Background: Severe aplastic anemia (SAA) is a rare, life-threatening disease characterized by pancytopenia and hypocellular bone marrow (BM). Immunosuppressive therapy (IST) is the standard of care for pediatric patients (pts) who lack a matched sibling donor. Approximately one-third of pts do not respond to IST or relapse following treatment. Therefore, effective and well-tolerated therapies are needed to improve outcomes of IST in pediatric pts with untreated or refractory/relapsed SAA. Aims: ESCALATE (CETB115E2201; NCT03025698) is a multi-institutional Phase II dose-escalation study to evaluate the pharmacokinetics (PK), safety, efficacy, and acceptability of the thrombopoietin receptor agonist eltrombopag (ETB) in pediatric pts who have refractory/relapsed SAA after IST for SAA (Cohort A) or who have previously untreated SAA (Cohort B). Methods: Patients (1 to <18 years [y] of age) received ETB as tablets or powder for oral suspension. Cohort A pts received ETB with IST (horse antithymocyte globulin [hATG] + cyclosporin A [CsA]) or ETB + CsA, based on investigator choice. Cohort B pts received ETB + hATG + CsA. The ETB starting dose was 50 mg/day (25 mg/day in pts aged <6 y) and was adjusted to achieve a target platelet count of 50-200×109/L. The maximum allowed daily dose was 150 mg. ETB was administered for 26 weeks and initiated together with CsA (duration of ≥104 weeks) +/- hATG (Days 1-4). Study follow-up included an additional 52 weeks during which ETB could be continued (data to Week 52 included here). ETB PK were the primary endpoint; secondary endpoints included safety/tolerability, overall response rate (ORR), BM cellularity, morphology, cytogenetics, paroxysmal nocturnal hemoglobinuria (PNH) clonal evolution, and acceptability/palatability (full data to be presented). ORR was defined as the proportion of pts with a complete (CR) or partial (PR) response (see Table 1 footnote). Results: Fifty-one pts (14 in Cohort A, 37 in Cohort B) were enrolled. The ORRs at Week 26 were 71% (95% CI 42-92) and 46% (30-63), respectively, for Cohorts A and B, and 57% (95% CI 29-82) and 51% (34-68) at Week 52 (Table 1). The most common ETB/hATG/CsA-related adverse events (AEs) (>20%) over the study period were increased bilirubin (43%), increased ALT (41%), increased creatinine (39%), increased AST (33%), hypertension (31%), hypomagnesemia (26%), and increased blood urea (24%). The most common serious AE was pyrexia (29%). Twenty-six pts discontinued ETB treatment, including 11 pts due to physician decision, 7 pts due to AEs (increased ALT/AST/blood bilirubin), 4 pts due to pt/guardian decision, 3 pts no longer requiring treatment, and 1 pt due to progressive disease. Two pts had BM chromosomal abnormalities post baseline (1 with 47XY+Y[2]/46XY[18] at Week 26 [normal at baseline and at Weeks 12 and 52]; 1 with 46,XY,t(2,3)(p23,q12)[2]/46,XY[18] at Week 182 [normal at baseline]). One pt evolved to PNH and 1 pt progressed to acute myeloid leukemia. Most pts reached the maximum daily dose of 150 mg regardless of age. The median dose intensity was 116.6 mg/day in pts aged <6 y and 94.8 mg/day in those aged 6 to <18 y. In pts who maintained the highest dose achieved for ≥14 days, the geometric mean (CV%) AUCtau was μg⋅h/mL (43%, n=8) and 733 μg⋅h/mL (63%, n=19) for pts aged 1 to <6 y and 6 to <18 y, respectively. Corresponding Cmax values were 71.6 μg/mL (33%, n=9) and 36.2 μg/mL (62%, n=22). Dose-adjusted (to 50 mg) geometric mean AUCtau was 447 μg⋅h/mL (54%, n=8) and 321 μg⋅h/mL (58%, n=19) for pts aged 1 to <6 y and 6 to <18 y, respectively. Corresponding Cmax values were 25.8 μg/mL (46%, n=9) and 16.6 μg/mL (52%, n=22). The higher ETB exposure in younger pts was a consequence of slower clearance: geometric mean CLss/F was 0.112 L/h (54%, n=8) and 0.156 L/h (58%, n=19) for pts aged 1 to <6 y and 6 to <18 y, respectively. This age effect on ETB PK is supported by data in adult SAA pts (dose-adjusted AUCtau and Cmax of 257 μg⋅h/mL and 13.4 μg/mL, respectively). Conclusion: The overall response rate to ETB in pediatric refractory/relapsed SAA pts was encouraging. ETB exposure was higher in pts aged 1 to <6 y than in those aged 6 to <18 y because of the age-related increase in ETB clearance. Despite the higher exposure in the younger pts, the daily dose achieved was generally 150 mg in both the 1 to <6 y and 6 to <18 y groups. The observed AEs reflected the disease itself and the safety profiles of hATG, CsA, and ETB. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal