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Ruxolitinib Plus Fostamatinib for Steroid Refractory cGvHD

ConditionChronic Graft Versus Host Disease
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18-80
SponsorStefanie Sarantopoulos, MD, PhD.

About this trial

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

This trial does not accept healthy volunteers

Qualifiers

Patient is able and willing to provide written informed consent prior to any study related screening procedures are performed.

Age ≥ 18 years old at the time of informed consent

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.

Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

Disqualifiers

Prior or ongoing treatment with ruxolitinib for treatment of cGvHD for longer than 3 weeks prior to anticipated C1D1.

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.

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.

Patients with relapsed primary malignancy, or who have been treated for relapse after the allogeneic HCT was performed

Trial design

Design model

Sequential

Treatments tested in this trial

  • Fostamatinib

    Drug

    Fostamatinib will be administered as part of the initial dose escalation cohort and then two candidate doses will be identified to be administered for the safety expansion cohort.

  • Ruxolitinib

    Drug

    Ruxolitinib 10mg BID will be administered in combination with Fostamatinib in each of the study arms.

Treatment groups

30 Participants
are divided into 6 treatment groups

6

Treatment groups

See each treatment group below.

Group A: Dose escalation phase: Dose level 0Experimental treatment 2 interventions
Group B: Dose escalation phase: Dose level 1Experimental treatment 2 interventions
Group C: Dose escalation phase: Dose level 2Experimental treatment 2 interventions
Group D: Dose escalation phase: Dose level 3Experimental treatment 2 interventions
Group E: Candidate Dose #1Experimental treatment 2 interventions
Group F: Candidate Dose #2Experimental treatment 2 interventions

Trial outcomes

Primary outcomes

1

Minimum safe and biologically effective dose

Minimum safe and biologically effective dose will be determined by dose limiting toxicities and overall response rate of the combination regimen, as well as pharmacokinetic and pharmacodynamic markers of fostamatinib (if available)

Time frame
6 months

Secondary outcomes

1

Overall response rate

Overall response rate, as defined by achievement of a complete response (CR) or partial response (PR), using the 2014 NIH Consensus criterion, during the first 6 months of therapy.

Time frame
6 months
2

Duration of Response

The length of time that a patient's response to treatment lasts.

Time frame
1 year
3

1-year cGvHD-free survival

The cGVHD-free survival is a composite endpoint that measures survival free from the diagnosis of chronic GVHD at any stage. cGvHD activity assessment includes medical history, physical exam, and laboratory studies per the 2014 NIH Consensus Response Criteria.

Time frame
1 year
4

Overall survival

The length of time that a patient lives following treatment.

Time frame
1 year

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Stefanie Sarantopoulos, MD, PhD.

Lead sponsor

Duke University

Sponsor institution

Incyte Corporation

Collaborator

Rigel Pharmaceuticals

Collaborator

National Institutes of Health (NIH)

Collaborator

Source ClinicalTrials.gov
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