Combination Chemotherapy in Treating Young Patients With Langerhans Cell Histiocytosis

Sponsor

Histiocyte Society (Other)

Overall Status

Completed

CT.gov ID

NCT00276757

Collaborator

(none)

376

Enrollment

Locations

146

Duration (Months)

11.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Childhood Langerhans Cell Histiocytosis	Drug: leucovorin calcium Drug: methotrexate Drug: prednisolone Drug: vinblastine sulfate	N/A

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

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 Design

Study Type:

Interventional

Anticipated Enrollment :

376 participants

Allocation:

Randomized

Primary Purpose:

Treatment

Official Title:

Treatment Protocol of the Third International Study For Langerhans Cell Histiocytosis

Study Start Date :

Apr 1, 2001

Actual Study Completion Date :

Jun 1, 2013

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota	United States	55455
2	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
3	Vanderbilt Children's Hospital	Nashville	Tennessee	United States	37232-9700
4	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital	Houston	Texas	United States	77030-2399
5	Hospital de Pediatria Garrahan	Buenos Aires		Argentina	1245
6	St. Anna Children's Hospital	Vienna		Austria	A-1090
7	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
8	CHR Hotel Dieu	Nantes		France	44093
9	University Medical Center Hamburg - Eppendorf	Hamburg		Germany	D-20246
10	Our Lady's Hospital for Sick Children Crumlin	Dublin		Ireland	12
11	Fondazione I.R.C.C.S. Policlinico San Matteo	Pavia		Italy	27100
12	Karolinska University Hospital - Solna	Stockholm		Sweden	S-171 76
13	Birmingham Children's Hospital	Birmingham	England	United Kingdom	B4 6NH
14	Institute of Child Health at University of Bristol	Bristol	England	United Kingdom	BS2 8AE
15	Addenbrooke's Hospital	Cambridge	England	United Kingdom	CB2 2QQ
16	Leeds Cancer Centre at St. James's University Hospital	Leeds	England	United Kingdom	LS9 7TF
17	Leicester Royal Infirmary	Leicester	England	United Kingdom	LE1 5WW
18	Children's Cancer and Leukaemia Group	Leicester	England	United Kingdom	LE1 6TH
19	Royal Liverpool Children's Hospital, Alder Hey	Liverpool	England	United Kingdom	L12 2AP
20	Royal London Hospital	London	England	United Kingdom	E1 1BB
21	Great Ormond Street Hospital for Children	London	England	United Kingdom	WC1N 3JH
22	Royal Manchester Children's Hospital	Manchester	England	United Kingdom	M27 4HA
23	Sir James Spence Institute of Child Health at Royal Victoria Infirmary	Newcastle-Upon-Tyne	England	United Kingdom	NE1 4LP
24	Queen's Medical Centre	Nottingham	England	United Kingdom	NG7 2UH
25	Oxford Radcliffe Hospital	Oxford	England	United Kingdom	0X3 9DU
26	Children's Hospital - Sheffield	Sheffield	England	United Kingdom	S10 2TH
27	Southampton General Hospital	Southampton	England	United Kingdom	SO16 6YD
28	Royal Marsden - Surrey	Sutton	England	United Kingdom	SM2 5PT
29	Royal Belfast Hospital for Sick Children	Belfast	Northern Ireland	United Kingdom	BT12 6BE
30	Royal Aberdeen Children's Hospital	Aberdeen	Scotland	United Kingdom	AB25 2ZG
31	Royal Hospital for Sick Children	Edinburgh	Scotland	United Kingdom	EH9 1LF
32	Royal Hospital for Sick Children	Glasgow	Scotland	United Kingdom	G3 8SJ
33	Childrens Hospital for Wales	Cardiff	Wales	United Kingdom	CF14 4XW