Trial in Progress: A Multicenter, Open-Label, Phase Ib/II Study to Determine the Dose and Safety of Asciminib in Pediatric Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Treated with ≥1 Prior Tyrosine Kinase Inhibitor

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). In adults, 5 TKIs are approved: imatinib, dasatinib, nilotinib, bosutinib and ponatinib. In the pediatric population, however, only imatinib, dasatinib and nilotinib are approved. Pediatric pts have similar cytogenetic and molecular response rates to first-line (1L) imatinib and 1L second-generation TKIs nilotinib and dasatinib as adults. While the safety profiles for TKIs are similar in adult and pediatric pts, growth retardation has been reported specifically in the pediatric population. Therefore, safer and more efficacious options are needed for pediatric pts. Asciminib is an investigational drug that inhibits BCR-ABL1 by specifically targeting the ABL myristoyl pocket (STAMP inhibitor). Asciminib has shown promising efficacy and safety in adults with CML-CP in phase I-III trials, given without food for 1 hour prior and 2 hours after taking asciminib (fasted). In the phase I asciminib monotherapy trial in heavily pretreated adult pts, 48% and 28% without and with T315I mutations, respectively, achieved or maintained major molecular response (MMR) by 12 months. In the phase III ASCEMBL trial for adults with CML-CP who are resistant to or intolerant of ≥2 TKIs, 25.5% of pts on asciminib vs 13.2% of pts on bosutinib achieved MMR at 24 weeks. Here we present the phase Ib/II trial evaluating asciminib monotherapy in pediatric pts. OBJECTIVE: The primary objectives of this study are to characterize the pharmacokinetic (PK) profile of asciminib in pediatric pts and identify a pediatric formulation dose (taken with food) leading to an asciminib exposure comparable to that of 40 mg twice daily (BID) in adult pts (fasted). DESIGN: This is a multicenter, open-label, phase Ib/II study (NCT04925479, Figure 1). Eligible pts have Philadelphia chromosome-positive CML-CP resistant to or intolerant of ≥1 prior TKI, do not bear T315I mutations and are aged ≥1 to <18 years. Adolescent pts aged ≥14 to <18 years and weighing ≥40 kg will be enrolled in the exploratory adult formulation group, receiving 40 mg asciminib BID in the fasted state until the pediatric formulation is available. There is no prespecified sample size for this group. In part 1 (dose-determining cohort), 4 to 6 pts aged ≥1 to <18 years will receive the pediatric formulation (body weight-adjusted dose of asciminib minitablets taken with food) to obtain ≥4 participants evaluable for PK data. This evaluation will determine whether median exposure in pediatric pts is comparable to that of asciminib 40 mg BID in adult pts (fasted). Dose adjustments will be made if the minimum exposure is less than that of 20 mg BID in adults or higher than double the maximum exposure in adults at 40 mg BID. During the first 28 days after treatment initiation, safety will be assessed based on predefined dose-limiting toxicities. In part 2 (expansion cohort), the body weight-adjusted dosing determined in part 1 will be used, and the total pts enrolled on pediatric formulation will be increased to 30, including those from part 1 (15 pts aged 1 to <12 years and 15 pts aged 12 to <18 years). Pts receiving the adult formulation will have the opportunity to switch to the pediatric formulation in part 2 but will not be counted toward the 30 pts enrolled in part 2. A second interim PK and safety analysis will be conducted after all pts in part 2 have completed 28 days of treatment (Figure 2). The total duration of the study treatment period is 5 years. The primary analysis (primary PK endpoints, safety, and pharmacodynamics) will be assessed after all pts have been on study for 52 weeks or discontinued earlier. A final analysis will be completed after all pts have been on study for 5 years or discontinued earlier. Pts who discontinue the study early will be followed up for survival until the study is complete. MAIN OUTCOMES MEASURES: The primary endpoints include PK parameters. Secondary endpoints include treatment-associated AEs, hematologic and molecular responses, and acceptability and palatability of asciminib (Table 1). CONCLUSIONS: Data from this study will be used to support a strategy of full extrapolation from adult data to use in the pediatric setting. This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Hijiya: Novartis: Consultancy; Stemline Therapeutics: Consultancy. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Descamps: Novartis: Current Employment. Bayar: Novartis: Current Employment. Ramscar: Novartis: Current Employment.

Chapter 14: Prevention: vaccines and immunoglobulins

Worldwide there are 6 different TBE vaccines – two from Western Europe, three from Russia and one from China. The two western European vaccines and one of the Russian vaccines have an adult and a pediatric formulation. The products names are FSME IMMUN and FSME-IMMUN Junior; Encepur adults and Encepur children, Klesch-E-Vac, EnceVir and EnceVir Neo, Dry lyophilized TBE Moscow and Sen Tai Bao. All TBE vaccines except the one from China have similar but not identical immunization schedules with primary immunization (>3 doses) and regular booster vaccinations. For FSME-IMMUN, Encepur and EnceVir rapid immunization schedules are also licensed. The Chinese vaccine is given with 2 primary doses 2 weeks apart followed by annual boosters. All vaccines induce significant immune responses. In the absence of a formal correlate of protection, the presence of neutralizing antibodies is used as a surrogate marker for protection. Recent clinical studies show long-term seropersistence of TBE antibodies after the first booster vaccination (dose 4) with the two European vaccines. An effectiveness of approximately 99% (years 2000–2006) and 98.7% (years 2000-2011) was calculated for regularly vaccinated persons in Austria, a country with established high vaccination uptake. Whereas in Western Europe post-exposure prophylaxis with immunoglobulins was discontinued in the late 1990s, in the highly endemic regions of Russia it continues to be common practice. Both – FSME-IMMUN and Encepur are well tolerated with a well-established safety profile. TBE-Moscow and EnceVir appear to be somewhat more reactogenic.

Polymeric and Lipid Nanoparticles: Which Applications in Pediatrics?

This review aims to provide the state of the art on polymeric and lipid nanoparticles, used or suggested to approach pediatric diseases’ problems and needs, and to inspire new researches in this field. Several drugs are currently not available in formulations suitable for pediatric patients. The United States Pediatric Formulation Initiative suggested applying new technologies to pediatric drug formulations, for instance, nanotechnology. The literature analysis showed that polymeric and lipid nanoparticles have been widely studied to treat pediatric diseases, and albumin nanoparticles and liposomes are already used in clinical practice. Nevertheless, these studies are focused almost exclusively on pediatric cancer treatment. Although nanomedicine may solve many needs of pediatric diseases and medicines, the unavailability of data on pharmacokinetics, safety and efficacy of both drugs and nanoparticles in pediatric patients limits the development of new pediatric medicines based on nanoparticles. Therefore, nanomedicine applied in pediatrics remains a significant challenge in the near future.

Chapter 14: Prevention: vaccines and immunoglobulins

Worldwide there are 6 different TBE vaccines – two from Western Europe, three from Russia and one from China. The two western European vaccines and one of the Russian vaccines have an adult and a pediatric formulation. The products names are FSME IMMUN and FSME-IMMUN Junior; Encepur adults and Encepur children, Klesch-E-Vac, EnceVir and EnceVir Neo, Dry lyophilized TBE Moscow and Sen Tai Bao All TBE vaccines except the one from China have similar but not identical immunization schedules with primary immunization (>3 doses) and regular booster vaccinations. For FSME-IMMUN, Encepur and EnceVir rapid immunization schedules are also licensed. The Chinese vaccine is given with 2 primary doses 2 weeks apart followed by annual boosters. All vaccines induce significant immune responses. In the absence of a formal correlate of protection, the presence of neutralizing antibodies is used as a surrogate marker for protection. Recent clinical studies show long-term seropersistence of TBE antibodies after the first booster vaccination (dose 4) with the two European vaccines. An effectiveness of approximately 99% (years 2000–2006) and 98.7% (years 2000-2011) was calculated for regularly vaccinated persons in Austria, a country with established high vaccination uptake. Whereas in Western Europe post-exposure prophylaxis with immunoglobulins was discontinued in the late 1990s, in the highly endemic regions of Russia it continues to be common practice. Both – FSME-IMMUN and Encepur are well tolerated with a well-established safety profile. TBE-Moscow and EnceVir appear to be somewhat more reactogenic.

Peanut butter–based formulations of amoxicillin for pediatric applications

Background Child mortality is a major global health challenge, especially in regions of limited resources. Accessibility to lifesaving medicine and adequate nutrition is essential to reduce child mortality and improve the health and well-being of the world’s most vulnerable children. Methods We have developed NutMox, a novel pediatric formulation of the β-lactam antibiotic amoxicillin in a matrix of peanut-based ready-to-use therapeutic food (RUTF) consisting of peanut butter, sugar, vegetable oil, dry milk and vitamins. NutMox is ready to use and thermostable, requires no chewing or pill swallowing and provides both an antibiotic and nutrition. Results Amoxicillin in NutMox formulations was stable for at least 12 months at storage temperatures of 4°C, 25°C and 37°C. Amoxicillin formulated in NutMox displayed similar pharmacokinetics in mice to that in suspension. Conclusions Our results demonstrated the feasibility of a peanut butter–based matrix for pediatric formulations of amoxicillin, suggesting that such a matrix can serve as a base for delivering medications in addition to its current use as an RUTF.

P55 Preventing inappropriate hydroxyurea dosing in children by introducing a child-appropriate preparation

BackgroundHydroxyurea (HU) is the only FDA- approved disease- modifying drug for sickle cell disease, by inducing the production of fetal hemoglobin and thus decreasing the sickling of red blood cells. Till recently HU was available only in adult doses of 1000 mg. This meant that to aim at the standard dose of 20 mg/kg/d, most young children had to be overdosed, or the dose had to be fluctuated daily to achieve the aimed mean dose. Because adherence improves with unchanged daily dose, and due to the more than 10 fold variability in HU pharmacokinetics in children, there was an urgent need for a pediatric formulation of HU.Methods and resultsThis issue has been solved with the FDA approval of the French-originated orphan HU, Siklos, a preparation of 50 and 100 mg, which prevents the risk of inappropriate dosing in children.Studies show that the child appropriate dose preparation much more closely allow young children to receive appropriate dose of Hydroxyurea, and increase adherence with this critical drug.ConclusionsIn summary, FDA approval of the French-originated orphan HU, Siklos in preparations of 50, 100 mg, prevents the risk of inappropriate dosing of the drug in children. This should encourage all involved in pediatric medicine, from health care physicians and pharmacists, to the pharmaceutical industry and regulators to act similarly in other therapeutic areas where inappropriate pediatric dose schedules are endangering the health and wellbeing of children.Disclosure(s)G Koren has been a consultant for Medunik USA.