Graft Versus Host Disease
Conditions
Keywords
Graft Versus Host Disease, GVHD, Efalizumab, Raptiva, Steroid, Refractory, Skin, Liver, Lineberger, University of North Carolina
Brief summary
RATIONALE: Efalizumab may be an effective treatment for graft-versus-host disease of the skin caused by a donor stem cell transplant. PURPOSE: This clinical trial is studying the side effects and how well efalizumab works in treating patients with graft-versus-host disease of the skin that did not respond to previous steroids.
Detailed description
OBJECTIVES: Primary * Assess the general safety of efalizumab in patients with cutaneous graft-vs-host disease (GVHD). * Study the feasibility of digital imaging to objectively quantify cutaneous GVHD. * Evaluate the feasibility of serial skin biopsies to monitor disease response to efalizumab in patients with cutaneous GVHD. Secondary * Assess the overall complete response rate in patients treated with this drug. * Assess the overall cutaneous response rate (complete cutaneous response rate and partial cutaneous response rate) in patients treated with this drug. * Assess the overall hepatic response rate (complete hepatic response rate and partial hepatic response rate) in patients treated with this drug. * Assess the duration of any responses observed. * Assess the effect of this drug on overall patient survival. * Use the preliminary efficacy and toxicity data collected in this small exploratory study to decide on the appropriateness of a larger, subsequent phase II trial to more formally assess toxicity and efficacy of this drug in this patient population. * Collect pharmacokinetic data on this drug in these patients. OUTLINE: Patients receive efalizumab subcutaneously once weekly for 8 weeks (total of 8 doses). Digital photographs of body regions are taken for determination of disease involved body surface area. Skin biopsies are obtained before and after treatment and analyzed for lymphocyte function associated antigen (LFA-1), intercellular adhesion molecule (ICAM-1), cluster of differentiation 4, 8, and possibly 20 (CD4, CD8, CD20) by immunohistochemistry. After completion of study therapy, patients are followed at 1 and 9 weeks.
Interventions
BIOLOGICALefalizumab
Efalizumab will be administered as a subcutaneous injection once a week for 8 weeks (total of 8 doses). First efalizumab injection will be dosed at 0.7mg/kg. Subsequent weekly injections given on days 8-50 will be dosed at 1mg/kg
Sponsors
Genentech, Inc.
UNC Lineberger Comprehensive Cancer Center
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. Skin disease * Patients must demonstrate evidence of an erythematous maculopapular rash which is felt to be clinically consistent with graft-versus-host disease. Patients must undergo skin biopsy prior to enrollment. Because the pathological findings of GVHD may be equivocal (6) a biopsy which is felt to be consistent with GVHD will be considered adequate. * Consider sclerodermatous skin changes may be present but will not by themselves adequate for enrollment. Patients must exhibit signs of an active inflammatory rash. 2. Liver disease • Although hepatic involvement is not required for study participation, patients with concomitant GVHD of the liver are encouraged to enroll. All patients with hepatic GVHD must also demonstrate cutaneous disease. Patients with liver dysfunction are encouraged but not required to undergo hepatic biopsy in order to document that liver injury is the result of GVHD. Patients with a pretreatment serum bilirubin ≥ 2.0 mg/dL and biopsy-confirmed cutaneous GVHD will be assumed to demonstrate hepatic GVHD if no other cause for the liver function test (LFT) elevation can be identified. 3. Age ≥ 18 years 4. Patients must be ≥ 30 days removed from allogeneic hematopoietic stem cell transplant in order to allow for engraftment. Patients receiving peripheral blood stem cells and/or bone marrow will be eligible, regardless of the degree of human leukocyte antigen (HLA) matching. 5. Steroid refractory disease • All patients must demonstrate evidence of steroid refractory graft-versus host disease of the skin or liver. In an effort to conform to a standard definition of steroid refractory disease, we will base our criteria on those described in a large intergroup trial examining the effectiveness of pentostatin for steroid refractory chronic GVHD (31). Because the present study, however, is designed to include patients with both acute and chronic GVHD based on traditional disease classification criteria, the required time intervals necessary to define steroid-refractoriness have been shortened. Patients will be considered steroid refractory if any one of the following conditions is met: * Worsening skin or liver disease despite 1 week on the equivalent of 1mg/kg of methylprednisolone * Failure to achieve a 50% reduction in the body surface area involved by GVHD or a 50% reduction in the total serum bilirubin after 4 weeks on the equivalent of at least 0.5 mg/kg of methylprednisolone * Requirement of ≥ the equivalent of 0.5mg/kg of methylprednisolone to maintain a response after 8 weeks of steroid therapy * Patients with progression of cutaneous or hepatic GVHD after a prior history of treatment with at least 8 weeks of corticosteroids now requiring the reintroduction of corticosteroids (\> the equivalent of 10mg/day of methylprednisolone) * Patients with GVHD not improving or progressing on alternative immunosuppressive agents will be eligible if steroid refractoriness has been established previously 6. Required initial laboratory values: Absolute neutrophil count (ANC) \> 1000/μL Platelet count ≥ 20,000/μL Serum creatinine ≤ 3.0 mg/dL
Exclusion criteria
1. Non-pregnant and non-nursing • Treatment under this protocol would expose an unborn child to significant risks. Women and men of reproductive potential must agree to use an effective means of birth control. 2. No HIV infection PRIOR CONCURRENT THERAPY: * See Disease Characteristics * At least 2 terminal half-lives since prior and no concurrent infliximab, daclizumab, etanercept, rituximab, antithymocyte globulin (ATG), or denileukin diftitox
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing Adverse Events | 120 days | The primary objective of this exploratory study is to evaluate the general tolerability of efalizumab in patients suffering from steroid refractory GVHD Subjects will be evaluated for drug toxicity each visit. Toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) common criteria. |
| Degree of Skin Involvement by GVHD Using Two Digital Photography Techniques. | 120 days | Estimate of the percentage of body surface area involved by GVHD using two digital photography techniques and computerized image analyses: 1. Digital photography and body surface area calculations: A total of 12 digital photographs were obtained from different body regions using systematic digital imaging and computerized image analysis. 2. Body surface area calculations: Using National Institutes of Health image software, each body region will be manually traced and the total area of the traced area determined. Using a similar technique, each part of the region that is involved by a GVHD rash will also be traced and its area measured. The areas involved by rash will then be summed, and finally divided by the total area of the region. In so doing, the percentage of each region that is involved by GVHD will be determined. |
| Exploratory Assessment of the Staining of Cutaneous Tissues for LFA-1, ICAM-1, CD4, CD8, and Possibly CD20 | 57 days | Numerical scoring system for both LFA-1 and ICAM-1 expression which could then be used in a larger phase II trial to correlate clinical response rates to pathological findings. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Complete Response Rate | 57 days | To assess the overall complete response rate on study days 29 and 57 after 4 and 8 doses of weekly subcutaneous efalizumab. A complete response (CR) was defined as the total resolution of skin disease, and a partial response was defined as \>=50% reduction in the proportion of total body surface area involved by rash. |
| Complete Cutaneous Response Rate | On study days 29 and 57 after 4 and 8 doses of weekly subcutaneous efalizumab | The complete disappearance of all signs of cutaneous graft-versus-host disease. Complete cutaneous response rate + partial cutaneous response rate |
| Overall Hepatic Response Rate | On study days 29 and 57 after 4 and 8 doses of weekly subcutaneous efalizumab | The normalization of the total serum bilirubin to \<2mg/dL |
Countries
United States
Participant flow
Pre-assignment details
Patients with evidence of an inflammatory, erythematous rash and skin biopsy consistent with cutaneous Graft-Versus-Host disease who had failed to improve after at least 4 weeks of methylprednisolone at 0.5mg/kg were eligible for enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Efalizumab All patients on study will receive a total of 8 injections of efalizumab
efalizumab: Efalizumab will be administered as a subcutaneous injection once a week for 8 weeks (total of 8 doses). First efalizumab injection will be dosed at 0.7mg/kg. Subsequent weekly injections given on days 8-50 will be dosed at
1mg/kg | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Efalizumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 2 |
| other Total, other adverse events | 1 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Degree of Skin Involvement by GVHD Using Two Digital Photography Techniques.
Estimate of the percentage of body surface area involved by GVHD using two digital photography techniques and computerized image analyses: 1. Digital photography and body surface area calculations: A total of 12 digital photographs were obtained from different body regions using systematic digital imaging and computerized image analysis. 2. Body surface area calculations: Using National Institutes of Health image software, each body region will be manually traced and the total area of the traced area determined. Using a similar technique, each part of the region that is involved by a GVHD rash will also be traced and its area measured. The areas involved by rash will then be summed, and finally divided by the total area of the region. In so doing, the percentage of each region that is involved by GVHD will be determined.
Time frame: 120 days
Population: Data was not collected for this objective due to limited number of participants. A minimum of 12 patients were needed for analysis.
Primary
Exploratory Assessment of the Staining of Cutaneous Tissues for LFA-1, ICAM-1, CD4, CD8, and Possibly CD20
Numerical scoring system for both LFA-1 and ICAM-1 expression which could then be used in a larger phase II trial to correlate clinical response rates to pathological findings.
Time frame: 57 days
Population: There is no data for this outcome measure because of the small number of patients and inability to make meaningful conclusions
Primary
Number of Subjects Experiencing Adverse Events
The primary objective of this exploratory study is to evaluate the general tolerability of efalizumab in patients suffering from steroid refractory GVHD Subjects will be evaluated for drug toxicity each visit. Toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) common criteria.
Time frame: 120 days
Population: Of the two patients, one patient completed all 8 doses of study medication according to schedule. The other patient received 6/8 scheduled efalizumab doses, but was subsequently taken off the study after developing transient coagulase negative staphylococcal bacteremia.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efalizumab | Number of Subjects Experiencing Adverse Events | 2 participants |
Secondary
Complete Cutaneous Response Rate
The complete disappearance of all signs of cutaneous graft-versus-host disease. Complete cutaneous response rate + partial cutaneous response rate
Time frame: On study days 29 and 57 after 4 and 8 doses of weekly subcutaneous efalizumab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efalizumab | Complete Cutaneous Response Rate | 1 participants |
Secondary
Overall Complete Response Rate
To assess the overall complete response rate on study days 29 and 57 after 4 and 8 doses of weekly subcutaneous efalizumab. A complete response (CR) was defined as the total resolution of skin disease, and a partial response was defined as \>=50% reduction in the proportion of total body surface area involved by rash.
Time frame: 57 days
Population: Of the two patients, one patient completed all 8 doses of study medication according to schedule. The other patient received 6/8 scheduled efalizumab doses, but was subsequently taken off the study after developing transient coagulase negative staphylococcal bacteremia. The patient demonstrated a complete response (CR).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Efalizumab | Overall Complete Response Rate | 1 Participants |
Secondary
Overall Hepatic Response Rate
The normalization of the total serum bilirubin to \<2mg/dL
Time frame: On study days 29 and 57 after 4 and 8 doses of weekly subcutaneous efalizumab
Population: There is no data for this outcome measure as no enrolled patients had an elevated bilirubin level.