Phase I Dose-Finding, Safety, and Tolerability Trial of Romiplostim to Improve Platelet Recovery After UCB Transplantation.

Platelet recovery is delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that has the potential to improve platelet engraftment after UCBT. The purpose of this study was to determine the safety profile and maximum tolerated dose (MTD) of romiplostim and to investigate whether romiplostim accelerates platelet recovery post-UCBT. It was a single-center, dose-finding, safety and tolerability phase I trial of weekly romiplostim in 20 adult patients who failed to achieve an un-transfused platelet count of 20 × 109/L by day +28 post-UCBT. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post-UCBT. Four dose levels (4, 6, 8, and 10 µg/kg per dose) were evaluated. The MTD of romiplostim was determined by the continual reassessment method, with a goal to identify a dose level with desired toxicity rate of ≤20%. Median age of the patients was 59.5 years, and 60% were female. Eleven patients received nonmyeloablative (NMA) double UCBT, seven patients received myeloablative single UCBT, and two patients received NMA single UCBT. Two patients received 4 µg/kg per dose, two received 6 µg/kg per dose, four received 8 µg/kg per dose, and the remaining 12 received 10 µg/kg per dose. Only five patients completed the full six doses of treatment. Of the 15 patients who received fewer than six doses, 12 were due to a platelet count of >100 × 109/L, two were due to platelet count of >400 × 109/L, and one was due to right upper extremity edema without thrombosis. All romiplostim-treated patients achieved platelet engraftment to 20 × 109/L at a median of 45 days post-UCBT compared to 90% of controls at a median of 45 days (P = .08). Similarly, 90% of romiplostim-treated patients achieved platelet engraftment to 50 × 109/L at a median of 48 days compared to 75% of controls at a median of 52 days (P = .09). All dose levels were effective with low toxicity; therefore, the MTD of romiplostim was 10 µg/kg per dose, and romiplostim is a safe and potentially effective therapy to counter delayed platelet recovery post-UCBT.

A phase I dose finding study of intravenous voriconazole in pediatric patients undergoing hematopoietic cell transplantation.

To optimize voriconazole dosing in pediatric hematopoietic cell transplantation (HCT), we conducted a phase I study with a modified 3 + 3 dose-escalation followed by an expansion cohort at the maximum tolerated, minimum efficacious dose (MTD/MED). Patients ≤21 years who required voriconazole for prevention or treatment of an invasive fungal infection were assigned to three age groups. Of the 59 evaluable patients, 13 were <2 years, 23 were 2-11, and 23 were 12-21. Therapeutic serum voriconazole troughs (1.5-5 µg/mL) drawn at 7 days after initiation determined efficacy. The MTD/MED was 12 mg/kg/dose q12 h × 2 loading doses, then 10 mg/kg/dose q12 h in patients <2, and was 10 mg/kg/dose q12 h in patients 2-11. The 12-21 age group had no dose-limiting toxicity at 8 mg/kg/dose q12 h; however, the MED was not reached. Drug-related AEs ≥grade 3 included increased bilirubin, transaminases, and creatinine, all occurring in <10%. There was no significant association between supra-therapeutic troughs and AEs. Five of 17 patients who had supra-therapeutic troughs (29%) had an AE, compared to 8 of 42 who did not (19%, p = 0.38). Observational population pharmacokinetic analysis demonstrated that inter-individual variability on voriconazole clearance was >100% CV, and clearance increased with age.