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

Langerhans Cell Histiocytosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02205762
• Other study ID #: 13-428
• Secondary ID: 2011-001699-2004
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: November 2, 2016
• Est. completion date: July 2025

Study information

• Verified date: March 2023
• Source: North American Consortium for Histiocytosis
• Contact: Heidi M Clough, BSN, RN
• Phone: 901-595-0362
• Email: Heidi.clough[@]stjude.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1400
• Est. completion date: July 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

• 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

• 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.

Exclusion Criteria:

• 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.

• 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)

Related Conditions & MeSH terms

• Histiocytosis
• Histiocytosis, Langerhans-Cell
• Langerhans Cell Histiocytosis

Intervention

Drug:
• Prednisone
Stratum I
• Vinblastine
Stratum I
• mercaptopurine
Stratum I
• INDOMETHACIN
Indomethacin fixed dose given daily orally in two divided doses with gastric protection for total treatment duration of 24 months.
• Methotrexate
fixed dose weekly orally for total treatment duration of 24 months.
• Cytosine Arabinoside

• 2-chlorodeoxyadenosine

Procedure:
• hematopoietic stem cell transplantation (RIC-HSCT)

Biological:
• Intravenous immunoglobulin

Locations

Country	Name	City	State
United States	Children's Healthcare of Atlanta, Emory	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Children's of Alabama	Birmingham	Alabama
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Medical University of South Carolina (MUSC)	Charleston	South Carolina
United States	Carolinas Medical Center, Levine Children's Hospital	Charlotte	North Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies & Children's Hospital, University Hospitals	Cleveland	Ohio
United States	Children's Medical Center Dallas, UT Southwestern	Dallas	Texas
United States	Greenville Health System BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Children's Mercy Hospitals	Kansas City	Kansas
United States	University of Kentucky A.B.Chandler Medical Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Children's Hospital of Los Angeles	Los Angeles	California
United States	University of Louisville, Norton Children's Hospital	Louisville	Kentucky
United States	Valley Children's Healthcare	Madera	California
United States	American Family Children's Hospital University of Wisconsin	Madison	Wisconsin
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Minnesota	Minneapolis	Minnesota
United States	Cohen Children's Medical Center	New Hyde Park	New York
United States	Columbia University / Herbert Irving Cancer Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	UCSF Benioff Children's Hospital of Oakland	Oakland	California
United States	Children's Hospital of Orange County	Orange	California
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	UPMC Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	UCSF Helen Diller Family Cancer Center	San Francisco	California
United States	Providence Sacred Heart Children's Hospital	Spokane	Washington
United States	SUNY Upstate Medical University	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	The Toledo Hospital, Toledo Children's Hospital	Toledo	Ohio
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
North American Consortium for Histiocytosis	Histiocyte Society

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Patients with Reactivation Free Survival	Stratum I, II, VI	12 Months
Primary	Response Rate of Second Cycle	Stratum III	9 weeks
Primary	Overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT)	Stratum IV	3 Years
Primary	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
Primary	The time interval and cumulative incidence of progression of radiological neurodegeneration to clinically manifested ND-CNS-LCH	Stratum V	2 Years
Primary	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	Overall Survival	Stratum I	2 Years
Secondary	Number of Participants with Serious and Non-Serious Adverse Events		2 Years
Secondary	Incidence of Permanent Consequences	All Stratum	2 Years
Secondary	Cumulative incidence of reactivations in risk organs		2 Years
Secondary	Time to complete disease resolution	Stratum III	2 Years
Secondary	Response rate to the combination of prednisone, vincristine and cytarabine	Stratum II	2 years
Secondary	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	2 Years
Secondary	Percentage of treatment-related toxicities	Stratum II	2 Years
Secondary	Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX.	Stratum II	2 years
Secondary	The type of subsequent intensive and/or maintenance therapy utilized	Stratum III	2 Years
Secondary	Early and late mortality	Stratum II	2 Years
Secondary	Early and late toxicity	Stratum III	2 Years
Secondary	d+100 transplant related mortality	Stratum IV	2 Years
Secondary	Incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT		2 Years
Secondary	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	2 Years
Secondary	Percentage of Participants with incidence of chronic GVHD	Stratum IV	2 Years
Secondary	Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy	Stratum V	2 years
Secondary	Response of isolated tumorous CNS-LCH to 2-CDA	Stratum V	2 Years
Secondary	Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH	Stratum V	2 Years
Secondary	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.	2 Years
Secondary	Need for systemic therapy later during disease course	Stratum VI	2 Years
Secondary	Identify possible risk factors for permanent consequences (PC)		2 Years