A Phase I Study of Abatacept in the Treatment of Patients With Steroid Refractory Chronic Graft Versus Host Disease (cGVHD)

Before the research starts (screening): After signing the consent form, the participant will
be asked to undergo some screening tests or procedures to find out if they can be in the
research study. Many of these tests and procedures are likely to be part of regular cGVHD
care and may be done even if it turns out that the participant does not take part in the
research study. If the participant has had some of these tests or procedures recently, they
may or may not have to be repeated.

- Complete Medical History and Physical Examination

- Blood Collection: 3-4 tablespoons of blood will be drawn to measure the participants
complete blood counts, kidney, liver and thyroid function

- Disease Assessment: Depending on what organs are affected by their cGVHD the participant
may undergo blood tests or a skin exam or an eye exam or a dental exam.

- Electrocardiogram (EKG): a noninvasive test that measures the electrical activity of the
participant's heart

- A tuberculin skin test and a quantiferon blood test to rule out tuberculosis

- Pregnancy testing if applicable

- HIV and Hepatitis blood test: 2-3 teaspoons of blood will be collected to perform an HIV
test. The participant will be asked to sign a separate consent form for this test. The
participant's doctor will discuss the results of this test with the participant and the
results will become a part of their permanent medical record. The participant may seek
private HIV testing prior to consenting, and based on the results may choose whether or
not to participate in this study or have the HIV test become part of their medical
records.

If these tests show that the participant is eligible to participate in the research study,
the participant will begin the study treatment. If the participant does not meet the
eligibility criteria, the participant will not be able to participate in this research study.

Additional research procedures to be performed at the time of screening:

- Research blood testing: to study measures of the participant's immune system

After the screening procedures confirm that the participant is eligible to participate in the
research study:

- Since the investigators are looking for the highest dose of the study drug that can be
administered safely without severe or unmanageable side effects in participants that
have abatacept, not everyone who participates in this research study will receive the
same dose of the study drug. The dose the participant gets will depend on the number of
participants who have been enrolled in the study before the participant and how well
they have tolerated their doses.

- The total duration of treatment on this study is approximately 113 days or 6 treatments.
Doses 1-3 will be administered every two weeks. One month following Dose 3, abatacept
will be administered every four weeks for the remaining three doses (Doses 4-6.) The
treatment will be given intravenously on these days. One month following your last dose
of treatment, the participant will be seen in clinic. The participant will be seen in
the clinic weekly through dose 4, then every 2 weeks for follow up even if the
participant doesn't have treatment.

- The first group of participants will be treated with a lower dose of abatacept. If this
dose is determined to be safe then the second group will be treated at a higher dose.

During treatment the participant will be seen in the clinic every two weeks. At every visit
the following will be performed:

- Complete Medical History and Physical Examination

- Blood Collection: 3-4 tablespoons of blood will be drawn to measure their complete blood
counts, kidney, liver and thyroid function

- Research blood testing: to study measures of the participant's immune system

- On the days of treatment the participant will undergo an assessment of cGVHD depending
on what organs are affected

After the final dose of the study drug:

After the participant has completed taking the drug on the study, the following procedures
and tests will take place:

- Safety assessment 28 days after the last dose of the study drug.

- Complete Medical History and Physical Examination

- Blood Collection: 3-4 tablespoons of blood will be drawn to measure the participant's
complete blood counts, kidney, liver and thyroid function

- Disease Assessment: by physical exam and blood tests if the participant has leukemia or
multiple myeloma, or physical exam and PET/CT or CT scan if the participant has
lymphoma. These will be done at the safety assessment visit and at the 3 and 6 month
follow up visits.

- Electrocardiogram

- Research blood testing: to study measures of your immune system

- Once the participant has completed treatment on study they will be followed monthly for
6 months

Inclusion Criteria:

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.

Exclusion Criteria:

- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study.

- Any serious medical condition (including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia), laboratory abnormality, or psychiatric illness/ social situation that
would prevent the subject from signing the informed consent form or limit compliance
with study requirements.

- Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.

- Use of any other experimental drug or therapy within 28 days of starting treatment
with abatacept.

- Use of biologic antibody therapy for cGVHD with rituximab, alemtuzumab, or ATG within
6 months of starting treatment with abatacept.

- Use of TNF alpha inhibitors within four weeks prior to study entry.

- Ongoing prednisone requirement >1 mg/kg/day (or equivalent)

- New immunosuppressive medication or ECP within 28 days of starting treatment with
abatacept.

- Donor lymphocyte infusion within 100 days prior to enrollment.

- Active malignant disease relapse or other active malignancy with the exception of
currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in
situ" of the cervix or breast.

- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Known seropositive for or positive viral load for HIV or positive viral loads for
infectious hepatitis, type B (HBV) or C (HCV).

- Uncontrolled intercurrent active infection. Controlled infection on long term
suppressive or maintenance therapy is permissible.

- Use of live vaccines within four weeks of starting abatacept.