A Phase II Trial of Rituximab and Corticosteroid Therapy for Newly Diagnosed Chronic Graft Versus Host Disease

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Stanford University
ClinicalTrials.gov Identifier:
NCT00350545
First received: July 5, 2006
Last updated: December 12, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention
Graft vs Host Disease
Blood and Marrow Transplant (BMT)
Drug: Rituximab
Drug: Prednisone
Drug: cyclosporine A
Drug: tacrolimus

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Rituximab and Corticosteroid Therapy for Newly Diagnosed Chronic Graft Versus Host Disease

Resource links provided by NLM:


Further study details as provided by Stanford University:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To have physician documentation of clinical GVHD response using organ staging and scoring scale [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • To evaluate steroid use at one year after enrollment on the trial. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • To monitor patient reported outcomes of GVHD response [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • To monitor infectious complications [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • To report freedom from progression (FFP), event free survival (EFS), and overall survival (OS) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • To document treatment failure-defined as initiation of another immunosuppressive agent [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 36
Study Start Date: August 2006
Estimated Study Completion Date: June 2014
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: rituximab + prednisone arm Drug: Rituximab
375 mg/m2;IV infusion once weekly for four doses (days 1,8,15,22); option for second 4-week course at week 9
Other Names:
  • Rituxan
  • MabThera
Drug: Prednisone
1 mg/kg; po per day with taper
Other Names:
  • Deltasone
  • Liquid Pred
  • Meticorten
  • Orasone
Drug: cyclosporine A
trough 200-300 or lower; po
Other Names:
  • cyclosporine
  • Ciclosporin
Drug: tacrolimus
trough 5-10 or lower; po
Other Names:
  • FK-506
  • Fujimycin

Detailed 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.

  Eligibility

Ages Eligible for Study:   1 Year to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00350545

Locations
United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
Stanford University
Investigators
Principal Investigator: David Miklos Stanford University
Principal Investigator: Sally Arai Stanford University
  More Information

No publications provided

Responsible Party: Stanford University
ClinicalTrials.gov Identifier: NCT00350545     History of Changes
Other Study ID Numbers: BMT177, 96950, BMT177
Study First Received: July 5, 2006
Last Updated: December 12, 2013
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Cyclosporins
Cyclosporine
Tacrolimus
Rituximab
Prednisone
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anti-Inflammatory Agents

ClinicalTrials.gov processed this record on April 17, 2014