FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2892036979> ?p ?o ?g. }

• W2892036979 endingPage "627" @default.
• W2892036979 startingPage "623" @default.
• W2892036979 abstract "Acute leukaemias comprise approximately 32% of all childhood cancers (National Cancer Institute, 2018). Up to 20% of paediatric patients with acute myeloid leukaemia (AML) have mutations in FLT3, conferring a poor prognosis (Balgobind et al, 2011; Zwaan et al, 2015). Approximately 80% of infants with acute lymphoblastic leukaemia (ALL) have gene rearrangements in KMT2A (KMT2A-R ALL), often in combination with overexpression of mutation-negative FLT3 (Stam et al, 2007). This combination of KMT2A-R ALL and FLT3 overexpression is associated with particularly poor long-term outcomes (Stam et al, 2007; Chillon et al, 2012). Preclinical and clinical work suggests that targeted inhibition of FLT3 may be a promising strategy for paediatric acute leukaemias (Annesley & Brown, 2014). Midostaurin (PKC412), a multikinase inhibitor with targets that include FLT3, was approved in adults with newly diagnosed FLT3-mutated AML (Stone et al, 2017). Midostaurin has demonstrated antileukaemic activity in preclinical models of FLT3-mutated AML and FLT3-overexpressing KMT2A-R ALL (Weisberg et al, 2002; Armstrong et al, 2003). This dose-escalation and dose-expansion study evaluated the safety and efficacy of single-agent midostaurin in paediatric patients with relapsed or refractory (R/R) FLT3-mutated AML or KMT2A-R ALL (NCT00866281). Patients had documented diagnosis of FLT3-mutated AML or KMT2A-R ALL according to local laboratory assessment. FLT3 mutations were confirmed at a central laboratory but were not required for inclusion of patients with KMT2A-R ALL. The primary objective was to determine the maximum tolerated dose (MTD) or recommended dose for expansion (RDE) of oral midostaurin solution, developed for paediatric use, in each age group using a single 3-parameter Bayesian logistic regression model (Appendix S1). A dose-limiting toxicity (DLT) was defined as a nonhaematological grade 3/4 adverse event (AE), drug-related abnormal laboratory value, or AE leading to study discontinuation within 14 days of starting treatment occurring in the dose-determining set. Midostaurin was administered to children in 2 age groups: younger (≥3 months to ≤2 years) and older (>2 years to ≤18 years) (Figure S1). From September 2009 to October 2014, 22 patients were enrolled (9 FLT3-mutant AML, 13 KMT2A-R ALL). The study was terminated early due to slow accrual (Appendix S1). Baseline characteristics are presented in Table 1 and Table SI. All 9 patients with AML were in the older age group. Of 13 patients with KMT2A-R ALL, 11 were younger and 2 older. According to the central laboratory analysis of FLT3-mutation status, not all patients with AML had a FLT3 mutation (6 FLT3-internal tandem duplication, 1 FLT3-mutation–negative [FLT3-mut−], and 2 missing/nonevaluable) and only 1 patient with KMT2A-R ALL had a FLT3 mutation (FLT3-tyrosine kinase domain; 11 FLT3-mut−; 1 missing/nonevaluable) (Table SII). Potential reasons for discrepancy between the local and central laboratory analyses are discussed in the Supplementary Appendix. High levels of phosphorylated FLT3 were not detected in any patient sample (AML or KMT2A-R ALL) at baseline (Table SIII). Of 22 patients, 7 (3 with FLT3-mutated AML and 4 with KMT2A-R ALL per local assessment) received the starting dose (30 mg/m2 twice daily [bid]) and 15 (6 with FLT3-mutated AML and 9 with KMT2A-R ALL per local assessment) received the maximum dose (60 mg/m2 bid). All patients discontinued treatment (Figure S2). No DLTs or significant safety concerns were observed among the 6 patients who received the 30 mg/m2 bid dose; therefore, dose escalation proceeded to 60 mg/m2 bid. Among 11 patients in the dose-determining set who received the 60 mg/m2 bid dose, a DLT was reported in 1 patient (grade 3 alanine aminotransferase elevation). One patient with FLT3-mutated AML in the 60 mg/m2 bid cohort completed the per-protocol follow-up; the remaining 21 patients died. Median duration of exposure to midostaurin for all patients was 16 days. Because the study design did not allow dosing beyond 60 mg/m2 bid, a true MTD could not be determined and the 60 mg/m2 bid dose was chosen as the RDE (Table SIV). Most patients (95·5%) experienced ≥1 AE on treatment or during the 28-day follow-up period (Table SV). Overall, 77·3% of patients experienced grade 3/4 AEs, with more AEs occurring in the 60 mg/m2 cohort than in the 30 mg/m2 cohort. AEs suspected to be study treatment–related were reported in 72·7% of patients. Efficacy was evaluated in all 22 patients. The rate of best clinical response (assessed per modified Cheson criteria; Appendix S1) to single-agent midostaurin was 55·5% (95% confidence interval [CI], 21·2–86·3%) and 23·1% (95% CI, 5·0–53·8%) in paediatric patients with R/R FLT3-mutated AML and KMT2A-R ALL, respectively (Fig 1). One patient with FLT3-mutated AML achieved a complete remission with incomplete count recovery on day 14; she discontinued midostaurin therapy on day 64 but remained in remission until her last response assessment (day 67), received a haematopoietic stem cell transplant (day 76), and was alive on day 960. In patients with FLT3-mutated AML and KMT2A-R ALL, median time to response was 14 (range, 8–22) days and 8 (range, 3–8 ) days, respectively; median overall survival (95% CI) was 3·7 (2·7–8·3) months and 1·4 (1·0–2·9) months, respectively (Figure S3). This study was the first to evaluate the safety, efficacy, and pharmacokinetics (Appendix S1) of oral midostaurin solution in children. The RDE was set at 60 mg/m2 bid for the 2 age groups. Single-agent midostaurin showed limited clinical activity in these children with heavily pretreated FLT3-mutated AML or KMT2A-R ALL. Despite preclinical data suggesting that midostaurin sensitivity in infant KMT2A-R ALL overexpressing FLT3 was similar to that in FLT3-mutated AML (Stam et al, 2007), single-agent midostaurin showed no clinical activity in children with R/R KMT2A-R ALL, possibly because overexpression of FLT3 alone is not sufficient to drive the disease or because FLT3 was not inhibited enough at the doses tested to elicit responses. Future studies should aim to understand the kinetics of FLT3 mutations between diagnosis and relapse, as they present an important prognostic factor for patients with AML. The unmet need in paediatric patients with R/R FLT3-mutant AML or KMT2A-R ALL is high. Because midostaurin plus chemotherapy demonstrated clinical benefit in adults with FLT3-mutated AML and single-agent midostaurin was generally well tolerated in paediatric patients, midostaurin will be evaluated in combination with chemotherapy in paediatric patients with FLT3-mutated AML. This study was supported by funding from Novartis Pharmaceuticals Corporation. We thank the patients enrolled in this trial and their families for their participation. We also acknowledge all of the investigators at the study sites that participated in the trial: Erasmus MC–Sophia Children's Hospital, Rotterdam, the Netherlands; Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Hôpital Universitaire Robert-Debré, Paris, France; IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy; Fondazione MBBM, Azienda Ospedaliera San Gerardo, Monza, Italy; Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, A.O.U. Città della Salute e della Scienza di Torino, Ospedale Infantile Regina Margherita, Torino, Italy; Seattle Children's Hospital, Seattle, WA; Haematology Unit, IRCCS Instituto Giannina Gaslini, Genova, Italy; and Princess Máxima Centre for Paediatric Oncology, Utrecht, the Netherlands. We would also like to thank Katherine Mills-Luján, PhD, CMPP, Amarallys Cintron, PhD, and Pamela Tuttle, PhD, CMPP, of ArticulateScience LLC for medical editorial assistance with this manuscript, which was funded by Novartis Pharmaceuticals Corporation. This study was designed by the sponsor, Novartis Pharmaceuticals Corporation, and the study steering committee, CMZ, ML, and RP. CMZ, SS, BB, ML, CR, RWS, FF, PAH, C Dufour and RP enrolled patients. EB oversaw the conduct of the study. C Dutreix performed the pharmacokinetic analyses. Data were collected and analysed by the sponsor in conjunction with the authors, who had full access to the data. CMZ and RP wrote the manuscript, with medical writing support from ArticulateScience LLC. All authors contributed to draft revisions and approved the final version of the manuscript. CMZ is a consultant for and has received funding from Novartis Pharmaceuticals Corporation. C Dufour is a consultant for Pfizer and has participated in advisory committees for Novartis Pharmaceuticals Corporation. PAH is a current employee of and has equity ownership in Seattle Genetics. EB and C Dutreix are current or former employees of Novartis Pharmaceuticals Corporation. SS, BB, ML, CR, RWS, FF and RP have no competing interests. Medical editorial assistance with this manuscript was funded by Novartis Pharmaceuticals Corporation. Appendix S1. Supplementary Methods; Supplementary Results; Supplementary Discussion Table SI. Expanded Patient Baseline Characteristics Table SII.FLT3 Mutation Status per Central Laboratory Assessment Table SIII. FLT3 Expression and Phosphorylation Analysis Table SIV. Posterior Probabilities of Dose-Limiting Toxicity by Age Strata and Dose Table SV. Most Common Adverse Events (occurring in ≥10% of patients) With Single-Agent Midostaurin in Paediatric Patients With Relapsed or Refractory Acute Leukaemia Table SVI. Bioavailability and Safety of Midostaurin Oral Solution and Capsule Formulations in Healthy Volunteers in Study A2108 Table SVII. Modified Cheson Criteria for Response Fig S1. Trial Design Fig S2. Patient Disposition Fig S3. Overall Survival Fig S4. Pharmacokinetics of Midostaurin and Its Metabolites Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
• W2892036979 created "2018-09-27" @default.
• W2892036979 creator A5002362786 @default.
• W2892036979 creator A5005516784 @default.
• W2892036979 creator A5026261845 @default.
• W2892036979 creator A5033311808 @default.
• W2892036979 creator A5035292815 @default.
• W2892036979 creator A5057678079 @default.
• W2892036979 creator A5062398478 @default.
• W2892036979 creator A5064026375 @default.
• W2892036979 creator A5073707704 @default.
• W2892036979 creator A5078527916 @default.
• W2892036979 creator A5079129042 @default.
• W2892036979 creator A5088211725 @default.
• W2892036979 date "2018-09-11" @default.
• W2892036979 modified "2023-10-04" @default.
• W2892036979 title "A phase 1/2, open‐label, dose‐escalation study of midostaurin in children with relapsed or refractory acute leukaemia" @default.
• W2892036979 cites W1975136907 @default.
• W2892036979 cites W1981709629 @default.
• W2892036979 cites W1983999811 @default.
• W2892036979 cites W2033397751 @default.
• W2892036979 cites W2131292832 @default.
• W2892036979 cites W2132693111 @default.
• W2892036979 cites W2170202162 @default.
• W2892036979 cites W2715749014 @default.
• W2892036979 doi "https://doi.org/10.1111/bjh.15593" @default.
• W2892036979 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30203832" @default.
• W2892036979 hasPublicationYear "2018" @default.
• W2892036979 type Work @default.
• W2892036979 sameAs 2892036979 @default.
• W2892036979 citedByCount "21" @default.
• W2892036979 countsByYear W28920369792019 @default.
• W2892036979 countsByYear W28920369792020 @default.
• W2892036979 countsByYear W28920369792021 @default.
• W2892036979 countsByYear W28920369792022 @default.
• W2892036979 countsByYear W28920369792023 @default.
• W2892036979 crossrefType "journal-article" @default.
• W2892036979 hasAuthorship W2892036979A5002362786 @default.
• W2892036979 hasAuthorship W2892036979A5005516784 @default.
• W2892036979 hasAuthorship W2892036979A5026261845 @default.
• W2892036979 hasAuthorship W2892036979A5033311808 @default.
• W2892036979 hasAuthorship W2892036979A5035292815 @default.
• W2892036979 hasAuthorship W2892036979A5057678079 @default.
• W2892036979 hasAuthorship W2892036979A5062398478 @default.
• W2892036979 hasAuthorship W2892036979A5064026375 @default.
• W2892036979 hasAuthorship W2892036979A5073707704 @default.
• W2892036979 hasAuthorship W2892036979A5078527916 @default.
• W2892036979 hasAuthorship W2892036979A5079129042 @default.
• W2892036979 hasAuthorship W2892036979A5088211725 @default.
• W2892036979 hasBestOaLocation W28920369791 @default.
• W2892036979 hasConcept C121332964 @default.
• W2892036979 hasConcept C126322002 @default.
• W2892036979 hasConcept C142424586 @default.
• W2892036979 hasConcept C143998085 @default.
• W2892036979 hasConcept C3019800554 @default.
• W2892036979 hasConcept C535046627 @default.
• W2892036979 hasConcept C71924100 @default.
• W2892036979 hasConcept C87355193 @default.
• W2892036979 hasConceptScore W2892036979C121332964 @default.
• W2892036979 hasConceptScore W2892036979C126322002 @default.
• W2892036979 hasConceptScore W2892036979C142424586 @default.
• W2892036979 hasConceptScore W2892036979C143998085 @default.
• W2892036979 hasConceptScore W2892036979C3019800554 @default.
• W2892036979 hasConceptScore W2892036979C535046627 @default.
• W2892036979 hasConceptScore W2892036979C71924100 @default.
• W2892036979 hasConceptScore W2892036979C87355193 @default.
• W2892036979 hasFunder F4320310388 @default.
• W2892036979 hasIssue "3" @default.
• W2892036979 hasLocation W28920369791 @default.
• W2892036979 hasLocation W28920369792 @default.
• W2892036979 hasLocation W28920369793 @default.
• W2892036979 hasOpenAccess W2892036979 @default.
• W2892036979 hasPrimaryLocation W28920369791 @default.
• W2892036979 hasRelatedWork W2068316626 @default.
• W2892036979 hasRelatedWork W2110818089 @default.
• W2892036979 hasRelatedWork W2351796763 @default.
• W2892036979 hasRelatedWork W2351985199 @default.
• W2892036979 hasRelatedWork W2403502999 @default.
• W2892036979 hasRelatedWork W2567738959 @default.
• W2892036979 hasRelatedWork W2789412726 @default.
• W2892036979 hasRelatedWork W2923882796 @default.
• W2892036979 hasRelatedWork W4297834875 @default.
• W2892036979 hasRelatedWork W4366141624 @default.
• W2892036979 hasVolume "185" @default.
• W2892036979 isParatext "false" @default.
• W2892036979 isRetracted "false" @default.
• W2892036979 magId "2892036979" @default.
• W2892036979 workType "article" @default.