Clinical Trial: Rituximab for the Primary Treatment of Denovo Extensive Chronic Graft Versus Host Disease (GVHD)

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Phase II Trial Evaluating the Safety and Efficacy of Rituximab as Primary Treatment for Extensive Chronic Graft Versus Host Disease

Brief Summary: Rituximab is an attractive agent to bring to the upfront treatment of chronic graft-versus-host disease (cGVHD) due to its favorable toxicity profile, its proven efficacy in the treatment of steroid-refractory cGVHD, and its ability to serve as a steroid sparing agent in other autoimmune diseases. The investigators hope to demonstrate that Rituximab has significant activity in cGVHD when utilized early in the course of the process. In addition, the investigators hope to show that the early use of Rituximab may allow for the earlier discontinuation of immunosuppression while obviating the need for long courses of systemic corticosteroids, which should translate into reduced treatment-related morbidity and mortality associated with cGVHD.

Detailed Summary:

Although allogeneic hematopoietic stem cell transplantation (HSCT) remains an important curative therapy for many patients with hematological malignancies, treatment-related morbidity and mortality continue to be a major challenge. Chronic GVHD remains a major complication following allogeneic HSCT, with more than half of patients being affected. Although cGVHD has been associated with decreased relapse risk due to the well documented graft-versus-malignancy effect, it is also associated with significant adverse consequences in terms of morbidity, mortality, quality-of-life, and treatment costs associated with HSCT.

Rituximab has been investigated in a small number of patients with refractory cGVHD using the standard regimen of 375 mg/m2/week for 4 weeks. Ratanatharathorn et al. documented a sustained response in four of eight patients with steroid-refractory cGVHD with diffuse or localized sclerodermatous manifestations. Similarly, Canninga-vanDijk et al. and Okamoto et al. observed cases with clinical, laboratory and histological improvement after Rituximab treatment. Cutler et al. reported the results of their phase I-II study with Rituximab in 21 patients with steroid-refractory cGVHD. Treatment was well tolerated, and toxicity limited to infectious events, without any hematological toxicities and only a significant reduction in circulating immunoglobulins documented after therapy. Objective responses were documented in 70% of patients (including 10% complete response) primarily for those with skin and musculoskeletal involvement, allowing tapering, and in some cases withdrawing, of previous immunosuppressant therapy. A correlation between clinical response and decrease in the titre of antibodies against Y chromosome-encoded minor HLA antigens was shown. The results of these preliminary studies highlight the potential therapeutic activity of Rituximab on some cGVHD ma
Sponsor: Northside Hospital, Inc.

Current Primary Outcome:

  • Rate of Complete Response of cGVHD to Treatment. [ Time Frame: 2 years ]
  • Rate of Overall Response of cGVHD to Treatment [ Time Frame: 2 years ]
  • Rate of Partial Response of cGVHD to Treatment [ Time Frame: 2 years ]


Original Primary Outcome: To estimate the rate of complete, partial and overall response of cGVHD to treatment. [ Time Frame: 2 years ]

We will evaluate patients at 1, 2, 3, 6, 9, 12, 18 and 24 months from the start of treatment.


Current Secondary Outcome:

  • Requirement for Systemic Corticosteroid Use [ Time Frame: 2 years ]
  • Time to Immunosuppression Withdrawal [ Time Frame: 2 years ]
  • Incidence of Overall Survival [ Time Frame: 2 years ]
  • Duration of Systemic Corticosteroid Use [ Time Frame: 2 years ]
  • Incidence of Disease-free Survival [ Time Frame: 2 years ]
  • Incidence of Non-relapse Mortality [ Time Frame: 2 years ]


Original Secondary Outcome:

  • To estimate the requirement for and duration of systemic corticosteroids [ Time Frame: 2 years ]
    Steroids can be added to the treatment regimen if cGVHD progresses after 2 weeks of therapy and shows no improvement after 5 weeks. It a patient responds to steroids, they will be tapered every 4 days and should be discontinued in </= 4 weeks.
  • Estimate the time to immunosuppression withdrawal [ Time Frame: 2 years ]
    We will evaluate patients at 1, 2, 3, 6, 9, 12, 18 and 24 months from the start of treatment. Steroids can be added to the treatment regimen if cGVHD progresses after 2 weeks of therapy and shows no improvement after 5 weeks. It a patient responds to steroids, they will be tapered every 4 days and should be discontinued in </= 4 weeks.
  • Estimate incidence of non-relapse mortality, disease-free and overall survival [ Time Frame: 2 years ]
    Patients will be evaluated at 1, 2, 3, 6, 9, 12, 18 and 24 months after the start of treatment.


Information By: Northside Hospital, Inc.

Dates:
Date Received: July 12, 2010
Date Started: April 2011
Date Completion:
Last Updated: March 22, 2016
Last Verified: January 2016