Clinical Trials /

LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis

NCT02205762

Description:

The LCH-IV is an international, multicenter, prospective clinical study for pediatric Langerhans Cell Histiocytosis LCH (age < 18 years).

Related Conditions:
  • Langerhans Cell Histiocytosis
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis
  • Official Title: LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis

Clinical Trial IDs

  • ORG STUDY ID: 13-428
  • SECONDARY ID: 2011-001699-20
  • SECONDARY ID: 042011
  • NCT ID: NCT02205762

Conditions

  • Langerhans Cell Histiocytosis

Interventions

DrugSynonymsArms
PrednisoneStratum I
VinblastineVelban®, Vincaleukoblastine SulfateStratum I
mercaptopurine-Purinethol®, -6-MPStratum I
INDOMETHACINStratum II
MethotrexateStratum II
Cytosine ArabinosideCytarabine, Ara-CStratum II
2-chlorodeoxyadenosine2-CdA, Cladribin®, Leustatin®Stratum III
Intravenous immunoglobulinIVIGStratum V

Purpose

The LCH-IV is an international, multicenter, prospective clinical study for pediatric Langerhans Cell Histiocytosis LCH (age < 18 years).

Detailed Description

      The international efforts of the past 20 years have shown that combination therapy with
      vinblastine and prednisone is an effective therapy for Multi-system (MS)-LCH. The previous
      prospective trial LCH-III confirmed this regimen as a standard regimen for MS-LCH in
      patients with and without risk organ involvement. It also showed that prolonged treatment in
      the latter group (treatment duration of 12 vs. 6 months) is superior in preventing disease
      reactivations. The results of this trial are encouraging and serve as a basis for the LCH-IV
      study design.Due to the complexity of the disease presentations and outcomes, the LCH-IV
      study seeks to tailor treatment based on features at presentation and on response to
      treatment, leading to seven strata:

        -  Stratum I: First-line treatment for MS-LCH patients (Group 1) and patients with Single
           system (SS)-LCH with multifocal bone or "Central Nervous System (CNS)-risk" lesions
           (Group 2)

        -  Stratum II: Second-line treatment for non-risk patients (patients without risk organ
           involvement who fail first-line therapy or have a reactivation after completion of
           first-line therapy)

        -  Stratum III: Salvage treatment for risk LCH (patients with dysfunction of risk organs
           who fail first-line therapy)

        -  Stratum IV: Stem cell transplantation for risk LCH (patients with dysfunction of risk
           organs who fail first-line therapy)

        -  Stratum V: Monitoring and treatment of isolated tumorous and neurodegenerative CNS-LCH

        -  Stratum VI: Natural history and management of "other" SS-LCH (patients who do not need
           systemic therapy at the time of diagnosis)

        -  Stratum VII: Long-term Follow up (all patients irrespective of previous therapy will be
           followed for reactivation or permanent consequences once complete disease resolution
           has been achieved and the respective protocol treatment completed)
    

Trial Arms

NameTypeDescriptionInterventions
Stratum IExperimentalStratum I The combination of Prednisone and vinblastine is the standard first-line combination for patients needing systemic therapy (Stratum I). Patients with MS-LCH and involvement of risk organs, who do not respond to 6-12 weeks of standard therapy, will be immediately switched to alternative treatment approaches (Stratum III or Stratum IV). Further therapy prolongation (12 vs. 24 months) and intensification (± mercaptopurine) will further reduce the reactivation rate and the permanent consequences.
  • Prednisone
  • Vinblastine
  • mercaptopurine
Stratum IIExperimentalA uniform "intensive" 24-week course consisting of prednisolone, vincristine and cytosine-arabinoside will be introduced in Stratum II for eligible patients. It will be followed by a continuation therapy to total treatment duration of 24 months. Participants who after SL-IT (week 24) have a response (NAD or AD better) are eligible for randomization between the continuation arms "INDOMETHACIN" and "6-MP/MTX" (mercaptopurine and Methotrexate).
  • Prednisone
  • Vinblastine
  • mercaptopurine
  • INDOMETHACIN
  • Methotrexate
  • Cytosine Arabinoside
Stratum IIIExperimentalSalvage treatment for risk LCH To assess the efficacy of the combination 2-CdA/Ara-C (Cytosine Arabinoside and 2-chlorodeoxyadenosine) in MS-LCH (patients with risk organ involvement, who fail to respond to front-line (Stratum I) therapy. The initial therapy consists of 2 courses of 2-CdA/Ara-C. Continuation of outlined treatment to be assessed at assigned intervals in each stratum.
  • 2-chlorodeoxyadenosine
Stratum IVExperimentalTo determine the overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT). Salvage treatment option for MS-LCH patients with risk organ involvement, who fail to respond to front-line therapy (Stratum I) OR to the salvage 2- CdA/Ara-C regimen (Stratum III).
    Stratum VExperimentalStratum V Monitoring and Treatment of isolated tumorous and neurodegenerative CNS-LCH - Special regimens will be offered to patients with isolated tumorous CNS-LCH (repeated 2-CdA courses) and to patients with clinically manifested ND-CNS-LCH (+/- extracranial LCH manifestations). For the last group monotherapy with Ara-C courses or (Intravenous immunoglobulin)IVIG will be offered depending on physician's choice.
    • Cytosine Arabinoside
    • 2-chlorodeoxyadenosine
    Stratum VIExperimentalNatural history and management of "other" SS-LCH not eligible for stratum I group 2. Treatment Options- Management (mostly "wait & see" and topical treatment) is left to the discretion of the treating physician. All treatments and disease responses must be reported in the database. In the case of uncertainties please contact your National Coordinator. Patients being followed on Stratum VI who have progression of disease to MSLCH, multifocal bone disease or CNS-risk bone lesions should be enrolled on Stratum I therapy. Patients being followed on Stratum VI who develop isolated tumorous or neurodegenerative CNS-LCH should be enrolled on Stratum V.
    • Prednisone
    • Vinblastine
    • mercaptopurine
    • Cytosine Arabinoside
    • 2-chlorodeoxyadenosine

    Eligibility 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 according to the criteria described in Section 6.1
    
                   -  Signed informed consent form
    
              -  Stratum II
    
                   -  Patients of Stratum I who have:
    
                   -  Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
    
                   -  AD intermediate or worse in non-risk organs or AD better in risk organs after 12
                      weeks (Initial Course 2)
    
                   -  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
    
              -  Stratum III
    
                   -  Patients from Stratum I 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 week 12 (after Initial Course 2).
    
                   -  Presence of unequivocally severe organ dysfunction at the above mentioned
                      evaluation points (hematological dysfunction, liver dysfunction, or both of
                      them) as
    
                        -  Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
    
                        -  PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria
                           have to be fulfilled) AND/OR
    
                        -  Liver dysfunction (or digestive involvement with protein loss)
    
                        -  Total protein <55 g/L or substitution dependency
    
                        -  Albumin <25 g/L or substitution dependency (at least one of the two
                           criteria to be fulfilled)
    
              -  Stratum 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 week 12 (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 at the above mentioned
                      evaluation points (hematological dysfunction, liver dysfunction, or both of
                      them) as defined in Table XI (see Section 10.3.1).
    
                   -  Informed consent: All patients or their legal guardians (if the patient is <18
                      years of age) must sign an Ethics or institutional Review Board approved consent
                      form indicating their awareness of the investigational nature and the risks of
                      this study. When appropriate, younger patients will be included in all
                      discussions in order to obtain assent.
    
                   -  Adequate organ function: Patients should have adequate hepatic, renal, cardiac
                      and pulmonary function to undergo reduced intensity HCT based upon local
                      institutional guidelines, or at a minimum meet requirements noted in eligibility
                      checklist Appendix A-VIII_1. However, significant hepatic and pulmonary
                      dysfunction, if secondary to underlying LCH disease activity, will not exclude
                      patients from protocol enrollment and should be discussed with the National PI
                      Coordinator and the Coordinating Principal Investigator.
    
              -  Stratum V
    
                   -  All patients with verified diagnosis of LCH and MRI findings consistent with
                      ND-CNSLCH irrespective of previous treatments (also those not registered to
                      other Strata ofLCH-IV).
    
                   -  Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion
                      in the hypothalamus-pituitary axis). In patients with already established
                      diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a
                      biopsy of the lesion is not obligatory. In all other cases a biopsy of the
                      lesion is needed for inclusion into the study
    
              -  Stratum VI
    
                 -- Patients with newly diagnosed SS-LCH and localization other than "multifocal
                 bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
    
              -  Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as
                 consent for longterm follow-up has not been withheld.
    
            Exclusion Criteria:
    
              -  Stratum I
    
                   -  Pregnancy (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
    
              -  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
    
                   -  The presence of any of the following criteria will exclude the patient from the
                      study:
    
                   -  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 VI
    
                   -  Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible
                      for Stratum V),
    
                   -  Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible
                      for Stratum I, Group 2)
          
    Maximum Eligible Age:18 Years
    Minimum Eligible Age:N/A
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Percentage of Patients with Reactivation Free Survival
    Time Frame:12 Months
    Safety Issue:
    Description:Stratum I, II, VI

    Secondary Outcome Measures

    Measure:Overall Survival
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum I
    Measure:Number of Participants with Serious and Non-Serious Adverse Events
    Time Frame:2 Years
    Safety Issue:
    Description:
    Measure:Incidence of Permanent Consequences
    Time Frame:2 Years
    Safety Issue:
    Description:All Stratum
    Measure:Cumulative incidence of reactivations in risk organs
    Time Frame:2 Years
    Safety Issue:
    Description:
    Measure:Time to complete disease resolution
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum III
    Measure:Response rate to the combination of prednisone, vincristine and cytarabine
    Time Frame:2 years
    Safety Issue:
    Description:Stratum II
    Measure:The proportion of patients alive and free of disease without permanent consequences (e.g. diabetes insipidus, anterior pituitary dysfunction, radiological or clinical neurodegeneration)
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum II
    Measure:Percentage of treatment-related toxicities
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum II
    Measure:Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX.
    Time Frame:2 years
    Safety Issue:
    Description:Stratum II
    Measure:The type of subsequent intensive and/or maintenance therapy utilized
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum III
    Measure:Early and late mortality
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum II
    Measure:Early and late toxicity
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum III
    Measure:d+100 transplant related mortality
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum IV
    Measure:Incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT
    Time Frame:2 Years
    Safety Issue:
    Description:
    Measure:Record all occurrence of skin, GI or liver abnormalities fulfilling criteria of Grades II-IV acute GVHD
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum IV: Hematopoetic Stem Cell Transplantation for Risk LCH
    Measure:Percentage of Participants with incidence of chronic GVHD
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum IV
    Measure:Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy
    Time Frame:2 years
    Safety Issue:
    Description:Stratum V
    Measure:Response of isolated tumorous CNS-LCH to 2-CDA
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum V
    Measure:Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum V
    Measure:Methods of early identification of ND-CNS-LCH
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum V - Exploration of the value of neurochemistry, neurophysiology, and neuropsychology methods in early identification of ND-CNS-LCH and in assessing its severity, and comparison to MRI findings.
    Measure:Need for systemic therapy later during disease course
    Time Frame:2 Years
    Safety Issue:
    Description:Stratum VI
    Measure:Identify possible risk factors for permanent consequences (PC)
    Time Frame:2 Years
    Safety Issue:
    Description:

    Details

    Phase:Phase 2/Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:North American Consortium for Histiocytosis

    Trial Keywords

    • Langerhans cell histiocytosis

    Last Updated

    November 17, 2016