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

NCT02205762 | Active Not Recruiting Phase 2 DMC

• 3 other identifiers: 13-4282011-001699-20042011
• Study Type: interventional
• Target: 1,400
• Locations: 1 country
• Sites: 42

Brief Summary

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

Conditions

Langerhans Cell Histiocytosis

Keywords

Langerhans cell histiocytosis

Outcome Measures

Primary Outcomes (6)

• Percentage of Patients with Reactivation Free Survival

  Stratum I, II, VI

  12 Months

• Response Rate of Second Cycle

  Stratum III

  9 weeks

• Overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT)

  Stratum IV

  3 Years

• 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

  Stratum V

  2 Years

• The time interval and cumulative incidence of progression of radiological neurodegeneration to clinically manifested ND-CNS-LCH

  Stratum V

  2 Years

• Cumulative incidence of specific Permanent Consequences e.g. diabetes insipidus (DI), growth hormone deficiency (GHD), neuropsychological impairment, etc.

  From all treatment stratum via long-term follow up in Stratum VII

  2 Years

Secondary Outcomes (22)

• Overall Survival

  2 Years

• Number of Participants with Serious and Non-Serious Adverse Events

  2 Years

• Incidence of Permanent Consequences

  2 Years

• Cumulative incidence of reactivations in risk organs

  2 Years

• Time to complete disease resolution

  2 Years

Study Arms (6)

Stratum I

EXPERIMENTAL

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.

Drug: Prednisone; Drug: Vinblastine; Drug: mercaptopurine

Stratum II

EXPERIMENTAL

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).

Drug: Prednisone; Drug: Vinblastine; Drug: mercaptopurine; Drug: INDOMETHACIN; Drug: Methotrexate; Drug: Cytosine Arabinoside

Stratum III

EXPERIMENTAL

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.

Drug: 2-chlorodeoxyadenosine

Stratum IV

EXPERIMENTAL

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).

Procedure: hematopoietic stem cell transplantation (RIC-HSCT)

Stratum V

EXPERIMENTAL

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.

Drug: Cytosine Arabinoside; Drug: 2-chlorodeoxyadenosine; Biological: Intravenous immunoglobulin

Stratum VI

EXPERIMENTAL

Natural 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.

Drug: Prednisone; Drug: Vinblastine; Drug: mercaptopurine; Drug: Cytosine Arabinoside; Drug: 2-chlorodeoxyadenosine; Biological: Intravenous immunoglobulin

Interventions

Prednisone DRUG

Stratum I

Stratum I; Stratum II; Stratum VI

Vinblastine DRUG

Stratum I

Also known as: Velban®, Vincaleukoblastine Sulfate

Stratum I; Stratum II; Stratum VI

mercaptopurine DRUG

Stratum I

Also known as: -Purinethol®, -6-MP

Stratum I; Stratum II; Stratum VI

INDOMETHACIN DRUG

Indomethacin fixed dose given daily orally in two divided doses with gastric protection for total treatment duration of 24 months.

Stratum II

Methotrexate DRUG

fixed dose weekly orally for total treatment duration of 24 months.

Stratum II

Cytosine Arabinoside DRUG

Also known as: Cytarabine, Ara-C

Stratum II; Stratum V; Stratum VI

Intravenous immunoglobulin BIOLOGICAL

Also known as: IVIG

Stratum V; Stratum VI

2-chlorodeoxyadenosine DRUG

Also known as: 2-CdA, Cladribin®, Leustatin®

Stratum III; Stratum V; Stratum VI

hematopoietic stem cell transplantation (RIC-HSCT) PROCEDURE

Stratum IV

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• North American Consortium for Histiocytosis: lead
• Histiocyte Society: collaborator

Study Sites (42)

Children's of Alabama

Birmingham, Alabama, 35233, United States

Location

Phoenix Children's Hospital

Phoenix, Arizona, 85006, United States

Location

Arkansas Children's Hospital

Little Rock, Arkansas, 72202, United States

Location

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

Valley Children's Healthcare

Madera, California, 93636, United States

Location

UCSF Benioff Children's Hospital of Oakland

Oakland, California, 94609, United States

Location

Children's Hospital of Orange County

Orange, California, 92868, United States

Location

UCSF Helen Diller Family Cancer Center

San Francisco, California, 94158-0106, United States

Location

Connecticut Children's Medical Center

Hartford, Connecticut, 06106, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Johns Hopkins All Children's Hospital

St. Petersburg, Florida, 33701, United States

Location

Children's Healthcare of Atlanta, Emory

Atlanta, Georgia, 30342, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611-2991, United States

Location

Riley Hospital for Children - Indiana University

Indianapolis, Indiana, 46202, United States

Location

Children's Mercy Hospitals

Kansas City, Kansas, 64108, United States

Location

University of Kentucky A.B.Chandler Medical Center

Lexington, Kentucky, 40536, United States

Location

University of Louisville, Norton Children's Hospital

Louisville, Kentucky, 40202, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Children's Minnesota

Minneapolis, Minnesota, 55404, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Cohen Children's Medical Center

New Hyde Park, New York, 11040, United States

Location

Mount Sinai Hospital

New York, New York, 10029, United States

Location

Columbia University / Herbert Irving Cancer Center

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10170, United States

Location

SUNY Upstate Medical University

Syracuse, New York, 13210, United States

Location

Children's Hospital at Montefiore

The Bronx, New York, 10467, United States

Location

Carolinas Medical Center, Levine Children's Hospital

Charlotte, North Carolina, 28203, United States

Location

Akron Children's Hospital

Akron, Ohio, 44308, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Rainbow Babies & Children's Hospital, University Hospitals

Cleveland, Ohio, 44106, United States

Location

Russell J Ebeid Children's Hospital (Promedica)

Toledo, Ohio, 43606, United States

Location

UPMC Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

Medical University of South Carolina (MUSC)

Charleston, South Carolina, 29425, United States

Location

Greenville Health System BI-LO Charities Children's Cancer Center

Greenville, South Carolina, 29605, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Children's Medical Center Dallas, UT Southwestern

Dallas, Texas, 75235, United States

Location

Providence Sacred Heart Children's Hospital

Spokane, Washington, 99204, United States

Location

Madigan Army Medical Center

Tacoma, Washington, 98431, United States

Location

American Family Children's Hospital University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

MeSH Terms

Conditions

Histiocytosis, Langerhans-Cell

Interventions

Prednisone; Vinblastine; Mercaptopurine; Indomethacin; Methotrexate; Cytarabine; Cladribine; Hematopoietic Stem Cell Transplantation; Immunoglobulins, Intravenous

Condition Hierarchy (Ancestors)

Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Sulfhydryl Compounds; Sulfur Compounds; Organic Chemicals; Purines; Aminopterin; Pterins; Pteridines; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Deoxyadenosines; Deoxyribonucleosides; Ribonucleosides; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Immunoglobulin G; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Milen Minkov, MD, Ph.D

  Children's Cancer Research Institute / St. Anna Children's Hospital

  STUDY CHAIR

• Carlos Rodriguez-Galindo, MD

  North American Consortium for Histiocytosis

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 7, 2014
• First Posted: July 31, 2014
• Study Start: November 2, 2016
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: April 9, 2026

Record last verified: 2026-04

Locations

US (42)