Clinical trial NCT02205762: LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis
Official title: LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Langerhans Cell Histiocytosis
Keywords: Langerhans cell histiocytosis
Lead sponsor: North American Consortium for Histiocytosis
Sponsor class: OTHER
Collaborators: name: Histiocyte Society
First posted: 2014-07-31
Enrollment: 1400
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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)

Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of Patients with Reactivation Free Survival
timeFrame: 12 Months
measure: Response Rate of Second Cycle
timeFrame: 9 weeks
measure: Overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT)
timeFrame: 3 Years
measure: 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
timeFrame: 2 Years
measure: The time interval and cumulative incidence of progression of radiological neurodegeneration to clinically manifested ND-CNS-LCH
timeFrame: 2 Years
measure: Cumulative incidence of specific Permanent Consequences e.g. diabetes insipidus (DI), growth hormone deficiency (GHD), neuropsychological impairment, etc.
timeFrame: 2 Years
Secondary outcomes:
measure: Overall Survival
timeFrame: 2 Years
measure: Number of Participants with Serious and Non-Serious Adverse Events
timeFrame: 2 Years
measure: Incidence of Permanent Consequences
timeFrame: 2 Years
measure: Cumulative incidence of reactivations in risk organs
timeFrame: 2 Years
measure: Time to complete disease resolution
timeFrame: 2 Years
measure: Response rate to the combination of prednisone, vincristine and cytarabine
timeFrame: 2 years
measure: The proportion of patients alive and free of disease without permanent consequences (e.g. diabetes insipidus, anterior pituitary dysfunction, radiological or clinical neurodegeneration)
timeFrame: 2 Years
measure: Percentage of treatment-related toxicities
timeFrame: 2 Years
measure: Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX.
timeFrame: 2 years
measure: The type of subsequent intensive and/or maintenance therapy utilized
timeFrame: 2 Years
measure: Early and late mortality
timeFrame: 2 Years
measure: Early and late toxicity
timeFrame: 2 Years
measure: d+100 transplant related mortality
timeFrame: 2 Years
measure: Incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT
timeFrame: 2 Years
measure: Record all occurrence of skin, GI or liver abnormalities fulfilling criteria of Grades II-IV acute GVHD
timeFrame: 2 Years
measure: Percentage of Participants with incidence of chronic GVHD
timeFrame: 2 Years
measure: Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy
timeFrame: 2 years
measure: Response of isolated tumorous CNS-LCH to 2-CDA
timeFrame: 2 Years
measure: Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH
timeFrame: 2 Years
measure: Methods of early identification of ND-CNS-LCH
timeFrame: 2 Years
measure: Need for systemic therapy later during disease course
timeFrame: 2 Years
measure: Identify possible risk factors for permanent consequences (PC)
timeFrame: 2 Years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Madera
country: United States
facility: Valley Children's Healthcare
state: California
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital of Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Cancer Center
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta, Emory
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children - Indiana University
state: Indiana
city: Kansas City
country: United States
facility: Children's Mercy Hospitals
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky A.B.Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville, Norton Children's Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: Children's Minnesota
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Children's Hospital at Montefiore
state: New York
city: New Hyde Park
country: United States
facility: Cohen Children's Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Columbia University / Herbert Irving Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center, Levine Children's Hospital
state: North Carolina
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies & Children's Hospital, University Hospitals
state: Ohio
city: Toledo
country: United States
facility: Russell J Ebeid Children's Hospital (Promedica)
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Greenville
country: United States
facility: Greenville Health System BI-LO Charities Children's Cancer Center
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center Dallas, UT Southwestern
state: Texas
city: Spokane
country: United States
facility: Providence Sacred Heart Children's Hospital
state: Washington
city: Tacoma
country: United States
facility: Madigan Army Medical Center
state: Washington
city: Madison
country: United States
facility: American Family Children's Hospital University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Children's Cancer Research Institute / St. Anna Children's Hospital
name: Milen Minkov, MD, Ph.D
role: STUDY_CHAIR
affiliation: North American Consortium for Histiocytosis
name: Carlos Rodriguez-Galindo, MD
role: STUDY_CHAIR
References: