cGVHD, HSCT
Conditions
Keywords
cGVHD, Gecacitinib, HSCT
Brief summary
This study aims to evaluate the safety and efficacy of Gecacitinib in patients with steroid-refractory/dependent active chronic graft versus host disease (cGVHD).
Interventions
DRUGGecacitinib
Phase 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).
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years, regardless of gender. 2. Underlying hematologic malignancies or non-malignant disorders having received allogeneic hematopoietic stem cell transplantation. 3. Diagnosis of active cGVHD according to the 2014 NIH consensus criteria, meeting the definition of steroid-refractory or steroid-dependent cGVHD. Prior lines of cGVHD therapy are not restricted. Definitions are as follows: 1. 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. 2. 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. 4. Platelet count ≥50 × 10⁹/L and absolute neutrophil count (ANC) ≥0.5 × 10⁹/L, without the use of colony-stimulating factors, androgens, erythropoietin, thrombopoietin, or platelet transfusion within 7 days prior to screening. 5. Adequate major organ function, defined as meeting the following criteria: ALT and AST ≤ 2.5 × upper limit of normal (ULN); direct and total bilirubin ≤ 2.0 × ULN; serum creatinine ≤ 1.5 × ULN. 6. Stable underlying disease without evidence of progression or relapse. 7. Karnofsky Performance Status (KPS) ≥ 60%. 8. Voluntarily participate in this study, provide signed informed consent, demonstrate good compliance, and be able to adhere to the study and follow-up procedures
Exclusion criteria
1. Post-transplant lymphoproliferative disorder, or loss of full donor chimerism due to other reasons. 2. Previous use of, or current treatment with, other JAK inhibitors at the time of screening. 3. History or presence of major diseases or clinically significant organ dysfunction that cannot be adequately controlled by treatment and may interfere with study completion: 1. 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. 2. Uncontrolled diabetes (blood glucose \>250 mg/dL or \>13.9 mmol/L). 3. Hypertension that cannot be adequately controlled to systolic blood pressure \<160 mmHg and diastolic blood pressure \<100 mmHg despite combination antihypertensive therapy. 4. Peripheral neuropathy (Grade 2 or higher per NCI-CTCAE v5.0 criteria). 4. Patients with any uncontrolled bacterial, viral, or fungal infection. 5. Positive for HIV at screening, or active hepatitis B virus infection (HBsAg positive and HBV-DNA positive or above the upper limit of normal), or positive for HCV antibody with detectable HCV-RNA. 6. History of tuberculosis or positive interferon-γ release assay at screening. 7. Concurrent use of strong CYP3A4 inhibitors. 8. History of progressive multifocal leukoencephalopathy. 9. Known or suspected hypersensitivity to Gecacitinib hydrochloride, drugs of the same class, or any of their excipients. 10. Pregnant or lactating women, or patients unwilling to use effective contraception during Gecacitinib treatment and for 1 week after the last dose. 11. Inability to swallow oral tablets.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| phase Ib: Maximal Tolerable Dose (MTD) | Baseline up to 28 days | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| phase Ib: Recommended phase II dose (RP2D) | Baseline up to 28 days | Recommended dose for phase II (Patients in phase Ib) |
| phase IIa: Rate of Failure-free Survival (FFS) | Baseline to when the last participant reached Cycle 7 Day 1 | 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 | Cycle 7 Day 1 | 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) | Cycle 7 Day 1 | 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). |
| phase IIa: Proportion of patients who achieved ORR (CR+PR) at Cycle 4 Day 1. | Cycle 4 Day 1 | ORR was defined as the percentage of participants in each arm demonstrating a CR or 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. |
| phase IIa: Duration of Response (DOR) | From first response until cGVHD progression, death, or the date of change/addition of systemic therapies for cGVHD, whichever comes first, assessed up to Cycle 7 Day 1. | Duration of response (DOR) is assessed for responders only. DOR is defined as the time from first response until cGvHD progression, death, or the date of change/addition of systemic therapies for cGvHD. |
| phase IIa: Organ-Specific Response Rate | Cycle 7 day 1 | The proportion of patients who achieve organ-specific response, as defined by the 2014 NIH consensus criteria, in each involved organ at cycle 7 day 1. |
| phase IIa: Proportion of patients with ≥50% reduction in daily steroid dose | Cycle 7 Day1 | Proportion of patients achieving a reduction in daily steroid dose by ≥50% sustained for at least 4 weeks. |
| phase IIa: Proportion of patients successfully tapered off all steroids | Cycle 7 Day 1 | — |
| phase IIa: Change From Baseline in Functional Assessment of Cancer Therapy - Bone Marrow Transplantation (FACT-BMT) | Baseline; up to Cycle 7 Day 1 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The FACT-BMT is a 50-item self-report questionnaire that measures the effect of a therapy on domains including physical, functional, social/family, and emotional well-being, together with additional concerns relevant for bone marrow transplantation participants. The questions were based on a 5-point Likert scale, where 0 corresponds to "not at all" and 4 corresponds to "very much." The higher the final score, the better the quality of life. The FACT-BMT total score ranges from 0 to 148. |
| phase IIa: Change From Baseline in EQ-5D-5L | Baseline; up to Cycle 7 Day 1 | The EQ-5D-5L is a descriptive classification consisting of five dimensions of health: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort. The five-level version (no problems, slight problems, moderate problems, severe problems, and extreme problems) uses a 5-point Likert scale, with 1 being no problems and 5 being extreme problems. |
| phase IIa: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | From first dose to 28 days post last dose, up to Cycle 8 Day 1 | Adverse events were defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions that occurred after the participant's signed informed consent was obtained. Abnormal laboratory values or test results occurring after informed consent constituted adverse events only if they induced clinical signs or symptoms, were considered clinically significant, required therapy, or required changes in study medication(s). TEAEs were defined as those AEs that started or worsened during the on-treatment period |
Outcome results
None listed