Combination Chemotherapy in Treating Young Patients With Langerhans Cell Histiocytosis

NCT ID: NCT00276757

Last Updated: 2014-01-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 376 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2001-04-30
• Study Completion Date: 2013-06-30

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.

Conditions

Childhood Langerhans Cell Histiocytosis

Study Design

• Allocation Method: RANDOMIZED
• Primary Study Purpose: TREATMENT

Interventions

leucovorin calcium

Intervention Type: DRUG

methotrexate

Intervention Type: DRUG

prednisolone

Intervention Type: DRUG

vinblastine sulfate

Intervention Type: DRUG

Eligibility Criteria

Inclusion 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

• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Histiocyte Society

OTHER

Sponsor Role: lead

Principal Investigators

Kenneth L. McClain, MD, PhD

Role: STUDY_CHAIR

Texas Children's Cancer Center

Locations

Masonic Cancer Center at University of Minnesota

Minneapolis, Minnesota, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Vanderbilt Children's Hospital

Nashville, Tennessee, United States

Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital

Houston, Texas, United States

Hospital de Pediatria Garrahan

Buenos Aires, Buenos Aires, Argentina

St. Anna Children's Hospital

Vienna, , Austria

Hospital for Sick Children

Toronto, Ontario, Canada

CHR Hotel Dieu

Nantes, , France

University Medical Center Hamburg - Eppendorf

Hamburg, , Germany

Our Lady's Hospital for Sick Children Crumlin

Dublin, , Ireland

Fondazione I.R.C.C.S. Policlinico San Matteo

Pavia, , Italy

Karolinska University Hospital - Solna

Stockholm, , Sweden

Birmingham Children's Hospital

Birmingham, England, United Kingdom

Institute of Child Health at University of Bristol

Bristol, England, United Kingdom

Addenbrooke's Hospital

Cambridge, England, United Kingdom

Leeds Cancer Centre at St. James's University Hospital

Leeds, England, United Kingdom

Leicester Royal Infirmary

Leicester, England, United Kingdom

Children's Cancer and Leukaemia Group

Leicester, England, United Kingdom

Royal Liverpool Children's Hospital, Alder Hey

Liverpool, England, United Kingdom

Royal London Hospital

London, England, United Kingdom

Great Ormond Street Hospital for Children

London, England, United Kingdom

Royal Manchester Children's Hospital

Manchester, England, United Kingdom

Sir James Spence Institute of Child Health at Royal Victoria Infirmary

Newcastle upon Tyne, England, United Kingdom

Queen's Medical Centre

Nottingham, England, United Kingdom

Oxford Radcliffe Hospital

Oxford, England, United Kingdom

Children's Hospital - Sheffield

Sheffield, England, United Kingdom

Southampton General Hospital

Southampton, England, United Kingdom

Royal Marsden - Surrey

Sutton, England, United Kingdom

Royal Belfast Hospital for Sick Children

Belfast, Northern Ireland, United Kingdom

Royal Aberdeen Children's Hospital

Aberdeen, Scotland, United Kingdom

Royal Hospital for Sick Children

Edinburgh, Scotland, United Kingdom

Royal Hospital for Sick Children

Glasgow, Scotland, United Kingdom

Childrens Hospital for Wales

Cardiff, Wales, United Kingdom

Countries

United States; Argentina; Austria; Canada; France; Germany; Ireland; Italy; Sweden; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 23589673 (View on PubMed)

Other Identifiers

HISTSOC-LCH-III

Identifier Type: -

Identifier Source: secondary_id

CCLG-LCH-III

Identifier Type: -

Identifier Source: secondary_id

EU-20587

Identifier Type: -

Identifier Source: secondary_id

CCLG-LCH-2002-07

Identifier Type: -

Identifier Source: secondary_id

UMN-2006NT004

Identifier Type: -

Identifier Source: secondary_id

CDR0000454768

Identifier Type: -

Identifier Source: org_study_id