Graft Versus Host Disease
Conditions
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.
Interventions
DRUGpentostatin
4 mg/sq m IV infusion over 20-30 min q 2 weeks
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologic documentation of chronic GvHD following allogeneic HCT or donor lymphocyte infusion. 2. Patients may have progressive, quiescent, or de novo onset chronic GvHD. 3. 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 4. 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. 5. Patients with established chronic GvHD not improving or progressing on other immunosuppressive agents are also eligible if steroid refractoriness has been established previously. 6. Age ≥ 18 years 7. Performance Status 0-3 8. Patients on mechanical ventilation are excluded. 9. No active infection. Patients with active infection requiring antibiotic therapy are not eligible until infection is controlled. 10. No HIV infection. Patients with HIV infection are excluded because of safety concerns in this patient population. 11. 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). 12. Required Initial Laboratory Values: * Calc. Creatinine Clearance ≥ 30 mL/min/1.73 m\^2 * ANC \> 1000/μL * Platelets \> 50,000/μL without transfusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | 3 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Grade 3 or Higher Non-hematologic Adverse Events | Duration of treatment (up to 5 years) | Number of participants experiencing a grade 3, 4 or 5 clinically significant non-hematologic adverse events, at least possibly related to treatment. |
| Overall Survival At 1 Year | 1 year | Percentage of patients who were alive at 1 year. |
| Overall Survival At 2 Years | 2 year | Percentage of patients who were alive at 2 years. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics Association Between Exposure and Response At 3 Months | 3 months | The individual PK parameters will be derived by using a noncompartmental analysis of the plasma-concentration-time data |
Countries
United States
Participant flow
Recruitment details
Between December 2003 and March 2008, 39 participants were recruited to this study.
Pre-assignment details
1 participant cancelled prior to receiving treatment and is excluded from all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Pentostatin pentostatin: 4 mg/m\^2 IV infusion over 20-30 min q 2 weeks | 38 |
| Total | 38 |
Baseline characteristics
| Characteristic | Pentostatin |
|---|---|
| Age, Continuous | 48 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Region of Enrollment United States | 38 count of participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 34 |
| serious Total, serious adverse events | 14 / 34 |
Outcome results
Primary
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.
Time frame: 3 months
Population: 3 patients died before the 3 month evaluation and were not evaluated for the primary endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pentostatin | Response Rate | 20 percentage of participants |
Secondary
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.
Time frame: Duration of treatment (up to 5 years)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pentostatin | Grade 3 or Higher Non-hematologic Adverse Events | Fatigue | 3 count of participants |
| Pentostatin | Grade 3 or Higher Non-hematologic Adverse Events | Renal failure | 4 count of participants |
| Pentostatin | Grade 3 or Higher Non-hematologic Adverse Events | Anorexia | 2 count of participants |
| Pentostatin | Grade 3 or Higher Non-hematologic Adverse Events | Infection | 10 count of participants |
| Pentostatin | Grade 3 or Higher Non-hematologic Adverse Events | CNS hemmorrhage | 1 count of participants |
| Pentostatin | Grade 3 or Higher Non-hematologic Adverse Events | Rash | 1 count of participants |
| Pentostatin | Grade 3 or Higher Non-hematologic Adverse Events | Personality/behavioral | 1 count of participants |
| Pentostatin | Grade 3 or Higher Non-hematologic Adverse Events | Pneumonitis | 1 count of participants |
Secondary
Overall Survival At 1 Year
Percentage of patients who were alive at 1 year.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pentostatin | Overall Survival At 1 Year | 53 percentage of participants |
Secondary
Overall Survival At 2 Years
Percentage of patients who were alive at 2 years.
Time frame: 2 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pentostatin | Overall Survival At 2 Years | 50 percentage of participants |
Other Pre-specified
Pharmacokinetics Association Between Exposure and Response At 3 Months
The individual PK parameters will be derived by using a noncompartmental analysis of the plasma-concentration-time data
Time frame: 3 months