Clinical trial NCT02174263: Tocilizumab for Chronic Graft-versus-Host Disease Treatment
Official title: Tocilizumab in Chronic GVHD Refractory to at Least Two Prior Therapies
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Graft Versus Host Disease
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2014-06-25
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: FFS
timeFrame: At 6 months
Secondary outcomes:
measure: Patients achieving CR or PR based on objective measures, as recommended by the NIH Consensus Conference for chronic GVHD
timeFrame: At 6 months
measure: Patients achieving a CR or PR based on clinician judged response
timeFrame: At 6 months
measure: Relative change in daily prednisone dose
timeFrame: Baseline to 6 months
Other outcomes:
measure: B cell subsets
timeFrame: Up to week 21
measure: Tumor necrosis factor (ligand) superfamily, member 13b (BAFF) levels
timeFrame: Up to week 21
measure: T cell subsets
timeFrame: Up to week 21
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: Stephanie Lee
role: PRINCIPAL_INVESTIGATOR
References: