LCH-IV-G 2016

Langerhans cell Histiocytosis (LCH)

Controlled multi-center, randomized, open label, phase III trial

Primary objectives

Stratum I

To reduce reactivation rates and permanent consequences in MS-LCH through prolongation (12 vs. 24 months) and intensification [+/- Mercaptopurine(MP)] of continuation treatment (2x2 factorial randomizedtrial)
To reduce reactivation rates and permanent consequences in a subset of SS-LCH (multifocal bone or isolated “CNS-Risk” lesions through prolongation (6 vs. 12 months) of ontinuation therapy (randomized trial)

Stratum II

• To investigate the value continuation therapy (randomized: 24 months of indomethacin vs. MP/MTX) in patients with non-risk organ LCH (both non-responders to first-line regimen and those who experience disease reactivation in non-risk organs after its completion) with respect to achievement of complete disease resolution, prevention of further reactivations and permanent consequences

The standard induction therapy is given to all patients in stratum I and II and is therefore NOT part of the LCH-IV-G-2016 trial. Only chilren without any active desease after induction therapy can be included into this trial.

Stratum I - MS-LCH: 2x2 factorial randomazation (four therapy arms)
1) Therapy duration 12 month without intensivation
2) Therapy duration 12 month with intensivation
3) Therapy duration 24 month without intensivation
4) Therapy duration 24 month with intensivation

Stratum I - SS-LCH: single randomazation
1) Therapy duration 6 month
2) Therapy duration 12 month

Stratum II - Second-line Therapy: single randomazation
1) Therapy duration 24 month with Indomethacin
2) Therapy duration 24 month with Mercaptopurine and MTX

Stratum I

• Age: Patients must be less than 18 years of age at the ime of enrollment.
• No systemic therapy for LCH prior to the standardized induction therapy, e.g., prior to Initial Course 1 (IC-1) and, eventually, Initial Course 2 (IC-2) (pre-study)
• Evaluation demonstrates non-active disease after IC-1(independent of involvement of risk organs) or non-active disease or active disease better (only for patients without involvement of risk organs) after IC-2 [imaging studies need to be referenced regarding treatment response to initial course(s) (pre-study)]
• Patients must have a referenced histological verification of the diagnosis of LCH (pre-study)
• Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception (e.g., barrier contraception for males, contraceptive pill (“Pill”) for female) throughout the study and for at least 90 days (male subjects) and 30 days (female subjects) after the last dose of assigned study treatment.
• Signed informed consent of parent(s)/legal guardian(s) and/or patient (when applicable depending on age and patient’s compliance) prior to any protocol procedure.

Stratum II

• Age: Patients must be older than 2 years and less than 18 years of age at the time of enrollment
• No systemic therapy for progression/relapse of LCH prior to the standardized second line therapy, e.g., standardized 24-week second-line initial course (SL-IT), which is NOT part of the study
• Evaluation demonstrates non-active disease or active disease better after SL-IT [imaging studies need to be referenced regarding treatment response to second-line initial course (pre-study)]
• Patients must have a referenced histological verification of the diagnosis of LCH (pre-study)
• Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception (e.g., barrier contraception for males, contraceptive pill (“Pill”) for female) throughout the study and for at least 90 days (male subjects) and 30 days (female subjects) after the last dose of assigned study treatment.
• Signed informed consent of parent(s)/legal guardian(s) and/or patient (when applicable depending on age and patient’s compliance) prior to any protocol procedure

Stratum I

• Patients with any active disease after IC-1 or patients with active disease intermediate/worse (for patients without involvement of risk organs) or any active disease (for patients with involvement of risk organs) after IC-2
• Hypersensitivity for one of the trial drugs or any of its excipients or hypersensitivity to any other vinca-alkaloid or any of its excipients
• Leukopenia, which is not caused by LCH
• Severe uncontrolled infection
• Stomatitis or ulcera of the gastrointestinal tract
• Pregnancy (patients of child-bearing age must be appropriately tested before chemotherapy)
• Breastfeeding
• Participation in other clinical trials according to German drug law (§§40ff AMG)

Stratum II

• Patients with progressive disease in risk organs
• Patients with active disease intermediate/worse after second-line intensive course
• Hypersensitivity for one of the trial drugs or any of its excipients
• Pregnancy (patients of child-bearing age must be appropriately tested before chemotherapy
• Breastfeeding
• History of severe bleeding, ulcera of the gastrointestinaltract, history of CNS bleeding or other bleeding disorders unrelated to LCH
• Patient suffering from Crohn´s disease or Colitis ulcerosa
• History of asthma, urticaria, or other allergic-type reactions after taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs
• Known severe immunodeficiency, untreated blood disorders not caused by LCH or untreated functional disorders of the hematopoietic system*
• Severe impairment of liver, chronic liver disease, increased alcohol consumption
• Renal impairment (creatinine-clearance < 60 ml/min)
• Heart insufficiency
• Severe uncontrolled infection
• Participation in other clinical trials according to German drug la