An Open-Label, Single-Arm, Multicenter Study of Ibrutinib in Japanese Patients With Steroid-dependent/Refractory Chronic Graft-Versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) is a serious complication after allogeneic stem cell transplantation. There are no well-established treatment options for cGVHD after primary steroid-based treatment. Ibrutinib showed clinical benefit with an acceptable safety profile in steroid-dependent/refractory cGVHD patients in a Phase 1b/2 study (PCYC-1129-CA, NCT02195869), with which it was approved in the United States for adult cGVHD patients after failure of ≥1 systemic treatments. This open-label, single-arm, multicenter study was conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of ibrutinib in Japanese patients ≥12 years of age with steroid-dependent/refractory cGVHD (NCT03474679). Patients were assessed on the basis of the National Institutes of Health (NIH) Consensus Development Project Criteria for Clinical Trials in cGVHD (2014). All patients received ibrutinib at a dose of 420 mg orally once daily, with a dose reduction to 280 mg/d on the concomitant use of voriconazole. Nineteen patients, including 1 adolescent, were enrolled and treated with ibrutinib in the study. At the time of clinical data cutoff (when the last patient completed the efficacy assessment at week 37), 10 of 19 patients (52.6%) remained on treatment whereas 9 of 19 patients (47.4%) had discontinued ibrutinib. The median duration of ibrutinib treatment was 9.63 (range 0.6 to 16.7+) months. The best overall response rate was 73.7%, and the rate of sustained response for ≥20 weeks was 71.4% for the responders (52.6% of all patients). Responses were seen across all the involved organs for cGVHD. Median daily corticosteroid dose requirement decreased by 0.06 mg/kg/d from baseline to week 36, whereas an improvement in the Lee cGVHD Symptom Scale score was observed in 42.1% of patients. The most common treatment-emergent adverse events (TEAEs) were pneumonia and stomatitis (36.8% each), upper respiratory tract infection (31.6%), cellulitis and platelet count decreased (26.3% each), and nausea (21.1%). Furthermore, 11 of 19 patients (57.9%) were reported with ≥1 treatment-emergent serious adverse events; the most common being pneumonia (26.3%) and cellulitis (15.8%). In total, 4 of 19 patients (21.1%) died during the study, of which 3 of 19 patients (15.8%) had TEAEs leading to death whereas 1 patient died of peritonitis, which occurred >30 days after the last dose of ibrutinib. Treatment-emergent adverse events leading to ibrutinib discontinuation were reported in 3 of 19 patients (15.8%). Ibrutinib was rapidly absorbed with a median time to reach maximum plasma concentration (t) of ~4.0 hours. Steady-state exposures were ~3.0- and ~1.4-fold higher for the patients receiving fluconazole (n = 8) and voriconazole (n = 4) with ibrutinib, respectively, as compared with patients not receiving CYP3A inhibitors (n = 7). Mean Bruton's tyrosine kinase occupancy was 88.1% at 4 hours after dose on day 1, and occupancy levels were maintained throughout the assessment period, regardless of the ibrutinib daily dose. Ibrutinib showed a clinically meaningful response and an acceptable safety profile in Japanese patients with steroid-dependent/refractory cGVHD; the safety profile was consistent with the known safety profile of ibrutinib in adults and with that seen in cGVHD patients receiving concomitant steroid treatment. Overall, the results were generally consistent with findings observed in the PCYC-1129-CA study.