A Phase I Study of Abatacept in the Treatment of Patients With Steroid Refractory Chronic Graft Versus Host Disease (cGVHD)
The participant is invited to take part in this study because they have chronic Graft versus Host Disease (cGVHD) that is not responding to standard treatment with steroids. This research study is a way of gaining new knowledge about the treatment of patients with cGVHD. This research study is evaluating a drug called abatacept. Abatacept is a drug that alters and suppresses the immune system. Abatacept is approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe active rheumatoid arthritis in adults and of severe juvenile idiopathic arthritis (JIA) in patients who have failed prior therapy with disease-modifying anti-rheumatic drugs (DMARDs). These are autoimmune conditions, ie caused by an overactive immune system that attacks normal tissues and organs. It is currently being tested in a variety of other autoimmune conditions. In this case it is considered experimental. cGVHD is caused by the donor cells attacking various organs of the recipient. The investigators try to minimize this immune attack by using corticosteroids such as prednisone. In severe cases prednisone is not sufficient and other immunosuppressive medications are used in addition in order to more efficiently control cGVHD and to limit the dose and consequently the multiple side-effects of corticosteroids. This study is being done to determine if the use of abatacept is safe in patients with cGVHD and if it can facilitate a better control of cGVHD. During this study the participants will be evaluated for side effects from the treatment with abatacept, and for response of the cGVHD to the treatment. There will be two groups of participants in the study. The first group will be treated at a relatively low dose of abatacept. If this is found to be safe then the second group will be treated at a higher dose. Three to four tablespoons of blood will be drawn at every 2 week visit in order to determine your blood counts, kidney and liver function. Some of the blood will be used in a research lab in order to study measures of your immune system and how they might be affected by the treatment.
⁃ Participants must meet the following criteria on screening examination to be eligible to participate in the study:
• Participants must be recipients of an allogeneic bone marrow or stem cell transplantation with myeloablative or reduced intensity conditioning regimens.
• Participants must be at least 100 days after the transplantation or a donor lymphocyte infusion.
• Participants must have cGVHD (as defined by the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease)
• Participants may have either extensive or limited cGVHD requiring systemic treatment
• Participants must have steroid refractory cGVHD, defined as having persistent signs and symptoms of chronic GVHD despite the use of prednisone at ≥ 0. 5 mg/kg/day (or equivalent) for at least 4 weeks in the preceding 12 months. Patients may remain on steroids while enrolled in the study.
• No addition or subtraction of other immunosuppressive medications for at least 4 weeks prior to starting treatment.
• On stable immunosuppressive regimen for 2 weeks prior to enrollment. Adjustment of immunosuppressive medications to maintain a therapeutic level is permitted.
• Age ≥ 18 years at the time of signing the informed consent form.
⁃ Reproductive Status: Definition of Women of Child-Bearing Potential (WOCBP). WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal (see definition below).
⁃ Post-menopause is defined as:
• Women who have had amenorrhea for ≥ 12 consecutive months (without another cause) and who have a documented serum follicle-stimulating hormone (FSH) level \> 35 mIU/mL.
• Women who have irregular menstrual periods and a documented serum FSH level \> 35 mIU/mL.
• Women who are taking hormone replacement therapy (HRT).
⁃ The following women are WOCBP:
• Women using the following methods to prevent pregnancy: Oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as intrauterine devices or barrier methods (diaphragm, condoms, spermicides).
• Women who are practicing abstinence.
• Women who have a partner who is sterile (eg, due to vasectomy). WOCBP must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 10 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized.
• WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 0 to 48 hours before the first dose of study drug.
• Women must not be breast-feeding.
• Sexually active fertile men must use effective birth control if their partners are WOCBP.
• Life expectancy of greater than \> 3 months.
• ECOG performance status ≤ 2 (see Appendix A).
• Laboratory test results within these ranges:
• Absolute neutrophil count ≥ 1500/mm³
• Serum creatinine ≤ 2.0 mg/dL
• Renal function assessed by calculated creatinine clearance ≥ 60ml/min by Cockcroft-Gault formula (see Appendix B: Cockcroft-Gault estimation of CrCl).
• Total bilirubin ≤ 1.5 x ULN (unless hepatic dysfunction is caused by cGVHD)AST (SGOT) and ALT (SGPT) ≤ 3 x ULN (unless hepatic dysfunction is caused by cGVHD).
• Patients much have a negative PPD skin test and a negative Quantiferon assay.
• Must possess the ability to understand and the willingness to sign a written informed consent document.