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A Phase II Study of Rituximab Combined With Prednisone for the Initial Treatment of Chronic Graft Versus Host Disease

Phase 2
18 Years
Not Enrolling
Graft Versus Host Disease

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Trial Information

A Phase II Study of Rituximab Combined With Prednisone for the Initial Treatment of Chronic Graft Versus Host Disease

Host antigen-presenting cells (APC) have an important role in the pathogenesis of chronic
graft-versus-host disease (C-GVHD). B cell antigen-presenting cells may also be important in
activating T cells in vivo. In a murine leukemia model, B cells have been shown to be
important APCs in T cell responses. Rates of C-GVHD were shown to lower in a B cell
deficient murine model when compared to mice that received rabbit immunoglobulin, and the
rate of C-GVHD was even lower if grafts were depleted of B cells. It would appear that B
cells have an important role as APCs in the pathogenesis of C-GVHD.

The chimeric anti-CD20 antibody Rituximab has been demonstrated to have activity in
steroid-refractory graft versus host disease in a few small retrospective studies. Previous
evidence in indolent lymphoma has demonstrated that Rituximab is a potent B-cell depleting
agent. These observations suggest that B-cell depletion in graft versus host disease may be
an effective therapy. Rituximab is currently being evaluated in two separate phase II
studies currently enrolling patients who have had an allogeneic stem cell transplant
(allo-SCT) or have developed GVHD.

The Dana Farber BMT program has recently published a phase II study examining the safety and
effectiveness of rituximab monotherapy in the setting of steroid-refractory GVHD. Rituximab
was administered weekly at the standard dose of 375 mg/m2. The clinical response rate was
70% and responses were limited to patients with cutaneous and musculoskeletal manifestations
of C-GVHD. Median corticosteroid doses improved from 40 mg/day to 10 mg/day. The BMT program
at Stanford is enrolling patients in a phase II study examining the impact of 4 weekly doses
of 375 mg/m2 of Rituximab given starting on day +56 following allo-SCT in patients with
chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) in an attempt to prevent
the development of subsequent GVHD.

These two studies will provide important phase II data regarding the safety and efficacy of
Rituximab in the prevention of GVHD and the treatment of steroid-refractory GVHD. Another
area of interest would be the initial treatment of GVHD. Although there is no universally
recognized standard of care, corticosteroids form the backbone of treatment for GVHD and are
either given as single agents or part of a combination therapy strategy with Cyclosporine A
(CsA), Tacrolimus (FK506) or mycophenolate mofetil (MMF).

We propose a phase II study of rituximab in combination with prednisone as primary therapy
for C-GVHD.

Inclusion Criteria:

- Previously untreated symptomatic classical C-GVHD (with prior allogeneic stem cell
transplant) requiring systemic therapy (defined as per NIH Consensus: a)At least 3
sites of organ involvement or individual organ score of at least 2, b)Patients on
agents for GVHD prophylaxis (such as therapeutic dose or tapering cyclosporine A or
tacrolimus) or patients that have received therapy for acute GVHD prior to enrollment
are eligible

- Patients must be 18 years of age or older

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Patients must be accessible for treatment and follow-up. Patients registered on this
trial must be treated and followed at the participating centre. Investigators must
assure themselves the patients registered on this trial will be available for
complete documentation of the treatment, adverse events response assessment and

- Patient must be willing and able to complete the GVHD questionnaire

- For patients that have been started on prednisone therapy for cGVHD but otherwise
meet all of the eligibility criteria, registration into this trial must occur no
later than 14 days from the start of prednisone therapy.

Exclusion Criteria

- Uncontrolled infection at the time of study enrollment

- Recurrent malignancy at the time of study enrollment

- Previous systemic therapy for C-GVHD, a)Patients on agents for GVHD prophylaxis (such
as therapeutic dose or tapering cyclosporine A or tacrolimus) or patients that have
received therapy for acute GVHD prior to enrollment are eligible. b)Patients who have
been restarted on full doses of agents used for GVHD prophylaxis (ie. cyclosporine A
or tacrolimus) after these have tapered or discontinued are not eligible

- Inability to tolerate prednisone (includes pre-existing myopathy, diabetes with poor
glycemic control, uncontrolled hypertension or fluid retention) or rituximab

- Usage of additional concurrent agents which could treat C-GVHD (ie. chemotherapeutic
agents - cyclophosphamide, methotrexate or other immunosuppressive agents). Patients
may be continued on stable or tapering dose of GVHD prophylaxis agents such as
cyclosporine or tacrolimus, but must be tapered off by first study treatment

- The administration of anticancer therapies or other investigational agents is not
permitted. Use of hematopoietic colony stimulating factors to manage blood counts is

- Sexually active males and females of childbearing potential unwilling to practice
contraception during the study. Patients of childbearing potential must be willing to
use a reliable method of birth control (i.e. double barrier method).

- Women of childbearing potential with either a positive or no pregnancy test at
baseline or lactating. Postmenopausal women must have been amenorrheic for at least
12 months or surgically sterile to be considered of non-childbearing potential.

- Patients with immune deficiency are at increased risk of lethal infections.
Therefore, HIV-positive patients receiving combination anti-retroviral therapy are
excluded from the study because of possible pharmacokinetic interactions.

- Patients with active hepatitis B are excluded

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The efficacy of the combination of rituximab and prednisone as initial therapy for C-GVHD, which is defined as discontinuation of immunosuppressive therapy at 12 months with resolution of reversible manifestations of C-GVHD

Outcome Time Frame:

12 months

Safety Issue:


Principal Investigator

John Kuruvilla

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Health Network, Toronto


Canada: Ethics Review Committee

Study ID:

OZM-009 (GVHD-R01)



Start Date:

May 2010

Completion Date:

August 2011

Related Keywords:

  • Graft Versus Host Disease
  • graft versus host disease
  • chronic graft versus host disease
  • cGVHD
  • Graft vs Host Disease