LCH-IV, Protocolo Internacional de Tratamiento Colaborativo para Niños y Adolescentes con Histiocitosis de Células de Langerhans
The LCH-IV is an international, multicenter, prospective clinical study for pediatric Langerhans Cell Histiocytosis LCH (age < 18 years).
Descripción general del estudio
Estado
Condiciones
Descripción detallada
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)
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 2
- Fase 3
Contactos y Ubicaciones
Ubicaciones de estudio
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Alabama
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Birmingham, Alabama, Estados Unidos, 35233
- Children's of Alabama
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Arizona
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Phoenix, Arizona, Estados Unidos, 85006
- Phoenix Children's Hospital
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Arkansas
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Little Rock, Arkansas, Estados Unidos, 72202
- Arkansas Children's Hospital
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California
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Los Angeles, California, Estados Unidos, 90027
- Children's Hospital of Los Angeles
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Madera, California, Estados Unidos, 93636
- Valley Children's Healthcare
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Oakland, California, Estados Unidos, 94609
- UCSF Benioff Children's Hospital of Oakland
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Orange, California, Estados Unidos, 92868
- Children's Hospital of Orange County
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San Francisco, California, Estados Unidos, 94158-0106
- UCSF Helen Diller Family Cancer Center
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Connecticut
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Hartford, Connecticut, Estados Unidos, 06106
- Connecticut Children's Medical Center
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District of Columbia
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Washington D.C., District of Columbia, Estados Unidos, 20010
- Children's National Medical Center
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Florida
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St. Petersburg, Florida, Estados Unidos, 33701
- Johns Hopkins All Children's Hospital
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Georgia
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Atlanta, Georgia, Estados Unidos, 30342
- Children's Healthcare of Atlanta, Emory
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Illinois
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Chicago, Illinois, Estados Unidos, 60611-2991
- Ann & Robert H. Lurie Children's Hospital of Chicago
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Indiana
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Indianapolis, Indiana, Estados Unidos, 46202
- Riley Hospital for Children - Indiana University
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Kansas
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Kansas City, Kansas, Estados Unidos, 64108
- Children's Mercy Hospitals
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Kentucky
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Lexington, Kentucky, Estados Unidos, 40536
- University of Kentucky A.B.Chandler Medical Center
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Louisville, Kentucky, Estados Unidos, 40202
- University of Louisville, Norton Children's Hospital
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Maryland
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Baltimore, Maryland, Estados Unidos, 21287
- Johns Hopkins University
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Massachusetts
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Boston, Massachusetts, Estados Unidos, 02114
- Massachusetts General Hospital
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Boston, Massachusetts, Estados Unidos, 02115
- Dana Farber Cancer Institute
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Minnesota
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Minneapolis, Minnesota, Estados Unidos, 55404
- Children's Minnesota
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New Jersey
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Hackensack, New Jersey, Estados Unidos, 07601
- Hackensack University Medical Center
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New York
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New Hyde Park, New York, Estados Unidos, 11040
- Cohen Children's Medical Center
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New York, New York, Estados Unidos, 10029
- Mount Sinai Hospital
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New York, New York, Estados Unidos, 10032
- Columbia University / Herbert Irving Cancer Center
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New York, New York, Estados Unidos, 10170
- Memorial Sloan Kettering Cancer Center
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Syracuse, New York, Estados Unidos, 13210
- SUNY Upstate Medical University
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The Bronx, New York, Estados Unidos, 10467
- Children's Hospital at Montefiore
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North Carolina
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Charlotte, North Carolina, Estados Unidos, 28203
- Carolinas Medical Center, Levine Children's Hospital
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Ohio
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Akron, Ohio, Estados Unidos, 44308
- Akron Children's Hospital
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Cincinnati, Ohio, Estados Unidos, 45229
- Cincinnati Children's Hospital Medical Center
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Cleveland, Ohio, Estados Unidos, 44106
- Rainbow Babies & Children's Hospital, University Hospitals
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Toledo, Ohio, Estados Unidos, 43606
- Russell J Ebeid Children's Hospital (Promedica)
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Pennsylvania
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Pittsburgh, Pennsylvania, Estados Unidos, 15224
- UPMC Children's Hospital of Pittsburgh
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South Carolina
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Charleston, South Carolina, Estados Unidos, 29425
- Medical University of South Carolina (MUSC)
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Greenville, South Carolina, Estados Unidos, 29605
- Greenville Health System BI-LO Charities Children's Cancer Center
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Tennessee
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Memphis, Tennessee, Estados Unidos, 38105
- St. Jude Children's Research Hospital
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Nashville, Tennessee, Estados Unidos, 37232
- Vanderbilt-Ingram Cancer Center
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Texas
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Dallas, Texas, Estados Unidos, 75235
- Children's Medical Center Dallas, UT Southwestern
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Washington
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Spokane, Washington, Estados Unidos, 99204
- Providence Sacred Heart Children's Hospital
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Tacoma, Washington, Estados Unidos, 98431
- Madigan Army Medical Center
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Wisconsin
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Madison, Wisconsin, Estados Unidos, 53792
- American Family Children's Hospital University of Wisconsin
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
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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
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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
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Stratum III
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Patients from Stratum I who fulfill the following criteria:
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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).
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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)
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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.
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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
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Stratum VI
-- Patients with newly diagnosed SS-LCH and localization other than "multifocal bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
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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:
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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
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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
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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
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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
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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)
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
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Experimental: Stratum I
Stratum 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. |
Stratum I Stratum I
Otros nombres:
Stratum I
Otros nombres:
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Experimental: Stratum II
A 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). |
Otros nombres:
Stratum I Stratum I
Otros nombres:
Stratum I
Otros nombres:
Indomethacin fixed dose given daily orally in two divided doses with gastric protection for total treatment duration of 24 months. fixed dose weekly orally for total treatment duration of 24 months. |
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Experimental: Stratum III
Salvage 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. |
Otros nombres:
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Experimental: Stratum IV
To 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). |
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Experimental: Stratum V
Stratum 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. |
Otros nombres:
Otros nombres:
Otros nombres:
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Experimental: Stratum VI
Natural history and management of "other" SS-LCH not eligible for stratum I group 2.
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Otros nombres:
Otros nombres:
Otros nombres:
Stratum I Stratum I
Otros nombres:
Stratum I
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Percentage of Patients with Reactivation Free Survival
Periodo de tiempo: 12 Months
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Stratum I, II, VI |
12 Months
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Response Rate of Second Cycle
Periodo de tiempo: 9 weeks
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Stratum III |
9 weeks
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Overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT)
Periodo de tiempo: 3 Years
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Stratum IV |
3 Years
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The cumulative incidence of radiological and clinical neurodegeneration in patients with isolated tumorous CNS-LCH, DI, anterior pituitary dysfunction, and those with CNS-risk lesions
Periodo de tiempo: 2 Years
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Stratum V |
2 Years
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The time interval and cumulative incidence of progression of radiological neurodegeneration to clinically manifested ND-CNS-LCH
Periodo de tiempo: 2 Years
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Stratum V |
2 Years
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Cumulative incidence of specific Permanent Consequences e.g. diabetes insipidus (DI), growth hormone deficiency (GHD), neuropsychological impairment, etc.
Periodo de tiempo: 2 Years
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From all treatment stratum via long-term follow up in Stratum VII |
2 Years
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Número de participantes con eventos adversos graves y no graves
Periodo de tiempo: 2 años
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2 años
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Incidencia acumulada de reactivaciones en órganos de riesgo
Periodo de tiempo: 2 años
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2 años
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Incidencia de recuperación hematopoyética y quimerismo del donante en d+100 y 1 año post RIC-HSCT
Periodo de tiempo: 2 años
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2 años
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Identificar posibles factores de riesgo de consecuencias permanentes (PC)
Periodo de tiempo: 2 años
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2 años
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Overall Survival
Periodo de tiempo: 2 Years
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Stratum I |
2 Years
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Incidence of Permanent Consequences
Periodo de tiempo: 2 Years
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All Stratum |
2 Years
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Time to complete disease resolution
Periodo de tiempo: 2 Years
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Stratum III |
2 Years
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Response rate to the combination of prednisone, vincristine and cytarabine
Periodo de tiempo: 2 years
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Stratum II |
2 years
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The proportion of patients alive and free of disease without permanent consequences (e.g. diabetes insipidus, anterior pituitary dysfunction, radiological or clinical neurodegeneration)
Periodo de tiempo: 2 Years
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Stratum II |
2 Years
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Percentage of treatment-related toxicities
Periodo de tiempo: 2 Years
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Stratum II |
2 Years
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Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX.
Periodo de tiempo: 2 years
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Stratum II |
2 years
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The type of subsequent intensive and/or maintenance therapy utilized
Periodo de tiempo: 2 Years
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Stratum III |
2 Years
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Early and late mortality
Periodo de tiempo: 2 Years
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Stratum II |
2 Years
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Early and late toxicity
Periodo de tiempo: 2 Years
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Stratum III |
2 Years
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d+100 transplant related mortality
Periodo de tiempo: 2 Years
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Stratum IV |
2 Years
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Record all occurrence of skin, GI or liver abnormalities fulfilling criteria of Grades II-IV acute GVHD
Periodo de tiempo: 2 Years
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Stratum IV: Hematopoetic Stem Cell Transplantation for Risk LCH |
2 Years
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Percentage of Participants with incidence of chronic GVHD
Periodo de tiempo: 2 Years
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Stratum IV |
2 Years
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Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy
Periodo de tiempo: 2 years
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Stratum V |
2 years
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Response of isolated tumorous CNS-LCH to 2-CDA
Periodo de tiempo: 2 Years
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Stratum V |
2 Years
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Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH
Periodo de tiempo: 2 Years
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Stratum V |
2 Years
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Methods of early identification of ND-CNS-LCH
Periodo de tiempo: 2 Years
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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. |
2 Years
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Need for systemic therapy later during disease course
Periodo de tiempo: 2 Years
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Stratum VI |
2 Years
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Colaboradores e Investigadores
Patrocinador
Colaboradores
Investigadores
- Silla de estudio: Milen Minkov, MD, Ph.D, Children's Cancer Research Institute / St. Anna Children's Hospital
- Silla de estudio: Carlos Rodriguez-Galindo, MD, North American Consortium for Histiocytosis
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimado)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades de las vías respiratorias
- Enfermedades pulmonares
- Enfermedades linfáticas
- Enfermedades Pulmonares Intersticiales
- Histiocitosis
- Enfermedades hemic y linfáticas
- Histiocitosis de células de Langerhans
- Aminoácidos, péptidos y proteínas
- Proteínas
- Compuestos de azufre
- Químicos orgánicos
- Compuestos heterocíclicos, 1 anillo
- Compuestos heterocíclicos
- Compuestos heterocíclicos, 2 anillos
- Compuestos heterocíclicos, anillo fusionado
- Terapéutica
- Procedimientos quirúrgicos, operativo
- Ácidos nucleicos, nucleótidos y nucleósidos
- Alcaloides
- Compuestos policíclicos
- Trasplante
- Indoles
- Anticuerpos
- Inmunoglobulinas
- Inmunoproteínas
- Proteínas de la sangre
- Globulinas séricas
- Globulinas
- Purinas
- Citidina
- Nucleósidos de pirimidina
- Pirimidinas
- Espierra
- Embarazos
- Esteroides
- Compuestos de anillo fusionado
- Nucleósidos
- Ribonucleósidos
- Pterins
- Pteridinas
- Madreadiediols
- Alcaloides de Vinca
- Alcaloides de triptamina de secologanina
- Alcaloides de indol
- Indolizidinas
- Indolizinas
- Arabinonucleósidos
- Aminopterina
- Isotipos de inmunoglobulina
- Inmunoglobulina G
- Trasplante de células
- Terapia basada en células y tejidos
- Terapia biológica
- Desoxirribonucleósidos
- Trasplante de células madre
- 2-cloroadenosina
- Adenosina
- Nucleósidos de purina
- Desoxiadenosinas
- Compuestos de sulfhidrilo
- Metotrexato
- Prednisona
- Citarabina
- Mercaptopurina
- Vinblastina
- Inmunoglobulinas Intravenosas
- Cladribina
- Indometacina
- Trasplante de células madre hematopoyéticas
Otros números de identificación del estudio
- 13-428
- 2011-001699-20 (Número EudraCT)
- 042011 (Otro identificador: Children's Cancer Research Institute)
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