Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921

Pediatric patients; Intolerant; Chronic myeloid leukemiaPacientes pediátricos; Intolerantes; Leucemia mieloide crónicaPacients pediàtrics; Intolerants; Leucèmia mieloide crònicaPurpose Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. Patients and Methods In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. Results Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 μg h/mL, 2.52 μg h/mL, and 2.66 μg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. Conclusion Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.Sponsorship for the study was provided by Erasmus MC/Sophia Children's Hospital, Department of Pediatrics, Rotterdam, the Netherlands

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921

PURPOSE Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m$^{2}$ once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m$^{2}$, 11 at 350 mg/m$^{2}$ (one DLT), and 10 at 400 mg/m$^{2}$ (one DLT). The mean AUCs at 300 mg/m$^{2}$, 350 mg/m$^{2}$, and 400 mg/m$^{2}$ were 2.20 μg h/mL, 2.52 μg h/mL, and 2.66 μg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m$^{2}$ once daily (max 600 mg/d) with food in R/I patients and 300 mg/m$^{2}$ once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia:Results From the Phase I Part of Study ITCC054/COG AAML1921

PURPOSE Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. Results Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 g h/mL, 2.52 g h/mL, and 2.66 g h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.</p

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia:Results From the Phase I Part of Study ITCC054/COG AAML1921

PURPOSE Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. Results Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 g h/mL, 2.52 g h/mL, and 2.66 g h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.</p

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921

PURPOSE Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. Results Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 g h/mL, 2.52 g h/mL, and 2.66 g h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience

Farmacocinetica clinica di daptomicina nel paziente con gravi infezioni

Negli ultimi anni, l’incidenza di infezioni sostenute da batteri Gram-positivi ha registrato un significativo incremento; complice anche il sempre maggiore riscontro di ceppi resistenti alle terapie standard. In questo contesto, daptomicina riveste un ruolo fondamentale nel trattamento delle infezioni più gravi ed in modo particolare per quanto riguarda quelle sostenute da Staphylococcus aureus meticillina-resistente (MRSA) ed Enterococcus spp. vancomicina-resistente (VRE). Daptomicina è il capostipite di una nuova classe di composti chimici, noti come lipopeptidi ciclici, dotati di una spiccata attività battericida nei confronti della maggior parte dei batteri Gram-positivi ed impiegato per il trattamento della infezioni complicate della cute e dei tessuti molli (SSSIs) e della batteriemia ed endocardite delle sezioni destre (RIE) da MRSA e VRE. L’azione antibatterica di daptomicina risulta essere concentrazione-dipendente e pertanto predetta dal rapporto tra area sotto la curva concentrazione-tempo (AUC) e minima concentrazione inibente (MIC). Tuttavia, è da sottolineare come la cinetica di daptomicina sia comunque soggetta a variazioni individuali non trascurabili, e che gli studi condotti in popolazioni di pazienti con sepsi, sepsi grave e shock settico sono caratterizzati da altrettanto ampia variabilità individuale in termini di clearance (Cl) del farmaco e volume di distribuzione (Vd). Il presente studio si propone di investigare, attraverso un protocollo di monitoraggio terapeutico ed analisi statistica, la farmacocinetica di daptomicina nella specifica popolazione di pazienti con infezioni gravi sostenute da Gram-positivi, definendo un modello farmacocinetico in grado di spiegare e prevedere la variabilità interindividuale dei processi di assorbimento, distribuzione, metabolismo ed escrezione di daptomicina. Nel periodo dal 2014 ad oggi, 186 pazienti, provenienti da diverse Unità Operative dell’Azienda Ospedaliera Universitaria Pisana, sono stati arruolati nel presente studio, andando ad ampliare il precedente database contenente dati ottenuti da 58 pazienti. La presente analisi è stata condotta all’interno del protocollo di studio DAPTOLIN (protocollo no. 55945), valutato positivamente dal Comitato Etico dell’Azienda Ospedaliero Universitaria Pisana in data 24/09/2009. Il protocollo di monitoraggio terapeutico (TDM) è consistito nel prelevare un campione di sangue venoso periferico a 0.5, 1.0 e 23.5 ore dall’inizio dell’infusione di daptomicina in 30 minuti, somministrata a dosaggi tra 4 mg/kg e 12 mg/Kg. I campioni sono stati analizzati con la cromatografia liquida ad alte prestazioni, ottenendo un totale di 449 valori di concentrazione plasmatiche di daptomicina. I dati raccolti per l’elaborazione del modello farmacocinetico di popolazione sono stati analizzati con l’ausilio di NONMEM software v.7.1. La validità del modello, lo screening delle covariate e l’analisi dell’errore residuo sono state eseguite attraverso un controllo grafico e numerico, utilizzando Xpose e PsN software. Il modello farmacocinetico finale è stato un monocompartimentale con cinetica di eliminazione di primo ordine, con clearance stimata di 0.80 ± 0.14 L/h e un volume di distribuzione di 0.19 ± 0.05 L/kg. La clearance della creatinina (ClCr ) è risultata avere un'influenza significativa sulla variabilità della clearance di daptomicina, e la riduzione di ClCr ad di sotto di 30 mL/min (rispetto al valore mediano 80 mL/min) è stata associata ad una riduzione della Cl di daptomicina da 0,80 L/h a 0,73 L/h. Per i 186 pazienti arruolati nello studio, i valori di MIC sono stati considerati pari a 1 µg/ml, in accordo con i dati EUCAST (European Committee on Antimicrobial Susceptibility Testing). Valori di AUC/MIC maggiori di 400 sono stati considerati batteriostatici, mentre valori superiori a 800 sono stati associati ad azione battericida. Il valore medio nella popolazione del parametro AUC/MIC così calcolato è risultato essere 662, soltanto in 2 pazienti è stato inferiore a 400 (241 e 397 rispettivamente), mentre per 31 pazienti è risultato superiore a 800. In conclusione, i pazienti affetti da gravi infezioni Gram-positivi possono presentare una alterazione della cinetica di daptomicina, con conseguente raggiungimento di concentrazioni plasmatiche inferiori rispetto a quelle misurate in studi precedenti. Rispetto alla letteratura disponibile, i risultati presentanti in questo studio suggeriscono che parte della variabilità individuale, osservata nella farmacocinetica della daptomicina, potrebbe essere dovuta alla presenza di infezioni gravi. Pertanto, è necessario considerare un aumento della dose giornaliera fino a 8-10 mg/kg (rispetto ai 4-6 mg/kg da scheda tecnica), in funzione della gravità dell'infezione e della condizione clinica del paziente. Il presente modello farmacocinetico può quindi essere applicato in ambito clinico per guidare la terapie con daptomicina in pazienti con infezioni gravi da Gram-positivi

Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial

Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1–18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m2. Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9–93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49–20.07). One year Event Free Survival was 36.7% (95% CI: 22.2–60.4%), and Overall Survival was 55.1% (95% CI: 39.1−77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT