risk organ involvement and without response to 1st-line therapy •Randomized investigation of prolongation or intensification of continuation therapy to reduce reactivationsa and late sequelae in ms-LCH, •Randomized investigation to reduce reactivation rate, late sequelae by prolongation of continuation therapy (6 vs. 12 m) in single-system (ss)-LCH with isolated “CNS-Risk” lesion or multifocal bone (mfb) lesions. •Investigation to achieve disease resolution, prevent reactivations, late sequelae in non-risk organ involvement pati. with 2nd-line treatment (PRED/ARA-C/VCR for 24 weeks, followed by 24m of continuation therapy: Indomethacin vs. 6-MP/MTX) in non-responders to 1st-line treatment or in patients with reactivations ;Secondary Objective: •To validate prospectively a new scoring system for disease activity and treatment response assessment. •To investigate the cumulative incidence of radiographic and clinical neurodegeneration in patients with “CNS-Risk” bone lesions and endocrine deficits. •To study the natural history of LCH in patients not needing upfront systemic therapy and the long-term consequences and quality of life of all registered (with and without systemic therapy) patients ;Primary end point(s): •Stratum I Reactivation-free survival •Stratum II Reactivation-free survival •Stratum III The response after 2 cycles of 2-CdA/ARA-C, •Stratum IV overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT) •Stratum V To study the the course of neurodegenerative-CNS-LCH, Response of isolated tumorous CNS lesions to 2-CdA, Stratum VI Reactivation free survival Stratum VII Rate and spectrum of permanent consequences To study the course of Neurodegenerative-CNS-LCH, Response of isolated tumorous CNS lesions to 2-CdA, •Stratum VI Reactivation free survival •Strat | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •Stratum I Overall survival, Incidence of permanent consequences, Toxicity of treatment, The proportion of patients alive and free of disease without permanent consequences, Cumulative incidence of reactivations in risk organs •Stratum II To determine the response rate to the combination of prednisone, vincristine and cytarabine, The proportion of patients alive and free of disease without permanent consequences, To describe treatment-related toxicities, To compare reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX. •Stratum III Time to complete disease resolution (Non-Active Disease) The type of subsequent intensive and/or maintenance therapy utilized The early and late mortality The early and late toxicity •Stratum IV To determine d+100 transplant related mortality, To determine the incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT, To determine the incidence of grades II-IV and III-IV acute GVHD, To determine the incidence of chronic GVHD •Stratum V To assess whether systemic therapy can be beneficial for patients with clinically manifest ND-CNS-LCH, To assess the role of 2-CdA in preventing ND-CNS-LCH in patients with isolated tumorous CNS-LCH, To study the efficacy of intravenous immunoglobulin and intravenous cytarabine in the treatment of ND-CNS-LCH, To assess markers of neurodegeneration and LCH activity in the spinal fluid of patients who have diabetes insipidus as well as patients with radiologic and/or clinical signs of CNS-LCH •Stratum VI Need for systemic therapy later during disease course, Spectrum and cumulative incidence of permanent consequences •Stratum VII Identify possible risk factors for PC, Assess the role of systemic treatment in preventing PC ;Timepoint(s) of evaluation of this end point: Stratum I, Stratum II Final analyses: seven year recruitment+5 years minimum follow-up Stratum III half a year after study closure Stratum IV after year recru | — |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Canada, Czech Republic, Denmark, Greece, India, Ireland, Israel, Italy, Korea, Republic of, Netherlands, New Zealand, Norway, Poland, Russian Federation, Serbia, Spain, Sweden, Switzerland, Turkey, United States
Contacts
Public ContactProf Sandra Jacbos
UZ Leuven
Outcome results
None listed