About this trial
This study aims to evaluate the safety and efficacy of Gecacitinib in patients with steroid-refractory/dependent active chronic graft versus host disease (cGVHD).
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Age ≥ 18 years, regardless of gender.
Underlying hematologic malignancies or non-malignant disorders having received allogeneic hematopoietic stem cell transplantation.
Steroid-refractory cGVHD is defined as meeting any of the following criteria: disease progression despite the use of prednisone ≥1 mg/kg/day (or equivalent dose of corticosteroids) for at least 1 week; OR, persistent disease symptoms with no improvement despite the use of prednisone ≥0.5 mg/kg/day or ≥1 mg/kg every other day (or equivalent dose of corticosteroids) for at least 4 weeks.
Steroid-dependent cGVHD is defined as the requirement for a maintenance dose of prednisone >0.25 mg/kg/day or >0.5 mg/kg every other day (or equivalent dose of corticosteroids) to prevent disease flare or progression, and failure to successfully taper the dose to a lower level in at least 2 separate attempts spaced ≥8 weeks apart.
Disqualifiers
Post-transplant lymphoproliferative disorder, or loss of full donor chimerism due to other reasons.
Previous use of, or current treatment with, other JAK inhibitors at the time of screening.
Congestive heart failure of New York Heart Association (NYHA) class III-IV, or documented history of diastolic or systolic dysfunction (e.g., left ventricular ejection fraction <40% by echocardiography), or uncontrolled/unstable angina or myocardial infarction.
Uncontrolled diabetes (blood glucose >250 mg/dL or >13.9 mmol/L).
Trial design
Single group
Treatments tested in this trial
Gecacitinib
DrugPhase Ib: Four dose cohorts of Gecacitinib are planned: 50 mg qd, 50 mg bid, 150 mg/day, and 100 mg bid. Dose escalation or de-escalation will follow the standard "3+3" design, starting at 50 mg BID. The dose may be escalated to 150 mg/day or 100 mg BID, or de-escalated to 50 mg qd. Subjects will receive continuous dosing for 28 days, or until they experience Dose-Limiting Toxicities (DLTs), cGVHD progression, or initiate new systemic therapy (whichever occurs first). Subjects who do not experience DLTs during Phase Ib may proceed to the Phase IIa dose-expansion stage. Phase IIa: Subjects will receive Gecacitinib at the Recommended Phase II Dose (RP2D). Treatment will continue until the completion of 6 treatment cycles (each cycle is comprised of 4 weeks), or until the occurrence of intolerable toxicity, cGVHD progression, or initiation of new systemic therapy (whichever occurs first).
Treatment groups
Trial outcomes
Primary outcomes
phase Ib: Maximal Tolerable Dose (MTD)
If dose limiting toxicity (DLT) occurs in 2 or more subjects in a given dose group, the dose level in the previous dose group is considered MTD. (Patients in phase Ib)
phase IIa: Overall response rate (ORR) on Cycle 7 Day 1
Percentage of participants achieving complete response (CR) and partial response (PR) during the study according to the cGVHD 2014 NIH Consensus Criteria.
Secondary outcomes
phase Ib: Recommended phase II dose (RP2D)
Recommended dose for phase II (Patients in phase Ib)
phase IIa: Rate of Failure-free Survival (FFS)
Composite time to event endpoint incorporating the following FFS events: (i) relapse or recurrence of underlying disease or death due to underlying disease, (ii) nonrelapse mortality, or (iii) addition or initiation of another systemic therapy for cGvHD.
phase IIa: Rate of Participants With Clinically Relevant Improvement of the Modified Lee cGvHD Symptom Scale Score
To assess improvement of symptoms based on the total symptom score (TSS); a responder was defined as having achieved a clinically relevant reduction from Baseline of the TSS. The scale consists of 30 items in 7 subscales (skin, eye, mouth, lung, nutrition, energy, and psychological). Participants reported their level of symptom "bother" over the previous month on a 5-point likert scale: not at all, slightly, moderately, quite a bit, or extremely. Subscale scores and the summary score range from 0 to 100, with a higher score indicating worse symptoms
phase IIa: Best overall response (BOR)
BOR was defined as the percentage of participants who achieved an overall response (CR+PR) based on cGvHD disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response at any time point (up to Cycle 7 Day 1 or the start of additional systemic therapy for cGvHD).
Other outcomes
phase IIa: Changes in concentration of cGVHD-associated biomarkers
Measurement of changes in the levels of soluble biomarkers associated with cGVHD activity (e.g., CXCL9, ST2, MMP3) in plasma or serum samples.
phase IIa: Changes in concentration of inflammatory cytokines.
Assessment of changes in the levels of pro-inflammatory cytokines (e.g., IL-6, TNF-α, IFN-γ) in peripheral blood samples.
phase IIa: Changes in absolute counts of lymphocyte subsets
Assessment of changes in the absolute numbers (cells/µL) of major lymphocyte subsets in peripheral blood, including T cells (CD3+), helper T cells (CD3+CD4+), cytotoxic T cells (CD3+CD8+), B cells (CD19+), and natural killer (NK) cells (CD16+CD56+).
Locations
Sponsors and contacts
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