11 results on '"Willekens, Christophe"'
Search Results
2. First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia.
- Author
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Salamero O, Montesinos P, Willekens C, Pérez-Simón JA, Pigneux A, Récher C, Popat R, Carpio C, Molinero C, Mascaró C, Vila J, Arévalo MI, Maes T, Buesa C, Bosch F, and Somervaille TCP
- Subjects
- Adult, Aged, Aged, 80 and over, Enzyme Inhibitors pharmacology, Female, Humans, Male, Middle Aged, Recurrence, Enzyme Inhibitors therapeutic use, Histone Demethylases antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML)., Methods: This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor., Results: Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m
2 /d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2 /d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm., Conclusion: Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).- Published
- 2020
- Full Text
- View/download PDF
3. Impact and consequences of intensive chemotherapy on intestinal barrier and microbiota in acute myeloid leukemia: the role of mucosal strengthening.
- Author
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Hueso T, Ekpe K, Mayeur C, Gatse A, Joncquel-Chevallier Curt M, Gricourt G, Rodriguez C, Burdet C, Ulmann G, Neut C, Amini SE, Lepage P, Raynard B, Willekens C, Micol JB, De Botton S, Yakoub-Agha I, Gottrand F, Desseyn JL, Thomas M, Woerther PL, and Seguy D
- Subjects
- Adult, Aged, Animals, Dysbiosis chemically induced, Dysbiosis microbiology, Fatty Acids, Volatile analysis, Feces chemistry, Feces microbiology, Female, Humans, Induction Chemotherapy adverse effects, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Leukemia, Myeloid, Acute microbiology, Leukemia, Myeloid, Acute pathology, Male, Mice, Mice, Transgenic, Middle Aged, Mucus metabolism, Antineoplastic Combined Chemotherapy Protocols adverse effects, Gastrointestinal Microbiome drug effects, Intestinal Mucosa drug effects, Leukemia, Myeloid, Acute drug therapy
- Abstract
Induction chemotherapy (7 + 3 regimen) remains the gold standard for patients with acute myeloid leukemia (AML) but is responsible for gut damage leading to several complications such as bloodstream infection (BSI). We aimed to investigate the impact of induction chemotherapy on the intestinal barrier of patients with AML and in wild-type mice. Next, we assessed the potential benefit of strengthening the mucosal barrier in transgenic mice releasing a recombinant protein able to reinforce the mucus layer (Tg222). In patients, we observed a decrease of plasma citrulline, which is a marker of the functional enterocyte mass, of short-chain fatty acids and of fecal bacterial load, except for Escherichia coli and Enterococcus spp., which became dominant. Both the α and β-diversities of fecal microbiota decreased. In wild-type mice, citrulline levels decreased under chemotherapy along with an increase of E. coli and Enterococcus spp load associated with concomitant histologic impairment. By comparison with wild-type mice, Tg222 mice, 3 days after completing chemotherapy, had higher citrulline levels, a faster healing epithelium, and preserved α-diversity of their intestinal microbiota. This was associated with reduced bacterial translocations. Our results highlight the intestinal damage and the dysbiosis induced by the 7 + 3 regimen. As a proof of concept, our transgenic model suggests that strengthening the intestinal barrier is a promising approach to limit BSI and improve AML patients' outcome.
- Published
- 2020
- Full Text
- View/download PDF
4. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib.
- Author
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Quek L, David MD, Kennedy A, Metzner M, Amatangelo M, Shih A, Stoilova B, Quivoron C, Heiblig M, Willekens C, Saada V, Alsafadi S, Vijayabaskar MS, Peniket A, Bernard OA, Agresta S, Yen K, MacBeth K, Stein E, Vassiliou GS, Levine R, De Botton S, Thakurta A, Penard-Lacronique V, and Vyas P
- Subjects
- Aminopyridines pharmacology, Cell Differentiation drug effects, Clone Cells, Cohort Studies, Hematopoiesis, Humans, Immunophenotyping, Isocitrate Dehydrogenase metabolism, Mutation genetics, Neoplasm Recurrence, Local pathology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Triazines pharmacology, Aminopyridines therapeutic use, Isocitrate Dehydrogenase antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Triazines therapeutic use
- Abstract
Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.
- Published
- 2018
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5. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.
- Author
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DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, and Kantarjian HM
- Subjects
- Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Cell Count, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Female, Follow-Up Studies, Glycine administration & dosage, Glycine adverse effects, Glycine pharmacokinetics, Hemoglobins analysis, Humans, Isocitrate Dehydrogenase antagonists & inhibitors, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mutation, Pyridines adverse effects, Pyridines pharmacokinetics, Recurrence, Remission Induction, Survival Rate, Young Adult, Enzyme Inhibitors administration & dosage, Glycine analogs & derivatives, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute drug therapy, Pyridines administration & dosage
- Abstract
Background: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1., Methods: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up., Results: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment., Conclusions: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).
- Published
- 2018
- Full Text
- View/download PDF
6. ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia.
- Author
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Maes T, Mascaró C, Tirapu I, Estiarte A, Ciceri F, Lunardi S, Guibourt N, Perdones A, Lufino MMP, Somervaille TCP, Wiseman DH, Duy C, Melnick A, Willekens C, Ortega A, Martinell M, Valls N, Kurz G, Fyfe M, Castro-Palomino JC, and Buesa C
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Tumor metabolism, Disease Models, Animal, Histone Demethylases antagonists & inhibitors, Histone Demethylases genetics, Humans, Leukemia, Myeloid, Acute genetics, Mice, Stem Cells drug effects, Stem Cells metabolism, Cell Differentiation drug effects, Histone Demethylases drug effects, Leukemia, Myeloid, Acute drug therapy
- Abstract
The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
7. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.
- Author
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Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, DeAngelo DJ, Levine RL, Flinn IW, Kantarjian HM, Collins R, Patel MR, Frankel AE, Stein A, Sekeres MA, Swords RT, Medeiros BC, Willekens C, Vyas P, Tosolini A, Xu Q, Knight RD, Yen KE, Agresta S, de Botton S, and Tallman MS
- Subjects
- Adult, Aged, Aged, 80 and over, Aminopyridines adverse effects, Aminopyridines pharmacokinetics, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Bone Marrow drug effects, Bone Marrow metabolism, Bone Marrow pathology, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Female, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Maximum Tolerated Dose, Middle Aged, Mutation, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Triazines adverse effects, Triazines pharmacokinetics, Young Adult, Aminopyridines therapeutic use, Antineoplastic Agents therapeutic use, Enzyme Inhibitors therapeutic use, Isocitrate Dehydrogenase antagonists & inhibitors, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute drug therapy, Triazines therapeutic use
- Abstract
Recurrent mutations in isocitrate dehydrogenase 2 ( IDH2 ) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant- IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498., (© 2017 by The American Society of Hematology.)
- Published
- 2017
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8. Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial.
- Author
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Willekens C, Blanchet O, Renneville A, Cornillet-Lefebvre P, Pautas C, Guieze R, Ifrah N, Dombret H, Jourdan E, Preudhomme C, and Boissel N
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Adolescent, Adult, Antineoplastic Agents therapeutic use, Biomarkers, Tumor metabolism, Blood Cells metabolism, Blood Cells pathology, Bone Marrow metabolism, Bone Marrow pathology, Chromosomes, Human, Pair 22, Chromosomes, Human, Pair 8, Consolidation Chemotherapy methods, Core Binding Factor Alpha 2 Subunit metabolism, Cytoskeletal Proteins metabolism, Female, France, Gene Expression, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Monitoring, Physiologic, Neoplasm, Residual, Prospective Studies, Proto-Oncogene Proteins metabolism, RUNX1 Translocation Partner 1 Protein, Real-Time Polymerase Chain Reaction, Recurrence, Remission Induction, Survival Analysis, Transcription Factors metabolism, Translocation, Genetic, Adaptor Proteins, Signal Transducing genetics, Biomarkers, Tumor genetics, Core Binding Factor Alpha 2 Subunit genetics, Cytoskeletal Proteins genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
In t(8;21)(q22;q22) acute myeloid leukemia, the prognostic value of early minimal residual disease assessed with real-time quantitative polymerase chain reaction is the most important prognostic factor, but how long-term minimal residual disease monitoring may contribute to drive individual patient decisions remains poorly investigated. In the multicenter CBF-2006 study, a prospective monitoring of peripheral blood and bone marrow samples was performed every 3 months and every year, respectively, for 2 years following intensive chemotherapy in 94 patients in first complete remission. A complete molecular remission was defined as a (RUNX1-RUNX1T1/ABL1)×100 ≤ 0.001%. After the completion of consolidation therapy, a bone marrow complete molecular remission was observed in 30% of the patients, but was not predictive of subsequent relapse. Indeed, 8 patients (9%) presented a positive bone marrow minimal residual disease for up to 2 years of follow-up while still remaining in complete remission. Conversely, a peripheral blood complete molecular remission was statistically associated with a lower risk of relapse whatever the time-point considered after the completion of consolidation therapy. During the 2-year follow-up, the persistence of peripheral blood complete molecular remission was associated with a lower risk of relapse (4-year cumulative incidence, 8.2%), while molecular relapse confirmed on a subsequent peripheral blood sample predicted hematological relapse (4-year cumulative incidence, 86.9%) within a median time interval of 3.9 months. In t(8;21)(q22;q22) acute myeloid leukemia, minimal residual disease monitoring on peripheral blood every 3 months allows for the prediction of hematological relapse, and to identify patients who could potentially benefit from intervention therapy. (ClinicalTrials.gov ID #NCT00428558)., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
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9. Prognosis and monitoring of core-binding factor acute myeloid leukemia: current and emerging factors.
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Duployez N, Willekens C, Marceau-Renaut A, Boudry-Labis E, and Preudhomme C
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- Animals, Core Binding Factors genetics, Humans, Leukemia, Myeloid, Acute genetics, Prognosis, Core Binding Factors metabolism, Leukemia, Myeloid, Acute metabolism
- Abstract
Core-binding factor acute myeloid leukemia (CBF-AML) - including AML with t(8;21) and AML with inv(16) - accounts for about 15% of adult AML and is associated with a relatively favorable prognosis. Nonetheless, relapse incidence may reach 40% in these patients. In this context, identification of prognostic markers is considered of great interest. Due to similarities between their molecular and prognostic features, t(8;21) and inv(16)-AML are usually grouped and reported together in clinical studies. However, considerable experimental evidences have highlighted that they represent two distinct entities and should be considered separately for further studies. This review summarizes recent laboratory and clinical findings in this particular subset of AML and how they could be used to improve management of patients in routine practice.
- Published
- 2015
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10. Minimal residual disease monitoring in t(8;21) acute myeloid leukemia based on RUNX1-RUNX1T1 fusion quantification on genomic DNA.
- Author
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Duployez N, Nibourel O, Marceau-Renaut A, Willekens C, Helevaut N, Caillault A, Villenet C, Celli-Lebras K, Boissel N, Jourdan E, Dombret H, Figeac M, Preudhomme C, and Renneville A
- Subjects
- Adolescent, Adult, Core Binding Factor Alpha 2 Subunit metabolism, Female, Genomics, Humans, Male, Middle Aged, Neoplasm, Residual, Oncogene Proteins, Fusion metabolism, RUNX1 Translocation Partner 1 Protein, Tumor Cells, Cultured, Young Adult, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit genetics, DNA, Neoplasm genetics, Leukemia, Myeloid, Acute genetics, Oncogene Proteins, Fusion genetics, Translocation, Genetic
- Abstract
Although acute myeloid leukemia (AML) with t(8;21) belongs to the favorable risk AML subset, relapse incidence may reach 30% in those patients. RUNX1-RUNX1T1 fusion transcript is a well-established marker for minimal residual disease (MRD) monitoring. In this study, we investigated the feasibility and performances of RUNX1-RUNX1T1 DNA as MRD marker in AML with t(8;21). In 17/22 patients with t(8;21)-positive AML treated in the French CBF-2006 trial, breakpoints in RUNX1 and RUNX1T1 were identified using long-range PCR followed by next-generation sequencing. RUNX1-RUNX1T1 DNA quantification was performed by real-time quantitative PCR using patient-specific primers and probe. MRD levels were evaluated in 71 follow-up samples from 16 patients, with a median of four samples [range 2-7] per patient. RUNX1 breakpoints were located in intron 5 in all cases. RUNX1T1 breakpoints were located in intron 1b in 15 cases and in intron 1a in two cases. RUNX1-RUNX1T1 MRD levels measured on DNA and RNA were strongly correlated (r = 0.8, P < 0.0001). Discordant MRD results were observed in 10/71 (14%) of the samples: in three samples from two patients who relapsed, RUNX1-RUNX1T1 was detectable only on DNA, while RUNX1-RUNX1T1 was detectable only on RNA in seven samples. MRD monitoring on genomic DNA is feasible, but with sensitivity variations depending on the patient breakpoint sequence and the qPCR assay efficiency. Although interpretation of the results is easier because it is closely related to the number of leukemic cells, this method greatly increases time, cost and complexity, which limits its interest in routine practice., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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11. First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia
- Author
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Salamero, Olga, Montesinos, Pau, Willekens, Christophe, Pérez-Simón, José Antonio, Pigneux, Arnaud, Récher, Christian, Popat, Rakesh, Carpio Segura, Cecilia del Carmen, Molinero, César, Mascaró, Cristina, Vila, Joaquim, Arévalo, M. Isabel, Maes, Tamara, Buesa, Carlos, Bosch José, Francesc Xavier, The University of Manchester, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Salamero O, Carpio C, Bosch F] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Montesinos P] Hospital Universitari I Politécnic La Fe, València, Spain. Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain. [Willekens C] Institut Gustave Roussy, Villejuif Cedex, France. [Pérez-Simón JA] Hospital Universitario Virgen del Rocío, Sevilla, Spain. Instituto de Biomedicina de Sevilla (Insitituto de Biomedicina De Sevilla/Consejo Superior De Investigaciones Científicas/Centro de Investigación Biomédica en Red de Cáncer), Universidad de Sevilla, Sevilla, Spain. [Pigneux A] Centre Hospitalier Universitaire CHU Bordeaux, Hôpital du Haut Lévêque, Pessac, France. [Récher C] Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, France, Vall d'Hebron Barcelona Hospital Campus, Ministerio de Economía y Competitividad (España), European Commission, Cancer Research UK, Centro para el Desarrollo Tecnológico Industrial (España), National Institute for Health Research (UK), University College London, and NIHR Biomedical Research Centre (UK)
- Subjects
Adult ,Male ,Cancer Research ,Myeloid ,Lysine-Specific Histone Demethylase 1A ,acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos [COMPUESTOS QUÍMICOS Y DROGAS] ,neoplasias::neoplasias por tipo histológico::leucemia::leucemia mieloide::leucemia mieloide aguda [ENFERMEDADES] ,Refractory ,In vivo ,Recurrence ,hemic and lymphatic diseases ,medicine ,Hematologic Malignancy ,Humans ,Other subheadings::/therapeutic use [Other subheadings] ,Enzyme Inhibitors ,Aged ,Aged, 80 and over ,Histone Demethylases ,business.industry ,Leucèmia mieloide aguda ,Otros calificadores::/uso terapéutico [Otros calificadores] ,Myeloid leukemia ,Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Myeloid::Leukemia, Myeloid, Acute [DISEASES] ,KDM1A ,ORIGINAL REPORTS ,Middle Aged ,medicine.disease ,In vitro ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors [CHEMICALS AND DRUGS] ,Cancer research ,Female ,business ,Inhibidors enzimàtics - Ús terapèutic - Abstract
[Purpose] Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML)., [Methods] This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor., [Results] Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm., [Conclusion] Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36)., Supported by Oryzon Genomics and IPT-2012-0673-010000 of the INNPACTO program of the Spanish Ministry of Economy and Competitiveness, with contribution of Fondo Europeo de Desarrollo Regional (FEDER) from the European Union and CDTI_CIIP-20131005/EUROSTAR_E18159. T.C.P.S. is supported by Cancer Research UK Grant No. C5759/A20971. R.P. is supported by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre.
- Published
- 2020
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