Phase II Study of Tocilizumab for Patients With Glucocorticoid-refractory Acute GVHD After Allogeneic Hematopoetic Stem Cell Transplant (HSCT)
Condition: Glucocorticosteroid Refractory Acute GVHD
Intervention: Toclizumab
Intervention description: 8 mg/kg IV, once every 1-2 weeks. The maximum dose per infusion should not exceed 800 mg.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to determine if Tocilizumab is a safe and effective treatment
      for steroid-refractory acute graft versus host disease.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Men or women ≥ 18 and ≤ 80 years of age

          -  Karnofsky Performance Status Scale ≥ 50%

          -  Glucocorticosteroid refractory acute GVHD Grade 2-4 by the Glucksberg functional
             classification.

          -  Patients who had experienced aGVHD grade 2-4 and responded to glucocorticosteroids in
             the past then had a flare of aGVHD requiring increasing immune suppression to 1 mg/kg
             of prednisone or equivalent are eligible for this study if they are refractory to
             steroids and provided that they did not receive a second line therapy for aGVHD in the
             past.

          -  Glucocorticosteroid refractory GVHD is defined as the following:

               -  No response to corticosteroid therapy at ≥ 1.0 mg/kg methylprednisolone or
                  equivalent after the onset of acute GVHD for a minimum of 3 and a maximum of 7
                  days OR

               -  Progression of at least 1 overall grade within 3 days of glucocorticosteroid use
                  OR

               -  Incomplete response by 14 days of glucocorticosteroid use

          -  Ability to comply with planned procedures

          -  Ability to understand the information provided and to provide written evidence of
             informed consent

          -  Willingness of females of childbearing potential to use adequate contraception.

          -  Post-menopausal for at least 1 year or surgical sterilization or hysterectomy at least
             3 months prior to screening

        Exclusion Criteria:

          -  Subjects with only grade 1 acute GVHD

          -  Concurrent medical condition or disease that may interfere with clinical trial
             participation

          -  Relapsed or persistent malignancy.

          -  Receiving other drugs for the treatment of glucocorticosteroid refractory GVHD.

          -  Severe hepatic veno-occlusive disease or sinusoidal obstruction syndrome.

          -  History of hypersensitivity or severe allergic reactions to humanized or murine
             monoclonal antibodies

          -  Receipt of any experimental, unregistered therapy within or outside a clinical trial
             within 30 days or 5 plasma half-lives (whichever is shorter) before dosing

          -  Planned or current participation in any other clinical trial for treatment of GVHD
             during this clinical trial. Subjects are permitted on this trial if 30 days (or 5
             half-lives) have passed since enrollment on other investigational drugs. If a subject
             develops another condition, he/she is permitted on other clinical trials to treat that
             condition. Subjects are not permitted to go on other clinical trials for steroid
             refractory acute GVHD. Subjects are permitted to participate in trials for chronic
             GVHD.

          -  Pregnancy (a negative serum or urine pregnancy test should be performed for all women
             of childbearing potential within 7 days of treatment) or lactation.

          -  Pre-existing or recent onset of demyelinating disorders

          -  Pre-existing or recent onset of gastrointestinal perforation

          -  Treatment with any investigational agent within 4 weeks of screening or 5 half-lives
             of the investigational drug (whichever is longer)

          -  Receipt of a live vaccine within 4 weeks prior to first infusion

          -  Previous treatment with Natalizumab (Tysabri®)

          -  History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
             antibodies

          -  Known active UNCONTROLLED bacterial, viral, fungal, mycobacterial, or other infection
             (including tuberculosis or atypical mycobacterial disease, but excluding fungal
             infections of nail beds).

          -  Concomitant malignancies.

          -  History of psychiatric disorder that would interfere with normal participation in this
             protocol

          -  Significant cardiac or pulmonary disease (including obstructive pulmonary disease)

          -  ANC < 0.5 x 103

          -  History of drug, alcohol, or chemical abuse within 6 months prior to screening

          -  Serum creatinine > 1.9 mg/dL (168 µmol/L). Patients with serum creatinine values
             exceeding limits may be eligible for the study if their estimated glomerular
             filtration rates (GFR) are >30

          -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times upper
             limit of normal (ULN) unless liver GVHD is suspected

          -  Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or render the patient at high risk from treatment
             complications