Combination Chemotherapy in Treating Young Patients With Langerhans Cell Histiocytosis

• ClinicalTrials.gov Identifier: NCT00276757
• Recruitment Status: Completed
• First Posted: January 13, 2006
• Last Update Posted: January 10, 2014
• Sponsor: Histiocyte Society
• Information provided by: National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: January 12, 2006
• First Posted Date: January 13, 2006
• Last Update Posted Date: January 10, 2014
• Study Start Date: April 2001
• Primary Completion Date: Not Provided
• Current Primary Outcome Measures: Not Provided
• Original Primary Outcome Measures: Not Provided
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combination Chemotherapy in Treating Young Patients With Langerhans Cell Histiocytosis
• Official Title: Treatment Protocol of the Third International Study For Langerhans Cell Histiocytosis

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of Langerhans cell histiocytosis, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may be an effective treatment for Langerhans cell histiocytosis.

PURPOSE: This randomized clinical trial is studying combination chemotherapy to see how well it works in treating young patients with Langerhans cell histiocytosis.

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy, in terms of response to initial therapy, of prednisolone, vinblastine, and mercaptopurine with vs without methotrexate and leucovorin calcium in young patients with Langerhans cell histiocytosis.
• Compare the progression-free survival of patients with low-risk Langerhans cell histiocytosis who responded to initial therapy who are then treated with 6-month vs 12-month continuation therapy comprising prednisolone and vinblastine.

Secondary

• Compare the acute and long-term toxicity and the incidence of permanent effects.
• Compare the overall and progression-free survival, response rate, and time until response.

OUTLINE: This is a randomized, multicenter study with one pilot nonrandomized stratum. Patients are stratified according to number of systems involved (multiple vs single) and organs involved (at risk vs low risk).

• Stratum 1 (at risk patients): Patients are further stratified according to participating center. Patients are randomized to 1 of 2 treatment arms (arms I and II).

  • Arm I:

    • Initial therapy: Patients receive oral prednisolone 3 times daily on days 1-28 followed by a taper on days 29-42 and vinblastine IV on days 1, 8, 15, 22, 29, and 36. Patients achieving nonactive disease (NAD) after course 1 proceed to continuation therapy. Patients achieving intermediate response or disease regression receive a second course* of initial therapy. Patients achieving NAD or disease regression after course 2 proceed to continuation therapy.
    • Continuation therapy: Patients receive oral mercaptopurine daily for 3 weeks, pulsed oral prednisolone 3 times daily on days 1-5, and vinblastine IV on day 1. Treatment repeats every 3 weeks until day 365 from the beginning of therapy in the absence of disease progression or unacceptable toxicity.

  • Arm II:

    • Initial therapy: Patients receive prednisone and vinblastine as in arm I initial therapy. Patients also receive methotrexate IV over 24 hours on days 1, 15, and 29 and oral leucovorin calcium twice daily on days 2,16, and 30. Patients achieving NAD after course 1 proceed to continuation therapy. Patients achieving intermediate response or disease regression receive a second course* of initial therapy. Patients achieving NAD or disease regression after course 2 proceed to continuation therapy.
    • Continuation therapy: Patients receive oral mercaptopurine daily for 3 weeks, pulsed oral prednisolone 3 times daily on days 1-5, vinblastine IV on day 1, and oral methotrexate on day 1. Treatment repeats every 3 weeks until day 365 from the beginning of therapy in the absence of disease progression or unacceptable toxicity.

• Stratum 2 (low-risk patients): Patients are stratified according to age at diagnosis (≤ 2 vs > 2) and participating center. Patients are randomized to 1 of 2 treatment arms (arms III and IV) after the first course of initial therapy.

  • Arm III:

    • Initial therapy: Patients receive prednisolone and vinblastine as in course 1 of stratum 1 arm I initial therapy. Patients achieving NAD or disease regression after course 1 proceed to continuation therapy. Patients achieving intermediate or worse response receive a second course* of initial therapy. Patients achieving NAD, disease regression, or intermediate response after course 2 proceed to continuation therapy.
    • Continuation therapy: Patients receive prednisolone and vinblastine as in stratum 1 arm I continuation therapy. Treatment continues until day 182 from the beginning of initial therapy in the absence of disease progression or unacceptable toxicity.

  • Arm IV:

    • Initial therapy: Patients receive 1-2 courses of prednisolone and vinblastine as in stratum 2 arm III.
    • Continuation therapy: Patients receive pulsed prednisolone and vinblastine as in stratum 1 arm I continuation therapy. Treatment continues until day 365 from the beginning of initial therapy in the absence of disease progression or unacceptable toxicity.

• Stratum 3 (pilot study) (patients with multifocal bone disease and/or special sites):

  • Initial therapy: Patients receive prednisolone and vinblastine as in stratum 1 arm I initial therapy. Patients achieving NAD or disease regression after course 1 proceed to continuation therapy. Patients with disease progression receive a second course* of initial therapy. Patients achieving NAD or disease regression after course 2 proceed to continuation therapy.
  • Continuation therapy: Patients receive pulsed prednisolone and vinblastine as in stratum 1 arm I continuation therapy. Treatment continues until day 182 from the beginning of initial therapy in the absence of disease progression or unacceptable disease.

NOTE: *Patients receive oral prednisolone 3 times daily on days 43-45, 50-52, 57-59, 64-66, 71-73, and 78-80 only during the second course of initial therapy.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 376 patients will be accrued for this study.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Primary Purpose: Treatment
• Condition: Childhood Langerhans Cell Histiocytosis

Intervention

• Drug: leucovorin calcium
• Drug: methotrexate
• Drug: prednisolone
• Drug: vinblastine sulfate

• Study Arms: Not Provided
• Publications *: Gadner H, Minkov M, Grois N, Potschger U, Thiem E, Arico M, Astigarraga I, Braier J, Donadieu J, Henter JI, Janka-Schaub G, McClain KL, Weitzman S, Windebank K, Ladisch S; Histiocyte Society. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013 Jun 20;121(25):5006-14. doi: 10.1182/blood-2012-09-455774. Epub 2013 Apr 15.

Recruitment Information

• Recruitment Status: Completed
• Estimated Enrollment (submitted: November 8, 2006): 376
• Original Enrollment: Not Provided
• Actual Study Completion Date: June 2013
• Primary Completion Date: Not Provided

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histopathologically confirmed diagnosis of Langerhans cell histiocytosis according to the criteria defined by the Histiocyte Society

  • Demonstration of CD1a antigenic determinants on the surface of lesional cells (by immunocytology or immunohistology) or Birbeck granules in lesional cells by electron microscopy

• Considered at risk or low risk according to the following criteria:

  • Multi-system at risk disease, defined as involvement of one or more risk organs (i.e., hematopoietic system, liver, spleen, or lungs)

    • No single-system lung involvement

  • Multi-system low-risk disease

    • Multiple organs involved but without involvement of risk organs

  • Single-system disease

    • Multifocal bone disease (i.e., lesions in 2 or more different bones)

    • Localized special site involvement, such as CNS-risk lesions with intracranial soft tissue extension or vertebral lesions with intraspinal soft tissue extension

      • Vault lesions are not regarded as CNS-risk lesions

PATIENT CHARACTERISTICS:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No prior treatment for Langerhans cell histiocytosis

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Austria, Canada, France, Germany, Ireland, Italy, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT00276757
• Other Study ID Numbers: CDR0000454768; HISTSOC-LCH-III; CCLG-LCH-III; EU-20587; CCLG-LCH-2002-07; UMN-2006NT004
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Not Provided
• Original Responsible Party: Same as current
• Current Study Sponsor: Histiocyte Society
• Original Study Sponsor: United Kingdom Children's Cancer Study Group
• Collaborators: Not Provided

Investigators

• Study Chair: Kenneth L. McClain, MD, PhD; Texas Children's Cancer Center

• PRS Account: National Cancer Institute (NCI)
• Verification Date: May 2007