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

• Sponsor: North American Consortium for Histiocytosis (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT02205762
• Collaborator: Histiocyte Society (Other)
• Enrollment: 1,400
• Locations: 36
• Arms: 6
• Duration (Months): 108
• Patients Per Site: 38.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Langerhans Cell Histiocytosis	Drug: Prednisone; Drug: Vinblastine; Drug: mercaptopurine; Drug: INDOMETHACIN; Drug: Methotrexate; Drug: Cytosine Arabinoside; Drug: 2-chlorodeoxyadenosine; Procedure: hematopoietic stem cell transplantation (RIC-HSCT); Biological: Intravenous immunoglobulin	Phase 2/Phase 3

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)

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 1400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis
• Study Start Date: Jul 1, 2014
• Anticipated Primary Completion Date: Jul 1, 2023
• Anticipated Study Completion Date: Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stratum I Stratum 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.	Drug: Prednisone; Stratum I; Drug: Vinblastine; Stratum I; Other Names: Velban® Vincaleukoblastine Sulfate ; Drug: mercaptopurine; Stratum I; Other Names: -Purinethol® -6-MP
Experimental: Stratum II A 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).	Drug: Prednisone; Stratum I; Drug: Vinblastine; Stratum I; Other Names: Velban® Vincaleukoblastine Sulfate ; Drug: mercaptopurine; Stratum I; Other Names: -Purinethol® -6-MP ; Drug: INDOMETHACIN; Indomethacin fixed dose given daily orally in two divided doses with gastric protection for total treatment duration of 24 months.; Drug: Methotrexate; fixed dose weekly orally for total treatment duration of 24 months.; Drug: Cytosine Arabinoside; Other Names: Cytarabine, Ara-C
Experimental: Stratum III Salvage 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.	Drug: 2-chlorodeoxyadenosine; Other Names: 2-CdA Cladribin® Leustatin®
Experimental: Stratum IV To 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).	Procedure: hematopoietic stem cell transplantation (RIC-HSCT)
Experimental: Stratum V Stratum 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.	Drug: Cytosine Arabinoside; Other Names: Cytarabine, Ara-C ; Drug: 2-chlorodeoxyadenosine; Other Names: 2-CdA Cladribin® Leustatin® ; Biological: Intravenous immunoglobulin; Other Names: IVIG
Experimental: Stratum VI Natural 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.	Drug: Prednisone; Stratum I; Drug: Vinblastine; Stratum I; Other Names: Velban® Vincaleukoblastine Sulfate ; Drug: mercaptopurine; Stratum I; Other Names: -Purinethol® -6-MP ; Drug: Cytosine Arabinoside; Other Names: Cytarabine, Ara-C ; Drug: 2-chlorodeoxyadenosine; Other Names: 2-CdA Cladribin® Leustatin® ; Biological: Intravenous immunoglobulin; Other Names: IVIG

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients with Reactivation Free Survival [12 Months]

   Stratum I, II, VI

2. Response Rate of Second Cycle [9 weeks]

   Stratum III

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

   Stratum IV

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 [2 Years]

   Stratum V

5. The time interval and cumulative incidence of progression of radiological neurodegeneration to clinically manifested ND-CNS-LCH [2 Years]

   Stratum V

6. Cumulative incidence of specific Permanent Consequences e.g. diabetes insipidus (DI), growth hormone deficiency (GHD), neuropsychological impairment, etc. [2 Years]

   From all treatment stratum via long-term follow up in Stratum VII

Secondary Outcome Measures

1. Overall Survival [2 Years]

   Stratum I

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

3. Incidence of Permanent Consequences [2 Years]

   All Stratum

4. Cumulative incidence of reactivations in risk organs [2 Years]

5. Time to complete disease resolution [2 Years]

   Stratum III

6. Response rate to the combination of prednisone, vincristine and cytarabine [2 years]

   Stratum II

7. The proportion of patients alive and free of disease without permanent consequences (e.g. diabetes insipidus, anterior pituitary dysfunction, radiological or clinical neurodegeneration) [2 Years]

   Stratum II

8. Percentage of treatment-related toxicities [2 Years]

   Stratum II

9. Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX. [2 years]

   Stratum II

10. The type of subsequent intensive and/or maintenance therapy utilized [2 Years]

    Stratum III

11. Early and late mortality [2 Years]

    Stratum II

12. Early and late toxicity [2 Years]

    Stratum III

13. d+100 transplant related mortality [2 Years]

    Stratum IV

14. Incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT [2 Years]

15. Record all occurrence of skin, GI or liver abnormalities fulfilling criteria of Grades II-IV acute GVHD [2 Years]

    Stratum IV: Hematopoetic Stem Cell Transplantation for Risk LCH

16. Percentage of Participants with incidence of chronic GVHD [2 Years]

    Stratum IV

17. Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy [2 years]

    Stratum V

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

    Stratum V

19. Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH [2 Years]

    Stratum V

20. Methods of early identification of ND-CNS-LCH [2 Years]

    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.

21. Need for systemic therapy later during disease course [2 Years]

    Stratum VI

22. Identify possible risk factors for permanent consequences (PC) [2 Years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's of Alabama	Birmingham	Alabama	United States	35233
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85006
3	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
4	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
5	Valley Children's Healthcare	Madera	California	United States	93636
6	UCSF Benioff Children's Hospital of Oakland	Oakland	California	United States	94609
7	Children's Hospital of Orange County	Orange	California	United States	92868
8	UCSF Helen Diller Family Cancer Center	San Francisco	California	United States	94158-0106
9	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
10	Children's National Medical Center	Washington	District of Columbia	United States	20010
11	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
12	Children's Healthcare of Atlanta, Emory	Atlanta	Georgia	United States	30342
13	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611-2991
14	Children's Mercy Hospitals	Kansas City	Kansas	United States	64108
15	University of Kentucky A.B.Chandler Medical Center	Lexington	Kentucky	United States	40536
16	University of Louisville, Norton Children's Hospital	Louisville	Kentucky	United States	40202
17	Johns Hopkins University	Baltimore	Maryland	United States	21287
18	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
19	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
20	Children's Minnesota	Minneapolis	Minnesota	United States	55404
21	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
22	Cohen Children's Medical Center	New Hyde Park	New York	United States	11040
23	Columbia University / Herbert Irving Cancer Center	New York	New York	United States	10032
24	Memorial Sloan Kettering Cancer Center	New York	New York	United States
25	SUNY Upstate Medical University	Syracuse	New York	United States	13210
26	Carolinas Medical Center, Levine Children's Hospital	Charlotte	North Carolina	United States	28203
27	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
28	Rainbow Babies & Children's Hospital, University Hospitals	Cleveland	Ohio	United States	44106
29	The Toledo Hospital, Toledo Children's Hospital	Toledo	Ohio	United States	43606
30	Medical University of South Carolina (MUSC)	Charleston	South Carolina	United States	29425
31	Greenville Health System BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
32	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
33	Children's Medical Center Dallas, UT Southwestern	Dallas	Texas	United States
34	Providence Sacred Heart Children's Hospital	Spokane	Washington	United States	99204
35	Madigan Army Medical Center	Tacoma	Washington	United States	98431
36	American Family Children's Hospital University of Wisconsin	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• North American Consortium for Histiocytosis
• Histiocyte Society

Investigators

• Study Chair: Milen Minkov, MD, Ph.D, Children's Cancer Research Institute / St. Anna Children's Hospital
• Study Chair: Carlos Rodriguez-Galindo, MD, North American Consortium for Histiocytosis

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: North American Consortium for Histiocytosis
• ClinicalTrials.gov Identifier: NCT02205762
• Other Study ID Numbers: 13-428; 2011-001699-20; 042011
• First Posted: Jul 31, 2014
• Last Update Posted: Feb 21, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by North American Consortium for Histiocytosis: Langerhans cell histiocytosis
• Additional relevant MeSH terms: Histiocytosis, Langerhans-Cell; Histiocytosis; Cytarabine; Prednisone; Indomethacin; Methotrexate; Mercaptopurine; Vinblastine; Cladribine; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin

Study Results

No Results Posted as of Feb 21, 2022