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Completed

NCT Number: NCT01104025

Hybrid Immunotherapy for Hemophagocytic LymphoHistiocytosis

Despite good progress during the last decade, hemophagocytic lymphohistiocytosis (HLH) remains difficult to treat. Two different treatment regimens have been used successfully. The first one, a treatment regimen based on two drugs called etoposide and dexamethasone, has been used worldwide. The second regimen, based on two drugs called Anti-thymocyte globulin (ATG) and prednisone, has been used mostly at one hospital in Paris, for over 15 years. With either regimen, about three quarters of treated children survive the most difficult time, the first two months after diagnosis. These two different regimens appear to work somewhat differently, and we suspect that combining them may give better results than either regimen alone. We are conducting this clinical trial to test the combination of ATG, dexamethasone, and etoposide for the treatment of HLH.

The purpose of this research study is to find out what effects (good and bad) this drug combination has on you and your HLH.

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Key information

Conditions

Hemophagocytic Lymphohistiocytosis Hemic and Lymphatic Diseases Histiocytosis Histiocytosis, Non-Langerhans-Cell Lymphatic Diseases Lymphohistiocytosis, Hemophagocytic

Age range

Up to 18 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

The Hospital for Sick Children, Toronto, Ontario, Canada

Loading trial locations.

About this study

Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder first recognized almost 70 years ago.(1) Genetic and animal studies have indicated that the familial form of HLH is clearly due to a deficiency of cytotoxic killing. Patients with HLH present with a potentially fatal syndrome of 'hyperimmunity.' These patients have severe inflammation, associated with cytopenias and variably severe bone marrow, liver, or CNS damage. Tissue damage and mortality appear to be due to hypercytokinemia related to persistent immune hyperactivation. An animal model of HLH and correlative human studies all suggest that excessive and abnormal activation of T cells drives the pathophysiology of this disorder, and that suppressing this excessive activation is critical for successful therapy of HLH. It is believed a combination of the two proven induction regimens for hemophagocytic lymphohistiocytosis (HLH) (anti-thymocyte globulin (ATG)- and etoposide-based) will result in response rates and overall survival rates at eight weeks which are comparable or better than the current standard of care (induction therapy per the HLH-94 protocol).

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • diagnosis of hemophagocytic lymphohistiocytosis
  • Patients <18 years of age
  • The patient must have active disease at the time of enrollment
  • Patient's legal guardians must sign an Institutional Review Board approved consent form indicating their awareness of the investigational nature and the risks of this study.
  • Eligible subjects must be enrolled with the protocol coordinating center

Exclusion criteria

  • Recent treatment, within 3 months, with another therapeutic regimen for HLH
  • Known active malignancy
  • Known rheumatologic diagnosis which may be the underlying cause of HLH
  • Pregnancy (as determined by serum or urine test) or active breast feeding
  • Failure to provide signed informed consent

Treatment and study plan

ATG, rabbit

Drug

ATG, rabbit (Thymoglobulin, Genzyme) will be dosed at 5 mg/kg/dose, given IV on 5 consecutive days (titrated over 4 to 8 hours).

Other names: Thymoglobulin

etoposide

Drug

Etoposide will be dosed at 150mg/m2, given IV. The first dose will be given 7 days (+/- 2 days) after the first dose of ATG, and be given weekly for a total of 7 doses.

Other names: Etopophos, Toposar, VePesid

methotrexate

Drug

Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients (CNS+ patients are those patients which have any of the following: elevated CSF (cerebral spinal fluid) protein or white count, seizures, focal or global neurologic deficit, MRI abnormalities consistent with CNS involvement by HLH.) in the following doses: age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg. It will be administered (+/- 3 days) on day 7, 14, 21 and 42.

Hydrocortisone

Drug

Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients (CNS+ patients are those patients which have any of the following: elevated CSF (cerebral spinal fluid) protein or white count, seizures, focal or global neurologic deficit, MRI abnormalities consistent with CNS involvement by HLH.) in the following doses: age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg. It will be administered (+/- 3 days) on day 7, 14, 21 and 42.

Dexamethasone

Drug

will be started with the ATG. It will be divided BID, given IV for at least 1 week before switching to PO. Dosing: 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days.

Primary outcomes

  1. Overall Survival

    Time frame: 8 Weeks

    To determine the overall survival of patients with hemophagocytic lymphohistiocytosis at 8 weeks after an ATG/etoposide-based induction regimen and to determine the feasibility of this approach in the context of a multicenter clinical trial.

Secondary outcomes

  1. Time to Response

    Time frame: 8 Weeks

    To determine the median time to complete response during 8 weeks of therapy

  2. Overall Survival

    Time frame: up to day 180

    To determine overall survival prior to the initiation of BMT (bone marrow transplant) preparative regimen (or day 180, if BMT preparative regimen not yet begun)

  3. Number of Participants Who Experienced Reactivation

    Time frame: up to 180 days

    To determine the frequency of disease reactivation prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun)

  4. Overall Survival to Day +100

    Time frame: up to day 280

    To determine overall survival to day +100 after BMT, for patients who have undergone BMT within 6 months of study entry

  5. Disease Status at BMT

    Time frame: up to day 180

    To determine the rate of complete response at the time of BMT preparative regimen initiation

Sponsors and collaborators

Lead sponsor

Children's Hospital Medical Center, Cincinnati

Other

Registry information

Official study title

An Open Label Phase II Pilot Study of Hybrid ImmunoTherapy(ATG/Dexamethasone/Etoposide) for Hemophagocytic LymphoHistiocytosis:HIT-HLH

Important dates

Study start
2010
Primary completion
2015
Study completion
2016
First posted
Apr 15, 2010
Registry last updated
Oct 19, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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