Graft Versus Host Disease
Conditions
Keywords
graft versus host disease
Brief summary
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
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.
Interventions
DRUGCyclophosphamide
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 75 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of High-dose Cyclophosphamide as Determined by Number of Participants Who Tolerated Each Dose of Cyclophosphamide | Day 28 | — |
| GVHD Response Rate | Day 28 | 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+). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cyclophosphamide Treatment with cyclophosphamide 50 mg/kg/d x 2 days, then dose adjusted according to continuous reassessment model according to toxicities until MTD found. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Cyclophosphamide |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Age, Continuous | 38 years |
| Region of Enrollment United States | 12 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 5 | 3 / 4 | 3 / 3 |
| other Total, other adverse events | 0 / 5 | 0 / 4 | 0 / 3 |
| serious Total, serious adverse events | 0 / 5 | 1 / 4 | 3 / 3 |
Outcome results
Primary
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+).
Time frame: Day 28
Population: This analysis excludes the two participants who died early because their responses were not assessed prior to death.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide 50 mg/kg | GVHD Response Rate | 1 Participants |
| Cyclophosphamide 100 mg/kg | GVHD Response Rate | 0 Participants |
| Cyclophosphamide 150 mg/kg | GVHD Response Rate | 1 Participants |
Primary
Maximum Tolerated Dose of High-dose Cyclophosphamide as Determined by Number of Participants Who Tolerated Each Dose of Cyclophosphamide
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide 50 mg/kg | Maximum Tolerated Dose of High-dose Cyclophosphamide as Determined by Number of Participants Who Tolerated Each Dose of Cyclophosphamide | 4 Participants |
| Cyclophosphamide 100 mg/kg | Maximum Tolerated Dose of High-dose Cyclophosphamide as Determined by Number of Participants Who Tolerated Each Dose of Cyclophosphamide | 4 Participants |
| Cyclophosphamide 150 mg/kg | Maximum Tolerated Dose of High-dose Cyclophosphamide as Determined by Number of Participants Who Tolerated Each Dose of Cyclophosphamide | 2 Participants |