Evaluation of Fostamatinib in Patients With cGVHD After Allogeneic Stem Cell Transplant

Design & Procedures

All patients will undergo allogeneic stem cell transplantation (HCT) according to the
program's standards. No specific conditioning regimen is mandated. The stem cell source must
have been peripheral blood stem cells. Prophylaxis against acute GVHD must be with standard
agents (sirolimus and/or tacrolimus and/or methotrexate and/or cyclosporine). Participation
in a trial evaluating novel agents for therapy of acute GVHD is allowed, as long as the
experimental agent was discontinued > 14 days prior to trial entry.

Therapy: Patients will receive 100mg daily, 150mg daily or 100 mg bid beginning 90 days after
allogeneic transplantation and continue for up to 1 year from day of transplant OR beginning
at time of steroid-refractory cGVHD. Dosage will be determined using the modified continual
reassessment method.

Patient evaluations: Patients will be evaluated for cGVHD and other toxicity at a minimum on
day 1(baseline), day 3, day 11, day 25, day 39, day 60, day 88, day 116, day 144, day 186,
day 228, and day 275 from initiation of protocol therapy. While the assessment for safety is
determined based on the evaluation at day 60, patients may stay on therapy for up to 1 year
after transplantation (study treatment day 275). In addition, patients will be observed for
one year after stopping study treatment with evaluation for toxicity and cGVHD during clinic
visits at 6 and 12 months after completion of study therapy. If at any time within the first
year after transplantation, a study subject is determined to have evidence of moderate or
severe stage cGVHD according to NIH consensus criteria for global severity, the subject will
be removed from this clinical trial and appropriate therapy for cGVHD will be administered
per the treating physician's discretion. The study subject may continue to receive
Fostamatinib as per the guidelines of this clinical trial in the event that mild stage cGVHD
is diagnosed. If cGVHD develops during the observation period, a second course of
Fostamatinib at 100% tolerated study dose may be given during the observation period.

Immunosuppressive and other medications should be tapered according to the treating
physicians' discretion with careful attention to the clinical trial or treatment plan to
which the participating subject is already enrolled.

Laboratory samples will be obtained according to the study schedule. The following tests are
to be collected and analyzed for the study: complete blood counts, serum chemistry, liver
function tests (LFTs), chimerism analysis if indicated, and immunology/correlative science
studies.

This study will be open to members of all demographic groups who meet the eligibility
criteria. Approximately 18 subjects will be recruited at Duke.

A total of eighteen patients will receive fostamatinib beginning at day 90 after allogeneic
transplantation. The safety assessment is determined at day 60. Patients with
steroid-refractory cGVHD are also eligible for this phase I study. Three dose levels are
considered: 100 mg qd, 150 mg qd, 100 mg bid, and the target dose-limiting toxicity (DLT)
probability is 0.33. The Bayesian model averaging continual reassessment method (BMA-CRM)
will be used for this trial.[15]

The investigators will study targeted molecular mechanisms underpinning aberrant B-cell
signaling in cGVHD. Corollary studies will determine whether B and T cell subsets and/or
soluble B-cell activation factors are altered after Syk inhibition. The objective is to
implement preemptive targeted therapies that decrease excessive immune activation in
patients.

Inclusion Criteria:

1. Patients who have undergone allogeneic stem cell transplantation for the treatment of
any hematological malignancy are eligible. Transplant must have occurred 90 days
before the start of study drug.

2. Peripheral blood stem cells must have been used as the stem cell source.

3. Patients must have received transplantation from adult donors (both related and
unrelated) who are Human Leukocyte Antigen (HLA) matched or mismatched at 1 locus
(5/6) or are mismatched at one allele (3/6). Class I and II typing is to be performed
by standard methods at our institution.

4. Complete remission of hematological malignancy prior to transplantation. All patients
must have undergone appropriate staging for their malignancy prior to transplantation
including bone marrow aspirate/biopsy and radiographic scanning if indicated.

5. Patients who have undergone a non-myeloablative stem cell transplant must have > 65%
donor lymphoid hematopoiesis within 30 days of study enrollment.

6. Patient age greater than 18 years of age.

7. ECOG performance status 0-2 or Karnofsky Performance Status (KPS) > 60.

8. Must be able to tolerate routine oral posaconazole or voriconazole as fungal
prophylaxis therapy.

9. Written informed consent.

Exclusion Criteria:

1. Recipients of allogeneic stem cell transplantation using a single or multiple
umbilical cord blood units or using bone marrow.

2. Participation in a clinical trial evaluating another preventative strategy for chronic
GVHD or ongoing participation in a clinical trial for therapy of acute GVHD. Prior
completion of experimental therapy for acute GVHD is permissible if the experimental
agent was used > 14 days prior to enrollment.

3. Evidence of relapsed hematologic malignancy based on routine restaging studies.

4. Evidence of any active uncontrolled infection (bacterial, viral or fungal) or evidence
of natural exposure to Hepatitis B, Hepatitis C or HIV without demonstration of PCR
negativity for said virus. Vaccination to Hepatitis B is not an exclusion criterion.

5. Any evidence of ongoing gastrointestinal or hepatic acute GVHD or evidence of greater
than ongoing Stage I cutaneous acute GVHD at time of enrollment. Ongoing, tapering
therapy for resolved acute GVHD is permissible.

6. Patients with GVHD with chronic features diagnosed prior to day +60 or prior to
enrollment are ineligible.

7. Patients may have received no more than one Donor Lymphocyte Infusion (DLI), DLI must
have been administered > 6 weeks prior to enrollment on study, and no plans for a DLI
in the upcoming 30 days.

8. Any major cardiovascular even within 6 months of study initiation, including but not
limited to myocardial infarction, unstable angina, cerebrovascular accident, pulmonary
embolism, heart failure uncontrolled by medications or New York Heart Association
Class III or IV heart failure.

9. Uncontrolled or poorly controlled hypertension, defined as systolic blood pressure >
140 mmHg or diastolic blood pressure > 90 mmHg, whether or not the subject is
receiving anti-hypertensive treatment. Subjects may be rescreened if the blood
pressure is successfully and promptly controlled within 5 days using conventional
anti-hypertensive therapy to achieve optimal blood pressure control (<140/90 mmHg).

10. Active hemolytic anemia.

11. History of arterial or venous thrombosis (unless a single episode of venous thrombosis
> 1 year prior to study initiation).

12. Liver function test abnormalities including ALT or AST > 3.0x ULN; total bilirubin >
1.5x ULN; alkaline phosphatase > 2.5 x ULN

13. Neutrophil count < 1.5 x 10e9/L or platelet count < 75 x10e9/L

14. Pregnancy or lactation.