Pentostatin in Treating Patients With Refractory Chronic Graft-Versus-Host Disease

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Pentostatin may be effective in treating chronic graft-versus-host disease by stopping the immune system from rejecting donor stem cells or donor white blood cells. PURPOSE: This phase II trial is studying how well pentostatin works in treating patients with chronic graft-versus-host disease that is refractory (not responsive) to treatment with steroids.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the response rate in patients with refractory chronic graft-versus-host disease treated with pentostatin. Secondary Determine the time to next immunosuppressive agent (i.e., the time to progression from best response) in patients treated with this drug. Determine the toxicity of this drug in these patients. Determine the infection rate in patients treated with this drug. Determine the pharmacokinetics of this drug in these patients. Determine the changes in lymphocyte populations in patients treated with this drug. Determine the survival of patients treated with this drug. OUTLINE: This is a multicenter study. Patients receive pentostatin IV over 20-30 minutes on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response after 6 courses receive 4 additional courses. Patients who achieve a partial response, minor response, or stable disease after 6 courses may receive up to 6 additional courses. Patients are followed every 4 weeks for 1 year, every 3 months for 2 years, and then annually for 5 years. PROJECTED ACCRUAL: Approximately 37 patients will be accrued for this study.

Official Title
-----------------
A Phase II Trial Of Intravenous Pentostatin For The Treatment Of Patients With Refractory Chronic Graft-Versus-Host Disease

Conditions
-----------------
Graft Versus Host Disease

Intervention / Treatment
-----------------
* Drug: pentostatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Histologic documentation of chronic GvHD following allogeneic HCT or donor lymphocyte infusion. Patients may have progressive, quiescent, or de novo onset chronic GvHD. Patients with extensive stage chronic GvHD requiring systemic immunosuppressive therapy are eligible. Patients with limited stage disease are excluded. Extensive stage is defined according to Seattle criteria (9) as either: Generalized skin involvement or Limited skin involvement or hepatic involvement with any one of the following: Liver histology showing chronic progressive hepatitis, bridging necrosis or cirrhosis Eye involvement (Schirmer's test with < 5 mm wetting) Involvement of minor salivary glands or oral mucosa Involvement of any other organ Patients must have failed treatment with, or experience progression after, prior corticosteroids for extensive stage chronic GvHD, as defined below. 4.1 Patients will be considered to have failed corticosteroids if they have any one of the following criteria: Progressive disease or less than a minor response in any organ system despite 2 weeks on corticosteroid treatment at least 1 mg/kg methylprednisolone or equivalent. Failure to achieve at least a minor response after at least 4 weeks of treatment with a dose of ≥ 0.5 mg/kg methylprednisolone or equivalent. Achievement of less than a partial response at 8 weeks of corticosteroid treatment despite use of a dose ≥ 0.5 mg/kg methylprednisolone or equivalent. Requirement of ≥ 0.5 mg/kg methylprednisolone or equivalent to maintain a partial response or better at 12 weeks of corticosteroid treatment. Requirement of > 10 mg/kg methylprednisolone or equivalent to maintain a partial response or better at 18 weeks of corticosteroid treatment. 4.2 Patients with progression of extensive stage chronic GvHD after a prior history of treatment with at least 18 weeks of corticosteroids, now requiring the reintroduction of corticosteroids (> 10 mg/day methylprednisolone or equivalent) or an additional agent (including photopheresis, PUVA) for treatment. Patients with established chronic GvHD not improving or progressing on other immunosuppressive agents are also eligible if steroid refractoriness has been established previously. Age ≥ 18 years Performance Status 0-3 Patients on mechanical ventilation are excluded. No active infection. Patients with active infection requiring antibiotic therapy are not eligible until infection is controlled. No HIV infection. Patients with HIV infection are excluded because of safety concerns in this patient population. Non-pregnant and non-nursing. Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial (although it is unlikely that successful pregnancy will occur in patients with chronic GvHD). Appropriate methods of birth control include oral contraceptives, implantable hormonal contraceptives (Norplant®), or double barrier method (diaphragm plus condom). Required Initial Laboratory Values: Calc. Creatinine Clearance ≥ 30 mL/min/1.73 m^2 ANC > 1000/μL Platelets > 50,000/μL without transfusion

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentostatin<br>treatment of pts with refractory graft vs host disease | Drug: pentostatin<br>* 4 mg/sq m IV infusion over 20-30 min q 2 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Percentage of participants who had a complete or partial response defined by the Hopkins scoring system. A complete response is defined as the disappearance of signs and symptoms of chronic GVHD in all involved systems that is sustained for at lest 4 weeks. A partial response is an improvement by 2 or more points in at least one system score, which is sustained for at least 4 weeks, with no signs of worsening in others. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 or Higher Non-hematologic Adverse Events | Number of participants experiencing a grade 3, 4 or 5 clinically significant non-hematologic adverse events, at least possibly related to treatment. | Duration of treatment (up to 5 years) | 
| Overall Survival At 1 Year | Percentage of patients who were alive at 1 year. | 1 year | 
| Overall Survival At 2 Years | Percentage of patients who were alive at 2 years. | 2 year |