Tocilizumab and Hemophagocytic Lymphohistiocytosis (HLH)

NCT02007239 | Withdrawn Phase 2 DMC

• 1 other identifier: 13-010459
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This study seeks to determine the efficacy of tocilizumab (TCZ) in patients with hemophagocytic lymphohistiocytosis (HLH) and high cytokine levels (proteins involved in inflammation) in an attempt to decrease the damage caused by these proteins; and secondarily to assess its safety and impact on disease activity.

Conditions

Hemophagocytic Lymphohistiocytosis

Keywords

tocilizumab; hemophagocytic lymphohistiocytosis (HLH); cytokine; cytokine release syndrome

Outcome Measures

Primary Outcomes (1)

• Reduction in serum interferon-gamma levels after tocilizumab (TCZ) administration

  Assess change in interferon gamma levels from the screening visit to the measurements taken within 24-36 hours and at 4-7 days after drug administration.

  baseline, 24 -36 hours, and 4-7 days after administration of TCZ

Secondary Outcomes (4)

• Change in other cytokine levels (interleukin-6, interleukin-10, tumor necrosis factor-alpha, etc.)

  baseline, 24-36 hour, then weekly for 4 weeks after administration of TCZ

• Presence of HLH disease activity for each subject following TCZ administration

  within 1 week of administration of TCZ

• Degree of hepatic function, cytopenias and infection in subjects following administration of TCZ

  up to 1 year of administration of TCZ

• Overall survival of subjects

  day 100 and survival to completion of therapy (blood/marrow transplant, if applicable)

Study Arms (1)

treatment

EXPERIMENTAL

single dose of tocilizumab (8mg/kg intravenously) within 24 hours of administration of standard immunochemotherapy.

Drug: tocilizumab

Interventions

tocilizumab DRUG

single dose of tocilizumab (8mg/kg intravenously) within 24 hours of administration of standard immunochemotherapy.

Also known as: TCZ

treatment

Eligibility Criteria

• Age: 3 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Males or females age 3 months to 25 years.
• Fulfill the clinical diagnostic criteria for HLH, as defined by the Histiocyte Society (see Table 1). Only patients with de novo HLH are eligible.
• Evidence of cytokine release syndrome (CRS), as defined by EITHER:
• i. Known elevated interferon-γ and interleukin-6 ≥2x ULN, OR ii. If cytokine levels are unknown at the time of study enrollment:
• a. Fever of at least 38.5º celsius at minimum of once every 24 hours for at least 48 hours, AND either i. Respiratory insufficiency requiring oxygen supplementation of at least 2 Liter by nasal cannula for at least 12 hours (also including invasive, noninvasive, continuous positive airway pressure or biphasic airway pressure for the purpose of treating respiratory failure), OR ii. Vasoactive infusion for at least 12 hours, including dopamine ≥5mcg/kg/min, dobutamine≥5mcg/kg/min, or any dose of epinephrine, norepinephrine, milrinone, or vasopressin.
• Patients must be planned to initiate HLH-directed therapy within 24 hours of study enrollment.
• Girls \>= 11 years of age must have a negative urine/serum pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study.
• Parental/guardian permission (informed consent)

You may not qualify if:

• On-going or planned participation in another clinical trial involving HLH-directed treatment
• Previous administration of any other biologic agent targeted at cytokine blockade within 5 days of enrollment.
• Renal insufficiency defined by estimated glomerular filtration rate (based on modified Schwartz formula) \<50 ml/min, or need for renal replacement therapy.
• Hepatic dysfunction as defined by serum alanine aminotransferase (ALT)\>=10x upper limit of normal (ULN). For the purposes of this study, the ULN for ALT is 45 U/L.
• HLH that is relapsed, refractory, or considered to be therapy-related, as in the case of T cell-activating therapies.
• Established prior diagnosis of underlying rheumatologic condition, including juvenile idiopathic arthritis.
• Pregnant or lactating females.
• Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
• Suspected gastrointestinal perforation.
• Known or suspected demyelinating central nervous system disease.
• Known history of tuberculosis.
• Transfusion-refractory thrombocytopenia defined as inability to maintain platelet count over 30,000/ul for at least 6 hours with transfusion support.
• Known active herpetic infection.
• Inability to start HLH-directed immunochemotherapy.

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead

Study Sites (1)

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (5)

• Henter JI, Samuelsson-Horne A, Arico M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, Komp D, Ladisch S, Webb D, Janka G; Histocyte Society. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002 Oct 1;100(7):2367-73. doi: 10.1182/blood-2002-01-0172.

  PMID: 12239144 BACKGROUND

• Tang Y, Xu X, Song H, Yang S, Shi S, Wei J, Pan B, Zhao F, Liao C, Luo C. Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome. Br J Haematol. 2008 Oct;143(1):84-91. doi: 10.1111/j.1365-2141.2008.07298.x. Epub 2008 Jul 31.

  PMID: 18673367 BACKGROUND

• Navarro-Millan I, Singh JA, Curtis JR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther. 2012 Apr;34(4):788-802.e3. doi: 10.1016/j.clinthera.2012.02.014. Epub 2012 Mar 22.

  PMID: 22444783 BACKGROUND

• Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, Nichols KE, Suppa EK, Kalos M, Berg RA, Fitzgerald JC, Aplenc R, Gore L, Grupp SA. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013 Jun 27;121(26):5154-7. doi: 10.1182/blood-2013-02-485623. Epub 2013 May 15.

  PMID: 23678006 BACKGROUND

• Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013 Apr 18;368(16):1509-1518. doi: 10.1056/NEJMoa1215134. Epub 2013 Mar 25.

  PMID: 23527958 BACKGROUND

MeSH Terms

Conditions

Lymphohistiocytosis, Hemophagocytic; Cytokine Release Syndrome

Interventions

tocilizumab

Condition Hierarchy (Ancestors)

Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Study Officials

• David Teachey, MD

  Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2013
• First Posted: December 10, 2013
• Study Start: December 1, 2013
• Primary Completion: May 1, 2021
• Study Completion: May 1, 2021
• Last Updated: March 28, 2022

Record last verified: 2022-03

Locations

US (1)