PF412 A PHASE 2 STUDY OF NILOTINIB (NIL) IN PEDIATRIC PATIENTS (PTS) WITH PHILADELPHIA CHROMOSOME–POSITIVE CHRONIC MYELOID LEUKEMIA (CML): SAFETY UPDATE AFTER 36 CYCLES OF TREATMENT

Background: In this ongoing phase 2, open‐label study in pediatric pts with newly‐diagnosed (ND) or imatinib/dasatinib (IMA/DAS) resistant/intolerant (R/I) CML (NCT01077544), oral NIL 230 mg/m 2 BID (rounded to nearest 50 mg; maximum dose 400 mg BID) was efficacious following 12, 28‐day treatment cycles, with no unexpected adverse event (AE) findings so far (Hijiya et al. Pediatr Blood Cancer 2017;64: e26772). Aims: To analyze the safety and tolerability of NIL in pediatric pts based on a longer follow‐up after 36 cycles of treatment. Methods: Eligible pts (1–<18 years) had CML in chronic or accelerated phase (CP/AP) R/I to IMA/DAS, or were ND with CML‐CP. Pts have been on NIL for ≥36 cycles of 28‐day treatment, or have discontinued treatment. Safety and tolerability assessments included incidence and severity of AEs, physical examinations and laboratory tests. Growth and sexual development were also assessed. Results: Fifty‐eight pts (R/I, n = 33; ND, n = 25) were enrolled and received NIL. No pts with CML‐AP enrolled. Median age was 13 years (range: 2–17) in the R/I to IMA/DAS cohort and 13 years (range: 10–16) in the ND cohort. At the data cut‐off (11 April 2018), median duration of exposure to NIL was 33 months (range: 0.5–55) in the R/I to IMA/DAS cohort and 33 months (range: 0.7–54) in the ND cohort. Safety results are shown in the Table . The most frequent all‐grade AEs occurring in the overall pt population were headache (44.8%), pyrexia (37.9%), increased alanine aminotransferase (ALT; 34.5%) and increased blood bilirubin (34.5%). The most common serious AEs were viral gastroenteritis, pyrexia, and viral infection (3.4% each). In total, 13 pts had ≥1 AE that led to treatment discontinuation; the most frequent of these were increased blood bilirubin (n = 3), hyperbilirubinemia (n = 3) and rash (n = 2). Assessment of AEs of special interest (AESIs) ( Table ) showed no clinical cardiovascular events. No grade 3/4 QT prolongation occurred. Grade 1/2 QT prolongation (≤500 msec and no signs/symptoms of arrhythmia) resolved in 9/9 pts; 6/9 pts required dose adjustment, in 2/9 pts the AE was considered serious and in 1 pt the AE was suspected to be related to NIL. Hepatic transaminase and bilirubin elevations were observed in 36 (62.1%) pts. Six pts had concomitant elevation of ALT >3 × ULN and bilirubin >2 × ULN, with alkaline phosphatase ≤2 × ULN. Bilirubin increase was mainly driven by unconjugated bilirubin and was consistent with the UGT1A1 inhibition by NIL. Grade 3/4 AESIs in the R/I to IMA/DAS and ND arms, respectively, included: hepatotoxicity, 24.2% and 24.0%; hepatic transaminase and bilirubin elevations, 21.2% and 24.0%; drug induced liver injury, 3.0% (n = 1, transaminase/bilirubin elevation without signs of severe or progressive liver dysfunction) and 0%; rash, 15.2% and 8.0%; and myelosuppression, 0% and 12.0%. No pt died while on treatment; one pt in the R/I to IMA/DAS cohort died due to disease progression during survival follow‐up. In assessments of growth and development, 7 (12.1%) pts experienced a decrease of two main height percentile lines when last available height was compared with baseline; no trend was seen in assessment of BMI, bone age, bone biomarkers, or sexual maturation. Summary/Conclusion: The safety profile of NIL in this 36‐cycle safety update was consistent with previously reported results and with the known AE profile of NIL in adults treated with 400 mg BID. AEs were manageable with monitoring and dose modification. A trend towards growth deceleration over time was identified, which warrants further observation.