Ibrutinib treatment for pediatric chronic graft versus host disease: A prospective phase 1/2 study

Abstract

Background: Pediatric chronic graft-versus-host disease (cGVHD) is a debilitating, life-threatening complication of allogeneic stem cell transplantation for which there is currently no approved therapy. In the US, the only therapy approved for adult patients with cGVHD after failure of ≥1 line of systemic therapy is ibrutinib, a once-daily oral Bruton's tyrosine kinase inhibitor. Previous studies have demonstrated that ibrutinib results in durable responses and improved quality of life for adults. Aims: To evaluate the PK, safety, and efficacy of ibrutinib in children with cGVHD in an open-label, multicenter, international phase 1/2 study (PCYC-1146; NCT03790332). Methods: Eligibility criteria included patients with refractory (≥1 to < 22 years) or new-onset (≥12 to < 22 years) moderate/severe cGVHD (stringently defined by 2014 NIH criteria); written informed consent or parental/guardian permission and assent of child capable of understanding the nature of the study were obtained. Patients aged < 12 years received once-daily ibrutinib 120mg/m2 (50% adult dose), which was escalated to 240mg/m2 (100% adult dose) if ibrutinib-related grade ≥3 toxicity did not occur within 14 days of therapy. Patients ≥12 years received once-daily ibrutinib 420mg. Treatment was discontinued upon initiation of a new systemic cGVHD therapy, cGVHD progression, underlying disease recurrence, unacceptable toxicity, or if therapy was no longer required. Preliminary PK, safety, and response assessment (per 2014 NIH criteria) are presented. Results: Fifteen children (median age, 11 years; range, 3-17) with a median 3 prior cGVHD regimens (range, 1-5) were enrolled. Preliminary assessment of ibrutinib (240mg/m2) plasma concentration-time profiles were consistent with those observed in adult cGVHD. Grade 3 serious AEs occurred in 4 (27%) patients. Invasive fungal disease was not observed; one patient experienced a grade 3 pneumocystis jirovecii pneumonia. Median follow-up was 1.9 months (range, 0.5-7.1); the best overall response rate (ORR) was 46% (6/13; 1 [8%] complete response [CR]; 5 [38%] partial response [PR]; 6 [46%] stable disease [SD]; 1 [8%] not evaluable [NE]). No patients had progressive disease. Among patients with sufficient follow-up data at week 5 (n = 13), ORR was 38% (5/13; 5 [38%] PR; 7 [54%] SD; 1 [8%] NE). ORR at week 13 was 50% (3/6; 1 [17%] CR; 2 [33%] PR; 3 [50%] SD). At time of this analysis, 12 patients are continuing on ibrutinib treatment (median duration, 1.9 months); the 3 discontinuations were not related to NIH-defined progression or AEs. Summary/Conclusion: The ibrutinib dosing regimen used in this preliminary analysis of heavily pretreated children with moderate/severe cGVHD achieved plasma concentration-time profiles consistent with those observed in adults with cGVHD. The safety profile was consistent with known risks; discontinuations due to PD did not occur. Ibrutinib treatment resulted in a best ORR of 46% at this early timepoint, based on strict application of 2014 NIH criteria. These findings demonstrate promising activity of ibrutinib in children resistant to multiple lines of prior therapy. Enrollment is ongoing and longer follow-up times are expected.L6324463522020-07-31 <br />