Hybrid Immunotherapy for Hemophagocytic LymphoHistiocytosis

NCT ID: NCT01104025

Last Updated: 2020-10-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 31 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-30
• Study Completion Date: 2016-04-30

Brief Summary

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.

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).

Conditions

Hemophagocytic Lymphohistiocytosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Induction Therapy

ATG, rabbit: intravenous, 5 mg/kg/dose, 5 consecutive days Dexamethasone: intravenous, 20mg/m2/day x7days, 10mg/m2/day x7days, 5mg/m2/day x14days, 2.5mg/m2/day x14days, 1.25mg/m2/day x14days Etoposide: intravenous, 150 mg/m2 weekly, starting 7 days after first dose of Thymoglobulin Methotrexate and hydrocortisone: intrathecal to patients with central nervous system involvement, age\< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, \>3 yrs: 12/15 mg, on day 7, 14, 21 and 42

Group Type: EXPERIMENTAL

ATG, rabbit

Intervention Type: 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).

Etoposide

Intervention Type: 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.

Methotrexate

Intervention Type: 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

Intervention Type: 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

Intervention Type: 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.

Interventions

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).

Intervention Type: 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.

Intervention Type: DRUG

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.

Intervention Type: 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.

Intervention Type: DRUG

Dexamethasone

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.

Intervention Type: DRUG

Other Intervention Names

Thymoglobulin; Etopophos; Toposar; VePesid

Eligibility 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

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital Medical Center, Cincinnati

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Jordan, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Medical Center, Cincinnati

Locations

Phoenix Children's Hospital

Phoenix, Arizona, United States

University of California, San Francisco Department of Pediatrics

San Francisco, California, United States

Stanford University

Stanford, California, United States

University of Colorado

Aurora, Colorado, United States

Nemours

Wilmington, Delaware, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Nemours

Jacksonville, Florida, United States

Florida All Children's Hospital

St. Petersburg, Florida, United States

Tulane University Medical Center

New Orleans, Louisiana, United States

Children's Hospital Boston

Boston, Massachusetts, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Texas Children's Cancer Center/Baylor College of Medicine

Houston, Texas, United States

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

Other Identifiers

HIT-HLH

Identifier Type: -

Identifier Source: org_study_id