Ruxolitinib Plus Fostamatinib for Steroid Refractory CGvHD

This is an open-label phase I study of fostamatinib in combination with ruxolitinib for the treatment of chronic GvHD with a suboptimal response to corticosteroids. The primary objective is to identify a minimum safe and biologically effective dose of fostamatinib when combined with standard of care ruxolitinib for the treatment of steroid refractory and steroid dependent cGVHD. The secondary objective is to estimate the efficacy of the combination of ruxolitinib and fostamatinib for the treatment of steroid refractory and steroid dependent cGVHD.

The target enrollment is 24-30 subjects. The study will begin with an initial dose escalation cohort employing a modified 3+3 design to investigate up to three doses of fostamatinib. Using safety, efficacy, pharmacodynamic (PD), and pharmacokinetic data (PK), an interim assessment will be performed to determine two candidate doses of the biologically optimal dose to investigate further. A safety expansion cohort will be opened to backfill these two candidate doses up to a total 12 patients per dose, including those in the dose escalation cohort who received the candidate doses. Patients will then be randomized to one of these two candidate doses in the expansion. If there is an imbalance in the two expansion cohorts, the remaining patient slots after 1:1 randomization will be sequentially backfilled to a total of 12 patients per cohort. A final analysis of safety, efficacy, and PK/PD data in patients who received the two candidate doses will be conducted to determine a minimum safety and biologically effective dose, which will be the recommended phase II dose (RP2D).

The primary hypothesis is that Fostamatinib combined with ruxolitinib is a safe therapy for and has synergistic activity in cGvHD. The recommended phase II dose will be determined by the study investigators in collaboration with the sponsors. The decision to select the recommended phase II dose will occur only after all patients in the part 1 have completed at least 28 days of therapy. The decision will be based on the valuation of all relevant, available data, and not solely on dose-limiting toxicities.


Eligibility Criteria:
Inclusion Criteria

1. Patient is able and willing to provide written informed consent prior to any study related screening procedures are performed.
2. Age ≥ 18 years old at the time of informed consent
3. Have undergone allogeneic hematopoietic cell transplantation (HCT) from any donor source (matched unrelated donor, sibling, haploidentical) using bone marrow, peripheral blood, or cord blood stem cells.
4. Adequate bone marrow function defined as:

   4.1 Absolute neutrophil count (ANC) ≥ 750 /mm3 4.2 Platelet count ≥ 40,000 /mm3 4.3 Hemoglobin ≥ 8.0 g/dL without transfusion support Note: Use of growth factor supplementation (myeloid, erythroid or megakaryocytic) is permitted to meet eligibility criteria.
5. Patients with clinically diagnosed cGvHD staging of mild to severe according to NIH Consensus Criteria4 prior to Cycle 1 Day 1 and with confirmed steroid refractoriness or steroid dependence irrespective of the concomitant use of a calcineurin inhibitor, as follows:

   5.1 Disease progression after administration of a minimum dose of 1.0 mg/kg/day or equivalent for at least 1 week at any time following diagnosis of cGvHD OR 5.2 Disease persistence despite continued treatment with prednisone \> 0.5mg/kg/d or equivalent for at least 4 weeks OR 5.3 Increase to prednisone \> 0.25 mg/kg/d after 1 unsuccessful attempt to taper the dose.

   5.4 Recurrence of chronic GVHD after attaining a complete response 5.5 Progression of chronic GVHD after attaining a partial response
6. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

Exclusion Criteria

1. Prior or ongoing treatment with ruxolitinib for treatment of cGvHD for longer than 3 weeks prior to anticipated C1D1.
2. Prior treatment with fostamatinib or another SYK inhibitor for the treatment of acute or chronic GVHD. Prior use of fostamatinib for conditions other than GVHD is permitted.
3. Ongoing systemic therapy for cGvHD other than corticosteroids, calcineurin inhibitor, or mycophenolate mofetil, aside from fewer than 3 weeks of ruxolitinib. Prior ruxolitinib use for the indication of acute GVHD is permitted.
4. Patients with relapsed primary malignancy, or who have been treated for relapse after the allogeneic HCT was performed
5. SR-cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. Patients who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible.
6. History of progressive multifocal leuko-encephalopathy (PML)
7. Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of infection progression are present.
8. Clinical evidence of active and clinically significant viral disease including HIV, CMV, HHV-6, HBV, HCV, or BK virus.
9. Patients on mechanical ventilation or have a resting O2 saturation \< 90% by pulse oximetry
10. Clinically significant and uncontrolled cardiovascular disease, including unstable angina, acute myocardial infarction, or stroke within 3 months, or NYHA Class III or IV congestive heart failure.
11. Uncontrolled hypertension with systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg.
12. Creatinine clearance by Cockcroft-Gault of \< 15 mL/min and not on dialysis
13. Total bilirubin \> 3 times ULN, ALT \> 5 times ULN, or AST \> 5 times ULN
14. QTc ≥ 470 ms as calculated by the Fridericia Formula
15. Active pregnancy or breast feeding, or currently seeking active pregnancy
16. Any patient who, in the opinion of the investigator, may not be able to comply with study procedures