Tocilizumab for Chronic Graft-versus-Host Disease Treatment

Tocilizumab in Chronic GVHD Refractory to at Least Two Prior Therapies

This phase II trial studies how well tocilizumab works in treating chronic graft-versus-host disease (GVHD) in patients that have not responded to treatment after at least two prior therapies. Tocilizumab blocks a protein that stimulates the body's immune system. By blocking this protein, the investigators may reduce the symptoms of chronic GVHD.

Study Overview

• Status: Withdrawn
• Conditions: Graft Versus Host Disease
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: quality-of-life assessment; Biological: tocilizumab

Detailed Description

PRIMARY OBJECTIVES:

I. Efficacy will be determined by the proportion of patients with failure free survival (FFS) at 6 months.

SECONDARY OBJECTIVES:

I. Patients achieving a complete response (CR) or partial response (PR) at 6 months based on clinician judged response.

II. Patients achieving a CR or PR by objective response measures at 6 months.

III. Failure-free survival (FFS) at 1 year.

IV. Change in steroid dose from enrollment to 6 months (mo).

TERTIARY OBJECTIVES:

I. Biologic studies will be done to determine possible mechanisms of response.

OUTLINE:

Patients receive tocilizumab intravenously (IV) over 1 hour every 2 weeks for 12 weeks (weeks 1, 3, 5, 7, 9, and 11) and then every 4 weeks for 12 weeks (weeks 13, 17, and 21).

After completion of study treatment, patients are followed up at 3 and 6 months.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject has moderate or severe overlap chronic (c)GVHD according to National Institutes of Health (NIH) criteria
• Active cGVHD despite treatment with at least two immunosuppressive treatments (not including GVHD prophylaxis) in the past year
• Subject underwent allogeneic stem cell transplantation at least 6 months prior to enrollment
• Subject has not started any new systemic immunosuppressive therapies within 2 weeks prior to enrollment
• Female subjects of child bearing potential must have a negative pregnancy test prior to first dose of tocilizumab and must agree to practice effective contraception during the study
• Subject meets the following medication restriction requirements and agrees to follow medication restrictions during the study; the following concomitant medications are not allowed: cyclophosphamide, abatacept, etanercept, adalimumab infliximab, golimumab, tofacitinib, and alemtuzumab; these medications also cannot have been used for 5 half-lives prior to enrollment
• Subject agrees to comply with the study requirements and agrees to come to the clinic for required study visits

Exclusion Criteria:

• Donor lymphocyte infusion in the preceding 100 days
• Subject has bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia or cryptogenic organizing pneumonia as the sole manifestation of cGVHD
• Uncontrolled bacterial, viral infection or invasive fungal infection
• Evidence of malignancy within 6 months of study enrollment; this is defined as clear morphologic, radiologic or molecular evidence of disease; mixed chimerism is allowed at the discretion of the clinician
• Treatment with any non-Food and Drug Administration (FDA) approved agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of study enrollment
• Immunization with a live, attenuated vaccine within 4 weeks prior to study enrollment
• History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies
• Tuberculosis requiring treatment within the past 3 years; all patients must have a negative quantiferon test within 4 weeks prior to starting study drug
• Pregnant or breast-feeding women
• Patients (both men and women) with reproductive potential not willing to use an effective method of contraception
• Serum creatinine > 1.6 mg/dL (141 umol/L) in females and > 1.9 mg/dL (168 umol/L) in males; patients with serum creatinine values exceeding these limits are eligible for the study if their estimated glomerular filtration rates (GFR) are > 30 ml/min/1.73 m^2
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN)
• Total bilirubin > upper limit of normal (ULN)
• Absolute neutrophil count < 1.5 x 10^9/L (1500/mm^3)
• Known active hepatitis B or C; patients must have a negative test for hepatitis B surface antigen, hepatitis B core antibody and hepatitis C antibody within 4 weeks prior to starting study drug
• Known uncontrolled cytomegalovirus (CMV) polymerase chain reaction (PCR) reactivation per institutional standards; once CMV has been treated and stable per institutional standards, patient may be enrolled; CMV PCR will be tested within two weeks prior to starting study drug
• History of diverticulitis, Crohn's disease or ulcerative colitis
• History of demyelinating disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Supportive care (tocilizumab); Patients receive tocilizumab IV over 1 hour every 2 weeks for 12 weeks (weeks 1, 3, 5, 7, 9, and 11) and then every 4 weeks for 12 weeks (weeks 13, 17, and 21).	Other: laboratory biomarker analysis; Correlative studies; Other: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment; Biological: tocilizumab; Given IV; Other Names: RoActemra; Actemra; MRA; R-1569; immunoglobulin G1, anti-(human interleukin 6 receptor) (human-mouse monoclonal MRA heavy chain), disulfide with human-mouse monoclonal MRA kappa chain dimer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
FFS	At 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients achieving CR or PR based on objective measures, as recommended by the NIH Consensus Conference for chronic GVHD		At 6 months
Patients achieving a CR or PR based on clinician judged response		At 6 months
Relative change in daily prednisone dose	Prednisone is not a pre-specified intervention; however, some patients may take prednisone while on this study.	Baseline to 6 months

Other Outcome Measures

Outcome Measure	Time Frame
B cell subsets	Up to week 21
Tumor necrosis factor (ligand) superfamily, member 13b (BAFF) levels	Up to week 21
T cell subsets	Up to week 21

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Stephanie Lee, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Anticipated): August 1, 2019

Study Registration Dates

• First Submitted: June 23, 2014
• First Submitted That Met QC Criteria: June 24, 2014
• First Posted (Estimate): June 25, 2014

Study Record Updates

• Last Update Posted (Estimate): May 6, 2016
• Last Update Submitted That Met QC Criteria: May 5, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Immunologic Factors; Immunoglobulins; Immunoglobulin G
• Other Study ID Numbers: 9130 (Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2014-01204 (Registry Identifier: CTRP (Clinical Trial Reporting Program))