Timothy P Hughes1, Michael J Mauro1, Jorge E Cortes1, Hironobu Minami1, Delphine Rea1, Daniel J DeAngelo1, Massimo Breccia1, Yeow-Tee Goh1, Moshe Talpaz1, Andreas Hochhaus1, Philipp le Coutre1, Oliver Ottmann1, Michael C Heinrich1, Juan L Steegmann1, Michael W N Deininger1, Jeroen J W M Janssen1, Francois-Xavier Mahon1, Yosuke Minami1, David Yeung1, David M Ross1, Martin S Tallman1, Jae H Park1, Brian J Druker1, David Hynds1, Yuyan Duan1, Christophe Meille1, Florence Hourcade-Potelleret1, K Gary Vanasse1, Fabian Lang1, Dong-Wook Kim1. 1. From the South Australian Health and Medical Research Institute and the University of Adelaide, Adelaide, SA, Australia (T.P.H., D.Y., D.M.R.); Memorial Sloan Kettering Cancer Center, New York (M.J.M., M.S.T., J.H.P.); University of Texas M.D. Anderson Cancer Center, Houston (J.E.C.); Kobe University Graduate School of Medicine, Kobe (H.M.), and the National Cancer Center Hospital East, Chiba (Y.M.) - both in Japan; Hôpital Saint-Louis, Paris (D.R.), and the University of Bordeaux, Bordeaux (F.-X.M.) - both in France; Dana-Farber Cancer Institute, Boston (D.J.D.); Sapienza University, Rome (M.B.); Singapore General Hospital, Singapore (Y.-T.G.); University of Michigan Comprehensive Cancer Center, Ann Arbor (M.T.); Universitätsklinikum Jena, Jena (A.H.), Charité Hospital, Berlin (P.C.), and the Department for Hematology-Oncology, Goethe University Hospital, Frankfurt am Main (F.L.) - all in Germany; University of Cardiff, Cardiff, United Kingdom (O.O.); Veterans Affairs Portland Health Care System (M.C.H.) and Oregon Health and Science University Knight Cancer Institute (M.C.H., B.J.D.), Portland; Hospital de la Princesa and Instituto de Investigación Sanitaria Princesa, Madrid (J.L.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City (M.W.N.D.); Amsterdam University Medical Centers, VU University Medical Center, Amsterdam (J.J.W.M.J.); Novartis Pharma, Basel, Switzerland (D.H., Y.D., C.M., F.H.-P., K.G.V.); and Seoul St. Mary's Hematology Hospital, Catholic University of Korea, Seoul, South Korea (D.-W.K.).
Abstract
BACKGROUND: Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. METHODS: In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS: Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS: Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).
BACKGROUND:Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeperT315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. METHODS: In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS:Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS:Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).
Authors: Hagop M Kantarjian; Neil P Shah; Jorge E Cortes; Michele Baccarani; Mohan B Agarwal; María Soledad Undurraga; Jianxiang Wang; Juan Julio Kassack Ipiña; Dong-Wook Kim; Michinori Ogura; Carolina Pavlovsky; Christian Junghanss; Jorge H Milone; Franck E Nicolini; Tadeusz Robak; Jan Van Droogenbroeck; Edo Vellenga; M Brigid Bradley-Garelik; Chao Zhu; Andreas Hochhaus Journal: Blood Date: 2011-12-09 Impact factor: 22.113
Authors: Susanne Saussele; Marie-Paloma Krauss; Rüdiger Hehlmann; Michael Lauseker; Ulrike Proetel; Lida Kalmanti; Benjamin Hanfstein; Alice Fabarius; Doris Kraemer; Wolfgang E Berdel; Martin Bentz; Peter Staib; Maike de Wit; Martin Wernli; Florian Zettl; Holger F Hebart; Markus Hahn; Jochen Heymanns; Ingo Schmidt-Wolf; Norbert Schmitz; Michael J Eckart; Winfried Gassmann; Andrea Bartholomäus; Antonio Pezzutto; Elisabeth Oppliger Leibundgut; Dominik Heim; Stefan W Krause; Andreas Burchert; Wolf-Karsten Hofmann; Joerg Hasford; Andreas Hochhaus; Markus Pfirrmann; Martin C Müller Journal: Blood Date: 2015-04-27 Impact factor: 22.113
Authors: Bruce D Cheson; John M Bennett; Kenneth J Kopecky; Thomas Büchner; Cheryl L Willman; Elihu H Estey; Charles A Schiffer; Hartmut Doehner; Martin S Tallman; T Andrew Lister; Francesco Lo-Coco; Roel Willemze; Andrea Biondi; Wolfgang Hiddemann; Richard A Larson; Bob Löwenberg; Miguel A Sanz; David R Head; Ryuzo Ohno; Clara D Bloomfield; Francesco LoCocco Journal: J Clin Oncol Date: 2003-12-15 Impact factor: 44.544
Authors: Susan Branford; Linda Fletcher; Nicholas C P Cross; Martin C Müller; Andreas Hochhaus; Dong-Wook Kim; Jerald P Radich; Giuseppe Saglio; Fabrizio Pane; Suzanne Kamel-Reid; Y Lynn Wang; Richard D Press; Kevin Lynch; Zbigniew Rudzki; John M Goldman; Timothy Hughes Journal: Blood Date: 2008-08-06 Impact factor: 22.113
Authors: J S Khorashad; M Anand; D Marin; S Saunders; T Al-Jabary; A Iqbal; S Margerison; J V Melo; J M Goldman; J F Apperley; J Kaeda Journal: Leukemia Date: 2006-04 Impact factor: 11.528
Authors: Andrew A Wylie; Joseph Schoepfer; Wolfgang Jahnke; Sandra W Cowan-Jacob; Alice Loo; Pascal Furet; Andreas L Marzinzik; Xavier Pelle; Jerry Donovan; Wenjing Zhu; Silvia Buonamici; A Quamrul Hassan; Franco Lombardo; Varsha Iyer; Michael Palmer; Giuliano Berellini; Stephanie Dodd; Sanjeev Thohan; Hans Bitter; Susan Branford; David M Ross; Timothy P Hughes; Lilli Petruzzelli; K Gary Vanasse; Markus Warmuth; Francesco Hofmann; Nicholas J Keen; William R Sellers Journal: Nature Date: 2017-03-22 Impact factor: 49.962
Authors: Yüksel Filik; Karin Bauer; Emir Hadzijusufovic; Patrick Haider; Georg Greiner; Nadine Witzeneder; Gregor Hoermann; Philipp J Hohensinner; Karoline V Gleixner; Johann Wojta; Wolfgang R Sperr; Peter Valent Journal: Am J Cancer Res Date: 2021-12-15 Impact factor: 6.166
Authors: Jonathan A Webster; Leo Luznik; Hua-Ling Tsai; Philip H Imus; Amy E DeZern; Keith W Pratz; Mark J Levis; Ivana Gojo; Margaret M Showel; Gabrielle Prince; Javier Bolaños-Meade; Lukasz P Gondek; Gabriel Ghiaur; W Brian Dalton; Tania Jain; Ephraim J Fuchs; Douglas E Gladstone; Christian B Gocke; Syed Abbas Ali; Carol Ann Huff; Ivan M Borrello; Lode Swinnen; Nina Wagner-Johnston; Richard F Ambinder; Richard J Jones; B Douglas Smith Journal: Blood Adv Date: 2020-10-27
Authors: Misty M Attwood; Doriano Fabbro; Aleksandr V Sokolov; Stefan Knapp; Helgi B Schiöth Journal: Nat Rev Drug Discov Date: 2021-08-05 Impact factor: 84.694