Overview

This trial is active, not recruiting.

Conditions graft vs host disease, blood and marrow transplant (bmt)
Treatments rituximab, prednisone, cyclosporine a, tacrolimus
Target CD20
Sponsor Stanford University
Start date August 2006
End date May 2012
Trial size 36 participants
Trial identifier NCT00350545, 96950, BMT177

Summary

We hypothesize the addition of rituximab to prednisone for the initial treatment of chronic GVHD will increase the overall response rate, and enable a more rapid and effective steroid taper.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
rituximab Rituxan
375 mg/m2;IV infusion once weekly for four doses (days 1,8,15,22); option for second 4-week course at week 9
prednisone Deltasone
1 mg/kg; po per day with taper
cyclosporine a cyclosporine
trough 200-300 or lower; po
tacrolimus FK-506
trough 5-10 or lower; po

Primary Outcomes

Measure
To determine the efficacy of two 4 week courses of Rituximab as first-line treatment for chronic GVHD. Efficacy endpoint will be defined as the ability to successfully taper prednisone to a dose of 0.25 mg/kg/day by 6 months without clinical relapse.
time frame: 6 months

Secondary Outcomes

Measure
To have physician documentation of clinical GVHD response using organ staging and scoring scale
time frame: 6 months
To evaluate steroid use at one year after enrollment on the trial.
time frame: 1 year
To monitor patient reported outcomes of GVHD response
time frame: 6 months
To monitor infectious complications
time frame: 6 months
To report freedom from progression (FFP), event free survival (EFS), and overall survival (OS)
time frame: 1 year
To document treatment failure-defined as initiation of another immunosuppressive agent
time frame: 6 months

Eligibility Criteria

Male or female participants from 1 year up to 75 years old.

Inclusion Criteria: Both children and adults with a new diagnosis of chronic GVHD, must include skin involvement, with indication for systemic immunosuppressive treatment to a dose of 1mg/kg prednisone who has undergone any type of donor hematopoietic cell graft or conditioning regimen. See Appendix for NIH Consensus Signs and symptoms Chronic GVHD. The NIH cGVHD Working group recommendation for Diagnosis of chronic GVHD requires a diagnostic sign or at least 1 distinctive manifestation of cGVHD with the diagnosis confirmed by pertinent biopsy or radiology confirmation or Schirmer's test. The guideline for indication to start systemic steroids is as follows: - 2 or more organs involved (must include skin) with organ score e 2 (see Appendix for organ scoring) - Stable doses of other immunosuppressive medications (e.g. calcineurin inhibitors, mycophenolate mofetil) for 2 weeks prior to enrollment. In addition, these other immunosuppressive medications should not be dose increased. - Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment. - All subjects must provide written informed consent. Exclusion Criteria: - Known life-threatening hypersensitivity to Rituximab or other anti-B cell antibody. - Treatment with prednisone (or equivalent) at doses higher than 1 mg/kg/day at the time of enrollment. Persistent prednisone treatment of acute GVHD that is less than 1mg/kg is allowed (i.e. Patient was treated for acute GVHD with prednisone, and developed chronic GVHD before completing taper). - Active, uncontrolled infection- CMV reactivation is excluded (i.e. pneumonitis, colitis). Peripheral blood CMV reactivation is allowed as long as it is not associated with CMV disease and is responding to therapy. - Known Hepatitis B surface Ag positive - Active malignant disease relapse. - Pregnancy or lactation - Inability to comply with the Rituximab treatment regimen.

Additional Information

Official title A Phase II Trial of Rituximab and Corticosteroid Therapy for Newly Diagnosed Chronic Graft Versus Host Disease
Principal investigator David Miklos
Description Effective treatments for chronic GVHD are currently limited to corticosteroids, and often requires prolonged treatment. The addition of a calcineurin inhibitor is not associated with an increased response rate or transplant-related mortality. Our laboratory studies have demonstrated allogeneic antibodies develop in association with chronic GVHD after HSCT. This implicates allogeneic B cell responses in the pathogenesis of chronic GVHD and supports testing anti-B cell therapy for chronic GVHD. In our DFCI phase I trial of 21 patients with steroid refractory chronic GVHD, rituximab provided 70% overall responses and 2 complete responses. Rituximab therapy facilitated corticosteroid tapering with a median dose of prednisone falling from 40 mg/day at trial initiation to 10 mg/day at one year (p = 0.0002). We hypothesize the addition of rituximab to prednisone for the initial treatment of chronic GVHD will increase the overall response rate, and enable a more rapid and effective steroid taper. If B cells or their product antibodies are contributing to chronic GVHD pathogenesis, and prednisone efficacy is partially active through a less-specific B cell effect, then it follows that rituximab addition to prednisone may increase chronic GVHD response rates and enable successful steroid tapering. To test this hypothesis, we have initiated a phase II clinical trial of rituximab and corticosteroids as front line therapy for patients with newly diagnosed chronic GVHD. Reported cGVHD trials have tested the benefit of adding an experimental agent to prednisone dosed 1mg/kg for 4 or 9 months before slowly tapering again on a fixed schedule. In these trials the primary endpoint was the cGVHD complete response rate, and 1mg/kg every other day prednisone yielded a 33% CR and 62% overall response rate after 9 months therapy thereby setting a standard for what single agent high-dose prednisone can achieve alone. However, long-term single-agent high-dose corticosteroid treatment of cGVHD causes significant morbidity being associated 20% incidence avascular necrosis. On that trial, only 50% could be weaned from steroids at 5 years. With this steroid toxicity in mind, we believe a clinically meaningful endpoint for phase II testing of promising cGVHD drugs may be their addition to high-dose steroids enables a successful steroid taper. As such, our primary endpoint is the ability to successfully taper prednisone to a dose of 0.25 mg/kg/day or less by six months without cGVHD relapse. The 0.25mg/kg/day primary endpoint was chosen for both physiological and clinical practice reasons. Patients receiving prednisone 20mg daily or greater are assumed to have functional suppression of hypothalamic-pituitary-adrenal function, frequently suffer steroid toxicities. Clinically, many HSCT clinicians taper patients to 10-20 mg prednisone a day and then only slowly further taper to avoid chronic GVHD recurrence.
Trial information was received from ClinicalTrials.gov and was last updated in December 2013.
Information provided to ClinicalTrials.gov by Stanford University.