Hybrid Immunotherapy for Hemophagocytic LymphoHistiocytosis

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2012 by Children's Hospital Medical Center, Cincinnati
Sponsor:
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier:
NCT01104025
First received: April 13, 2010
Last updated: October 31, 2012
Last verified: October 2012
  Purpose

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.


Condition Intervention Phase
Hemophagocytic Lymphohistiocytosis
Drug: ATG, rabbit
Drug: Etoposide
Drug: Intrathecal Methotrexate
Drug: hydrocortisone
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label Phase II Pilot Study of Hybrid ImmunoTherapy(ATG/Dexamethasone/Etoposide) for Hemophagocytic LymphoHistiocytosis:HIT-HLH

Resource links provided by NLM:


Further study details as provided by Children's Hospital Medical Center, Cincinnati:

Primary Outcome Measures:
  • Complete Response Rate [ Time Frame: 8 Weeks ] [ Designated as safety issue: Yes ]
    To determine the complete response rate and overall survival at 8 weeks after an ATG/Dexamethasone/Etoposide based induction regimen for patients with hemophagocytic lymphohistiocytosis


Secondary Outcome Measures:
  • Time to Response [ Time Frame: 8 Weeks ] [ Designated as safety issue: Yes ]
    To determine the median time to complete response

  • Overall Survival [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    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)

  • Incidence of Infection [ Time Frame: 8 Weeks or day 180 ] [ Designated as safety issue: Yes ]
    To determine the incidence of serious infection and other adverse events by week 8 and prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun)

  • Incidence and Time to Relapse [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    To determine the incidence and median time to relapse prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun)

  • Overall Survival to day +100 [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    To determine overall survival to day +100 after BMT, for patients who have undergone BMT within 6 months of study entry

  • Gather Biologic Samples [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    To gather biologic samples from patients with HLH to facilitate future basic and translational studies


Estimated Enrollment: 60
Study Start Date: April 2010
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: ATG, rabbit
    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 Name: Thymoglobulin
    Drug: Etoposide
    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
    Drug: Intrathecal Methotrexate
    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.
    Drug: hydrocortisone
    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.
Detailed Description:

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).

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01104025

Contacts
Contact: Angela Poston 513-636-8815 Angela.Poston@cchmc.org
Contact: Stephanie Edwards, RN 513-636-9292 Stephanie.Edwards@cchmc.org

Locations
United States, Arizona
Phoenix Children's Hospital Recruiting
Phoenix, Arizona, United States
United States, California
University of California, San Francisco Department of Pediatrics Recruiting
San Francisco, California, United States
United States, Florida
Florida All Children's Hospital Recruiting
St. Petersburg, Florida, United States
United States, Louisiana
Tulane University Medical Center Recruiting
New Orleans, Louisiana, United States
United States, Massachusetts
Children's Hospital Boston Recruiting
Boston, Massachusetts, United States
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States
United States, Texas
Texas Children's Cancer Center/Baylor College of Medicine Recruiting
Houston, Texas, United States
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Investigators
Principal Investigator: Michael Jordan, MD Children's Hospital Medical Center, Cincinnati
  More Information

No publications provided

Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT01104025     History of Changes
Other Study ID Numbers: HIT-HLH
Study First Received: April 13, 2010
Last Updated: October 31, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Children's Hospital Medical Center, Cincinnati:
hemophagocytic lymphohistiocytosis
hybrid immunotherapy
dexamethasone
Etoposide
ATG,rabbit

Additional relevant MeSH terms:
Lymphohistiocytosis, Hemophagocytic
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases
Hydrocortisone acetate
Hydrocortisone 17-butyrate 21-propionate
Cortisol succinate
Dexamethasone
Hydrocortisone
Etoposide phosphate
Etoposide
Methotrexate
Hydrocortisone-17-butyrate
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on September 30, 2014