Clinical trial NCT01475162: Tocilizumab for Treatment of Steroid Refractory Acute Graft-versus-Host Disease
Official title: Phase I-II Study Using Tocilizumab for Treatment of Steroid Refractory Acute Graft-versus-Host Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Acute Graft Versus Host Disease
Keywords: acute Graft versus Host Disease (aGVHD)
steroid refractory acute Graft versus Host Disease (aGVHD)
chronic Graft versus Host Disease (cGVHD)
corticosteroids
allogeneic hematopoietic stem cell transplantation
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
First posted: 2011-11-21
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This trial designed to evaluate the toxicity and efficacy of tocilizumab in the treatment of steroid refractory acute graft versus host disease (GVHD).

Detailed description: Patients who underwent an allogeneic hematopoietic stem cell transplantation, with biopsy proven GVHD, active acute GVHD requiring systemic immune suppressive therapy and that failed or did not respond to first line of therapy (corticosteroids ± other agent).

Tocilizumab will be administered intravenously at a dose of 8 mg/kg once every three weeks. Patients with documented responses will continue to receive treatment at 8 mg/kg once every 3 weeks for at least two months (day 56). Patients that have some degree of response but without complete resolution of signs and symptoms of acute GVHD may continue to receive 8 mg/kg on a 3-week cycle until complete response is achieved or lack of further improvement. In patients who are beyond day 56 and whose GVHD has resolved, the dose of Tocilizumab will be reduced to 4 mg/kg every 3 weeks. Subsequent discontinuation of Tocilizumab will occur once patients are off other immune suppressive medications (including extracorporeal photopheresis, ECP) or are receiving sub therapeutic levels of immunosuppression (i.e., Tacrolimus (FK) levels \<5 ng/mL) or prednisone dose \<20 mg/day (or equivalent) and are free of acute GVHD signs or symptoms for at least one month.

Patients who fulfill criteria of progression of GVHD not in the setting of immunosuppressive taper, no response of GVHD or require initiation of other immune suppressive treatment for GVHD will have Tocilizumab discontinued.

Tocilizumab shall be discontinued and not re-instituted if any one of the following criteria is met. The patient will be taken off study drug therapy at that point, but still followed for primary and secondary study endpoints. A response assessment will be made at the time of therapy discontinuation and at subsequent defined study endpoints. The patient will not be replaced on study. Follow-up data will be required unless consent for data collection is withdrawn:

* Additional systemic GVHD therapy is added for disease progression or non-response
* Steroid dose is escalated to ≥ 2.5 mg/kg/day of prednisone (or methylprednisolone equivalent of 2 mg/kg/day) for GVHD progression or no response
* Development of toxicity that requires withholding of study medication for more then 14 days

Eligibility criteria: Inclusion Criteria:

* Patients age 18 and older who underwent an allogeneic hematopoietic stem cell transplantation.
* Patients are required to have biopsy proven GVHD.
* Patients must have active acute GVHD requiring systemic immune suppressive therapy and that failed or did not respond to first line of therapy.

  * First line therapy needs to be a minimum of corticosteroids, methylprednisolone of 1.6mg/kg/day or prednisone of 2mg/kg/day, alone or combined to other agent.
  * Failure of GVHD therapy is defined as flare of signs and symptoms of acute GVHD or progression of GVHD grade after at least 72 hours from starting therapy.
  * No response to GVHD treatment (corticosteroids ± other agent) after a minimum of 7 days of treatment.
* Patient must be able to give informed consent.

Exclusion Criteria:

* Intolerance or allergy to Tocilizumab
* Active uncontrolled infection requiring ongoing treatment with antifungals, antibiotics or anti-viral drugs.
* Relapsed/persistent malignancy requiring rapid immune suppression withdrawal.
* Liver enzymes: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \> 3x upper limit of normal.
* Patients with severe sinusoidal obstruction syndrome who in the judgment of the treating physician are not expected to have normalized bilirubin by day 56 after enrollment.
* Serum bilirubin \> 2x upper limit of normal.

Primary outcomes:
measure: Number of Subjects Achieving Complete or Partial Response at Day 56 After Administration of Tocilizumab
timeFrame: Day 56
Secondary outcomes:
measure: Number of Patients With Partial, Mixed or no GVHD Responses
timeFrame: Day 56
measure: GVHD Flares
timeFrame: Day 90
measure: Discontinuation of Immunosuppression
timeFrame: Day 56, Day 180 and Day 365
measure: Overall Survival
timeFrame: 1 year
measure: Number of Subjects Experiencing at Least One Serious Adverse Event or Grade 3 Non-serious Adverse Event
timeFrame: Day 56
measure: Disease-free Survival
timeFrame: 6 and 12 months
measure: Non-relapse Mortality
timeFrame: 6 months
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Froedtert Hospital/Medical College of Wisconsin-Clinical Cancer Center
state: Wisconsin
Study officials:
affiliation: Medical College of Wisconsin
name: William R Drobyski, MD
role: PRINCIPAL_INVESTIGATOR
References: