High-Dose Cyclophosphamide for Steroid Refractory GVHD

Study Overview
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Brief Summary
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RATIONALE: High-dose cyclophosphamide may be an effective treatment for acute graft-versus-host disease that did not respond to steroid therapy. PURPOSE: This phase II trial is studying the side effects, best dose, and how well high-dose cyclophosphamide works in treating patients with acute graft-versus-host disease that did not respond to steroid therapy.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of high-dose cyclophosphamide in patients with steroid refractory acute graft-versus-host disease (GVHD). Determine the efficacy of this regimen at 28 days post-treatment in these patients. OUTLINE: This is a dose-escalation study. Patients receive high-dose cyclophosphamide once daily for 1-4 days beginning on day 1 and filgrastim (G-CSF) subcutaneously once daily beginning on day 10 and continuing until blood counts recover. Cohorts of 3-6 patients receive escalating doses of high-dose cyclophosphamide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. After completion of study treatment, patients are followed weekly for 4 weeks.

Official Title
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High-Dose Cyclophosphamide in Treating Patients With Acute Graft-Versus-Host Disease That Did Not Respond to Steroid Therapy

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed acute graft-versus-host disease (GVHD) ≥ clinical grade II, that is steroid refractory Steroid refractory GVHD is defined as GVHD that has progressed (increasing in grading) despite 49 hours of treatment with methylprednisolone of ≥ 2.0 mg/kg OR GVHD that has failed to improve (no change in grading stage) despite 4 days of treatment with methylprednisolone of ≥ 2.0 mg/kg Prior allogeneic hematopoietic stem cell transplantation using either bone marrow, peripheral blood stem cells, or cord blood OR prior donor lymphocyte infusion required Evidence of myeloid engraftment No chronic GVHD PATIENT CHARACTERISTICS: ECOG (Eastern Cooperative Oncology Group) performance status (PS) 0-2 OR Karnofsky PS 60-100% ANC (absolute neutrophil count) > 500/mm³ Not pregnant or nursing Fertile patients must use effective contraception Must be geographically accessible No allergy or intolerance to cyclophosphamide or mesna No HIV positivity No mechanical ventilation No active bleeding (excluding gastrointestinal bleeding) or history of hemorrhagic cystitis No other uncontrolled illness including, but not limited to, the following: Ongoing or active infection Medical condition precluding patient from stopping azoles (e.g., fluconazole, itraconazole, or voriconazole) or other adequate antifungal therapy during cyclophosphamide administration Symptomatic congestive heart failure Unstable angina pectoris Psychiatric illness/social situations that would preclude compliance PRIOR CONCURRENT THERAPY: See Disease Characteristics

Ages Eligible for Study
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Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclophosphamide 50<br>Treatment with cyclophosphamide 50 mg/kg/d x 1 days. | Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;|
| Experimental: Cyclophosphamide 100<br>Treatment with cyclophosphamide 50 mg/kg/d x 2 days. | Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;|
| Experimental: Cyclophosphamide 150<br>Treatment with cyclophosphamide 50 mg/kg/d x 3 days. | Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of High-dose Cyclophosphamide as Determined by Number of Participants Who Tolerated Each Dose of Cyclophosphamide |  | Day 28 | 
| GVHD Response Rate | Percentage of patients whose GVHD (as defined by Przepiorka criteria) responded to cyclophosphamide (complete response). Acute GVHD is defined by the Przepiorka criteria, which stages the degree of organ involvement in the skin, liver, and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least severe and stage 4+ being the most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, Liver 4+). | Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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graft versus host disease