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Langerhans Cell HistiocytosisPhase 2/3NCT02205762

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

A Phase 2/3 study testing Prednisone, Vinblastine and mercaptopurine in people with Langerhans Cell Histiocytosis, run by North American Consortium for Histiocytosis at 42 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial summary

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

Who is it for?
Ages Up to 18 years
Conditions the study is for
Langerhans Cell Histiocytosis
What is being tested?
Prednisone, Vinblastine and mercaptopurine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,400 participants
Where
42 sitesUnited States
Study dates
2 Nov 2016to Jul 2026
Phase
Phase 2/3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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:
Show all 33Show fewer
  • 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.

Who cannot join

  • 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
Show all 22Show fewer
  • 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)

Trial locations and contacts

42 sites in 1 country.

42 sites in 1 country

United States42 sites

  • Akron Children's Hospital

    Akron, Ohio, 44308

  • Children's Healthcare of Atlanta, Emory

    Atlanta, Georgia, 30342

  • Johns Hopkins University

    Baltimore, Maryland, 21287

  • Children's of Alabama

    Birmingham, Alabama, 35233

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02115

  • Medical University of South Carolina (MUSC)

    Charleston, South Carolina, 29425

  • Carolinas Medical Center, Levine Children's Hospital

    Charlotte, North Carolina, 28203

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

    Chicago, Illinois, 60611-2991

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • Rainbow Babies & Children's Hospital, University Hospitals

    Cleveland, Ohio, 44106

  • Children's Medical Center Dallas, UT Southwestern

    Dallas, Texas, 75235

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

    Greenville, South Carolina, 29605

  • Hackensack University Medical Center

    Hackensack, New Jersey, 07601

  • Connecticut Children's Medical Center

    Hartford, Connecticut, 06106

  • Riley Hospital for Children - Indiana University

    Indianapolis, Indiana, 46202

  • Children's Mercy Hospitals

    Kansas City, Kansas, 64108

  • University of Kentucky A.B.Chandler Medical Center

    Lexington, Kentucky, 40536

  • Arkansas Children's Hospital

    Little Rock, Arkansas, 72202

  • Children's Hospital of Los Angeles

    Los Angeles, California, 90027

  • University of Louisville, Norton Children's Hospital

    Louisville, Kentucky, 40202

  • Valley Children's Healthcare

    Madera, California, 93636

  • American Family Children's Hospital University of Wisconsin

    Madison, Wisconsin, 53792

  • St. Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • Children's Minnesota

    Minneapolis, Minnesota, 55404

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232

  • Cohen Children's Medical Center

    New Hyde Park, New York, 11040

  • Mount Sinai Hospital

    New York, New York, 10029

  • Columbia University / Herbert Irving Cancer Center

    New York, New York, 10032

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10170

  • UCSF Benioff Children's Hospital of Oakland

    Oakland, California, 94609

  • Children's Hospital of Orange County

    Orange, California, 92868

  • Phoenix Children's Hospital

    Phoenix, Arizona, 85006

  • UPMC Children's Hospital of Pittsburgh

    Pittsburgh, Pennsylvania, 15224

  • UCSF Helen Diller Family Cancer Center

    San Francisco, California, 94158-0106

  • Providence Sacred Heart Children's Hospital

    Spokane, Washington, 99204

  • Johns Hopkins All Children's Hospital

    St. Petersburg, Florida, 33701

  • SUNY Upstate Medical University

    Syracuse, New York, 13210

  • Madigan Army Medical Center

    Tacoma, Washington, 98431

  • Children's Hospital at Montefiore

    The Bronx, New York, 10467

  • Russell J Ebeid Children's Hospital (Promedica)

    Toledo, Ohio, 43606

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

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

Read the 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)
Being tested
Prednisone, Vinblastine, mercaptopurine, INDOMETHACIN, Methotrexate
Keywords
Langerhans cell histiocytosis
Medical subject headings
Histiocytosis, Langerhans-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PrednisoneDrug

    Stratum I

  • VinblastineDrug

    Also called Velban®, Vincaleukoblastine Sulfate

    Stratum I

  • mercaptopurineDrug

    Also called -Purinethol®, -6-MP

    Stratum I

  • INDOMETHACINDrug

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

  • MethotrexateDrug

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

  • Cytosine ArabinosideDrug

    Also called Cytarabine, Ara-C

  • 2-chlorodeoxyadenosineDrug

    Also called 2-CdA, Cladribin®, Leustatin®

  • hematopoietic stem cell transplantation (RIC-HSCT)Procedure or surgery

  • Intravenous immunoglobulinBiological

    Also called IVIG

Study groups in NCT02205762
Study groupRoleWhat they receive
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.
Receives: Drug: Prednisone; Drug: Vinblastine; Drug: 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).
Receives: Drug: Prednisone; Drug: Vinblastine; Drug: mercaptopurine; Drug: INDOMETHACIN; Drug: Methotrexate; Drug: 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.
Receives: Drug: 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).
Receives: Procedure: hematopoietic stem cell transplantation (RIC-HSCT)
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.
Receives: Drug: Cytosine Arabinoside; Drug: 2-chlorodeoxyadenosine; Biological: Intravenous immunoglobulin
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.
Receives: Drug: Prednisone; Drug: Vinblastine; Drug: mercaptopurine; Drug: Cytosine Arabinoside; Drug: 2-chlorodeoxyadenosine; Biological: Intravenous immunoglobulin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Patients with Reactivation Free Survival

    Stratum I, II, VI

    Measured: 12 Months

  2. Response Rate of Second Cycle

    Stratum III

    Measured: 9 weeks

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

    Stratum IV

    Measured: 3 Years

  4. 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

    Measured: 2 Years

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

    Stratum V

    Measured: 2 Years

  6. 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

    Measured: 2 Years

Secondary outcomes (22)

  1. Overall Survival

    Stratum I

    Measured: 2 Years

  2. Number of Participants with Serious and Non-Serious Adverse Events

    Measured: 2 Years

  3. Incidence of Permanent Consequences

    All Stratum

    Measured: 2 Years

  4. Cumulative incidence of reactivations in risk organs

    Measured: 2 Years

  5. Time to complete disease resolution

    Stratum III

    Measured: 2 Years

  6. Response rate to the combination of prednisone, vincristine and cytarabine

    Stratum II

    Measured: 2 years

  7. The proportion of patients alive and free of disease without permanent consequences (e.g. diabetes insipidus, anterior pituitary dysfunction, radiological or clinical neurodegeneration)

    Stratum II

    Measured: 2 Years

  8. Percentage of treatment-related toxicities

    Stratum II

    Measured: 2 Years

  9. Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX.

    Stratum II

    Measured: 2 years

  10. The type of subsequent intensive and/or maintenance therapy utilized

    Stratum III

    Measured: 2 Years

  11. Early and late mortality

    Stratum II

    Measured: 2 Years

  12. Early and late toxicity

    Stratum III

    Measured: 2 Years

  13. d+100 transplant related mortality

    Stratum IV

    Measured: 2 Years

  14. Incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT

    Measured: 2 Years

  15. Record all occurrence of skin, GI or liver abnormalities fulfilling criteria of Grades II-IV acute GVHD

    Stratum IV: Hematopoetic Stem Cell Transplantation for Risk LCH

    Measured: 2 Years

  16. Percentage of Participants with incidence of chronic GVHD

    Stratum IV

    Measured: 2 Years

  17. Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy

    Stratum V

    Measured: 2 years

  18. Response of isolated tumorous CNS-LCH to 2-CDA

    Stratum V

    Measured: 2 Years

  19. Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH

    Stratum V

    Measured: 2 Years

  20. Methods of early identification of ND-CNS-LCH

    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.

    Measured: 2 Years

  21. Need for systemic therapy later during disease course

    Stratum VI

    Measured: 2 Years

  22. Identify possible risk factors for permanent consequences (PC)

    Measured: 2 Years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jul 2014 (estimated)
  2. Study start2 Nov 2016
  3. Primary completionJul 2026 (estimated)
  4. Study completionJul 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
1,400 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02205762
Sponsor's protocol ID
13-428
Other IDs
2011-001699-20, 042011
Status last verified
Apr 2026
First submitted
7 Jul 2014
Last updated
9 Apr 2026
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Prednisone, Vinblastine and mercaptopurine in people with Langerhans Cell Histiocytosis, run by North American Consortium for Histiocytosis at 42 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 33 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 9 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 42 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Patients with Reactivation Free Survival (time frame: 12 Months). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02205762.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Apr 2026.

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