Phase I trial of ruxolitinib plus fostamatinib for the treatment of steroid refractory chronic graft versus host disease Free

Background and Significance: Current therapies for steroid-refractory chronic graft versus host disease (SR-cGVHD) feature limited rates of complete response (CR). The current standard of care for initial treatment is ruxolitinib. While ruxolitinib primarily addresses donor derived T-cells, preclinical studies have demonstrated the role of pathogenic B-Cell Receptor (BCR)-activated B cells in promoting inflammatory cytokine production and driving cGVHD. In murine models, inhibition of the BCR-signaling protein, spleen tyrosine kinase (Syk), has been shown to improve manifestations of pulmonary cGVHD. Fostamatinib is a Syk inhibitor approved for the treatment of chronic ITP. A phase I clinical trial of fostamatinib monotherapy in 14 patients with SR-cGVHD demonstrated an overall response rate of 77% (31% CR), with a median duration of response of 19.3 months.

Data on combinatorial strategies in cGVHD are currently limited. We hypothesize that targeting both pathologic B cells in addition to alloreactive T cells may have a synergistic effect in enhancing responses in SR-cGVHD.

Study Design and Methods: This is an open-label phase I clinical trial (NCT06233110) evaluating the combination of fostamatinib and ruxolitinib for the treatment of cGVHD with a suboptimal response to corticosteroids. This trial is currently actively enrolling at Duke University (Durham, NC, USA). The primary objective is to identify a minimum safe and biologically effective dose of fostamatinib when combined with standard of care ruxolitinib for SR-cGVHD. Secondary and exploratory objectives include evaluating the efficacy of treatment, assessing the impact on quality of life through the Lee Symptom Scale, and studying changes in pathogenic B cell hyperresponsiveness before and after treatment with ruxolitinib and fostamatinib.

The clinical trial features two phases: an initial dose escalation phase and a subsequent safety expansion phase. The dose escalation phase will follow a modified 3+3 design, evaluating fostamatinib at doses of 100mg daily, 150mg daily, and 100mg twice daily, in combination with ruxolitinib 10mg twice daily. Each dose level may be backfilled to a total of 6 patients for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. At the end of the dose escalation phase, two candidates for the biologically optimal fostamatinib dose will be selected based on PK, PD, efficacy, and safety data. The safety expansion phase will randomize additional patients to receive one of the two candidate fostamatinib doses together with standard dose ruxolitinib, enrolling up to 12 patients per arm.

In the absence of dose-limiting toxicity and progression of cGVHD, fostamatinib is continued for at least six months. In patients who achieve a CR, fostamatinib will be weaned at 6 months. Duration of ruxolitinib as a standard of care therapy is per investigator discretion.

Eligibility: Adults who have undergone an allogeneic hematopoietic cell transplantation and have active cGVHD with a suboptimal response to corticosteroids are eligible. Suboptimal response is defined as (1) cGVHD progression after prednisone 1 mg/kg/d x 1 week, (2) cGVHD persistence despite prednisone 0.5 mg/kg/d x 4 weeks, (3) increase in prednisone dose to 0.25 mg/kg/d or higher after 1 unsuccessful taper attempt, (4) recurrence of cGVHD after attaining a CR with steroids, or (5) progression of cGVHD after attaining a partial response with steroids. Additional major inclusion criteria include adequate bone marrow function, adequate organ function, and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Major exclusion criteria include prior treatment with a SYK inhibitor for cGVHD, active or relapsed malignancy, SR-cGVHD occurring after a non-scheduled donor lymphocyte infusion, active uncontrolled infections, uncontrolled hypertension > 160/100, and pregnancy. Of note, prior treatment with ruxolitinib for cGVHD for longer than 3 weeks is not permitted at this time, but there is a pending amendment to permit ruxolitinib use if longer than 6 months prior to enrollment and no prior severe toxicities. Prior ruxolitinib use for acute GVHD is permitted.