Extracorporeal Photopheresis and Low Dose Aldesleukin in Treating Patients With Steroid Refractory Chronic Graft-Versus-Host Disease

Study Overview
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Brief Summary
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This phase II trial studies efficacy of extracorporeal photopheresis and low dose aldesleukin (interleukin-2) in treating patients with chronic graft-versus-host disease (cGVHD) that does not respond to upfront treatment with steroids. In graft-vs-host disease, patients have a small quantity of a white blood cell called T regulatory cells or T-reg cells that helps to control the immune system. Extracorporeal photopheresis is a procedure where patient's blood is removed and treated with ultraviolet light and drugs that become active when exposed to light. The treated blood is then returned to the patient and may be effective in increasing T-reg cells in patients with cGVHD. Aldesleukin increases the activity and growth of white blood cells, and it has shown to enhance T-reg cells in patients with cGVHD and may be effective improving GVHD symptoms.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the anti-cGVHD activity of extracorporeal photopheresis (ECP) when combined with low dose IL-2 (interleukin 2) (aldesleukin), in patients with steroid refractory cGVHD, as assessed by overall cGVHD response rate (complete response [CR]+partial response [PR]+stable disease [SD]). SECONDARY OBJECTIVES: I. Characterize and evaluate toxicities, including type, frequency, severity, attribution, time course and duration. II. Estimate overall and failure-free survival, non-relapse mortality (NRM) and relapse, through 1 year after initiation of treatment. III. Characterize chronic GVHD Symptom Scale scores -self-report (with assistance from register nurses [RNs] and medical doctors [MDs]). IV. Assess the immunologic effects of low-dose daily subcutaneous (SC) IL-2 + ECP. V. Correlate clinical endpoints of response with ECP performance parameters. OUTLINE: Patients receive aldesleukin subcutaneously (SC) daily for 12 weeks. Patients also undergo ECP twice weekly on weeks 1-4 and then receive 2 ECP treatments every 2 weeks on weeks 5-12. Patients responding to upfront therapy with aldesleukin and ECP have the option to continue combination therapy per the discretion of the treating physician until clinical benefit is maintained or toxicities develop. After completion of study treatment, patients are followed up periodically.

Official Title
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Phase II Trial of Extracorporeal Photopheresis (ECP) Plus Low Dose IL-2 for Treatment of Steroid Refractory Chronic Graft-versus-Host Disease (cGVHD)

Conditions
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Chronic Graft Versus Host Disease

Intervention / Treatment
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* Biological: Aldesleukin
* Procedure: Extracorporeal Photopheresis
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipients of allogeneic stem cell transplantation with myeloablative or non-myeloablative conditioning regimens; alternative donor transplants (umbilical cord blood and haploidentical) are allowed Patients with chronic GVHD requiring systemic therapy are eligible Participants must have steroid-refractory cGVHD, which is defined as having persistent signs and symptoms of cGVHD despite the use of prednisone at 0.20 mg/kg/day (or 0.5 mg/kg every other day) for at least 4 weeks (or equivalent dosing of alternate corticosteroids) without complete resolution of signs and symptoms Karnofsky performance status of 70-100 % Estimated life expectancy greater than 3 months Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately Stable dose of corticosteroids for 2 weeks prior to enrollment, i.e. the patient's steroid dose (mg/kg) will remain unchanged (eg 0.5 mg/kg) in the 2 weeks preceding enrollment; allowances will be made for up or down titrating the dose based on changes in body weight Total bilirubin < 2.0 mg/dl-exception permitted in patients with Gilbert's syndrome Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x upper limit of normal (ULN), unless hepatic dysfunction is a manifestation of presumed cGVHD Abnormal liver function tests (LFTs) in the context of active cGVHD involving other organ systems may also be permitted if the treating physician documents the LFTs as being consistent with hepatic cGVHD and a liver biopsy will not be mandated in this situation Serum creatinine within normal institutional limits or creatinine clearance > 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal Absolute neutrophil count (ANC) > 1000/mm^3 Platelets > 50,000/mm^3 All subjects must have the ability to understand and the willingness to sign a written informed consent Patients with steroid refractory cGVHD typically have received salvage with multiple lines of therapy; hence in this trial there will be no restriction in terms of prior lines of therapy received; prior ECP exposure is allowed, however prior IL-2 use is excluded Exclusion Criteria: Patients should not have any uncontrolled illness including ongoing or active infection; patients with an ongoing prednisone requirement of > 1 mg/kg/day (or equivalent) will be excluded History of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment Donor lymphocyte infusion within 100 days prior to enrollment Active malignant relapse Uncontrolled cardiac angina or symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV) Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are ineligible Patients may not be receiving any other investigational agents, or concurrent parenteral biological, chemotherapy, or radiation therapy. Oral chemotherapeutic agents or biologics-for example ruxolitinib therapy (either past or current exposure)-is allowed History of allergic reactions attributed to compounds of similar chemical or biologic composition to IL-2 Patients must not have received prior chemotherapy (pentostatin) within 4 weeks before study enrollment, and those who have not recovered from the adverse events due to agents administered more than 4 weeks earlier are excluded Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with IL-2 Patients with other active malignancies are ineligible for this study, other than superficial localized skin cancer (basal or squamous cell carcinoma) Subjects, who in the opinion of the investigator may not be able to comply with IL-2 or ECP treatment requirements or the safety monitoring requirements of the study, will be excluded from participation

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supportive care (aldesleukin and ECP)<br>Patients receive aldesleukin SC daily for 12 weeks. Patients also undergo ECP twice weekly on weeks 1-4 and then receive 2 ECP treatments every 2 weeks on weeks 5-12. Patients responding to upfront therapy with aldesleukin and ECP have the option to continue combination therapy per the discretion of the treating physician until clinical benefit is maintained or toxicities develop. | Biological: Aldesleukin<br>* Given SC<br>* Other names: Recombinant Human Interleukin-2;Procedure: Extracorporeal Photopheresis<br>* Undergo ECP<br>* Other names: Photophoresis;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response (CR+ PR+SD) based on the National Institutes of Health cGVHD consensus criteria | The overall response rate (CR+PR) will be calculated as the percent of evaluable patients; exact 95% confidence intervals will be calculated for these estimates. Response rates will also be evaluated based on number and type of prior therapy(ies). Time to response and duration of response will be estimated using the product-limit method of Kaplan and Meier. | Up to 4 weeks after the end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in immunologic function | The following markers will be studied at baseline , 3 week intervals and at end of study to evaluate immunological response to ECP+ IL-2 treatment. Effector memory cells ( CD 45RA-CCR7-/CD62-) Th17 cells Tregs ( CD4+CD25+CD127-) TRECS (T cell receptor excision circles) CD3+ Cells ( T con)17 CD 19+( B cell marker ) CD3-CD16+CD56+( NK cells) FoxP3 gene methylation status Inflammatory Markers: IFN-γ, TNF α IL-2,IL-4,IL-6,IL-8 BAFF IL-2 receptor α (IL2R α) and hepatocyte growth factor (HGF) for systemic GVHD Elafin for skin GVHD Regenerating islet-derived 3α (REG3α) for gastrointestinal GVHD Suppression of tumorigenicity 2 (ST2) for steroid-refractoriness CXCL9 Micro RNA analysis Plasma banking to be done for microRNA analysis for cGVHD Skin biopsy specimens will be taken at beginning and end of therapy as clinically appropriate. | Baseline to up to 4 weeks after the end of treatment | 
| Chronic GVHD symptom score using the GVHD Symptom Scale | Self-Reported symptom Scales will be obtained at baseline and weeks 3, 7, 9, 12 and 16. | Up to 16 weeks | 
| ECP performance parameters will be analyzed based on Median time spent for each ECP session. | Clinical response to therapy will be co-related with ECP performance parameters which will include median time spent on ECP machine, second versus third generation device, and flow. | Up to 4 weeks after the end of treatment | 
| ECP performance parameters will be analyzed based on Flow rates during each ECP session. | Clinical response to therapy will be co-related with ECP performance parameters which will include median time spent on ECP machine, second versus third generation device, and flow. | Up to 4 weeks after the end of treatment | 
| ECP performance parameters will be analyzed based on Outcomes based on use of second or third generation devices. | Clinical response to therapy will be co-related with ECP performance parameters which will include median time spent on ECP machine, second versus third generation device, and flow. | Up to 4 weeks after the end of treatment | 
| Failure-free survival |  | From date of first dose of study drug to first documented cGVHD progression (necessitating change of treatment), malignancy relapse or progression or death from any cause, whichever occurs first, assessed up to 4 years | 
| Incidence of adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 | Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome. Baseline information (e.g. the extent/type of prior therapy) and demographic information will be presented as well to describe the patients treated in this study. | Up to 4 weeks after the end of treatment | 
| Non-relapse mortality |  | From date of first dose of study drug to death from any cause among patients without active disease, assessed up to 4 years | 
| Overall survival | Overall survival will be estimated using the product-limit method of Kaplan and Meier. | From date of first dose of study drug to date of death from any cause, assessed up to 4 years |