1. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia : a randomized, open-label phase 2 clinical trial
- Author
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James K. McCloskey, Andreas Hochhaus, Lori J. Maness, Michael W. Deininger, Vickie Lu, Tomasz Sacha, Christine Rojas, Charles Chuah, Moshe Talpaz, Beatriz Moiraghi, Tracey Hall, Anna G. Turkina, Jorge E. Cortes, Maria Undurraga Sutton, Hugues de Lavallade, Gianantonio Rosti, Christopher Arthur, Elza Lomaia, Michael J. Mauro, Charles A. Schiffer, Shouryadeep Srivastava, Jane F. Apperley, Carolina Pavlovsky, Jeffrey H. Lipton, Philippe Rousselot, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre Hospitalier de Versailles André Mignot (CHV), Bristol-Myers Squibb, BMS, Pfizer, Astellas Pharma US, APUS, Novartis, Takeda Pharmaceuticals U.S.A., TPUSA, Jazz Pharmaceuticals, Daiichi-Sankyo, Sun Pharma, Conflict-of-interest disclosure: J.C. has been a consultant to and received research funding from Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, and BioPath Holdings, has received research funding from Sun Pharma, Telios, Arog, Merus, and Immunogen, has held membership on the board of directors or advisory committee of BioPath Holdings, and has been a consultant to Amphivena Therapeutics and BiolineRx. J.A. has received honoraria and research funding and is on the speakers bureaus of Incyte and Pfizer, and has received honoraria and served on the speakers bureaus of Bristol Myers Squibb and Novartis. E.L. has served on the speakers bureaus of Novartis and Pfizer, and has received travel and accommodation reimbursement from Novartis, Pfizer, and Bristol Myers Squibb. B.M. has served on the speakers bureaus of Novartis, Pfizer, and Takeda. M.U.S. has served on the advisory boards of AbbVie, Janssen, Novartis, Pfizer, and Roche and on the speakers bureaus of Janssen, Novartis, and Pfizer. C.C. has received honoraria from Novartis and Korea Otsuka Pharmaceutical, received honoraria and research funding from Bristol Myers Squibb, and received travel reimbursement and research funding from Pfizer. T.S. has been a consultant to, has received honoraria from, and has served on the speakers bureaus of Bristol Myers Squibb, Novartis, Pfizer, and Incyte, and has been a consultant to and received honoraria from Adamed. J.H.L. has been a consultant to and has received research funding from Bristol Myers Squibb, Ariad, Pfizer, and Novartis. C.A.S. has been a consultant to Bristol Myers Squibb and Novartis, and has received research funding from Takeda. A.H. has received honoraria and research funding from Bristol Myers Squibb, Novartis, and Pfizer, research funding from Incyte and Merck Sharp & Dohme, and honoraria from Takeda. P.R. has been a consultant to and has received funding from Incyte and Pfizer, and has been a consultant to Bristol Myers Squibb, Novartis, and Takeda. G.R. has received research funding from and served on the speakers bureau for Pfizer, and has served on the speakers bureaus of Bristol Myers Squibb, Incyte, and Novartis. H. de L. has received honoraria and research funding from Bristol Myers Squibb and Incyte, and honoraria from Pfizer and Novartis. C.R. has received personal fees from AstraZeneca, Roche, Novartis, and Janssen. M.T. holds membership on the board of directors or advisory committees of Bristol Myers Squibb and Constellation Pharmaceuticals, has received research funding from Takeda and Novartis, and has been a consultant to IMAGO. M.M. has been a consultant to and has received honoraria, reimbursement of travel, accommodation and expenses, and research funding from Bristol Myers Squibb, Novartis, Takeda, and Pfizer, and research funding from Sun Pharma/SPARC. T.H. and V.L. are employees of Millennium Pharmaceuticals. S.S. is an employee of Takeda. M.D. is a consultant to, holds a membership on the board of directors or advisory committees of, was part of a study management committee of, and received research funding from Blueprint Medicines Corporation, is a consultant to Fusion Pharma, Medscape, and DisperSol, is a consultant to, has held membership on the board of directors or advisory committees of, and has received research funding from Takeda, is a consultant to and holds membership on the board of directors or advisory committee of Sangamo, is a consultant to and received research funding from Novartis, is a consultant to and received honoraria and research funding from Incyte, and has received research funding from SPARC, DisperSol, and the Leukemia and Lymphoma Society. C.P., A.T., C.K.A., J. M., and L.M. declare no competing financial interests., and Professional medical writing assistance was provided by Duprane Young of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and funded by Millennium Pharmaceuticals, Inc.
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Adult ,Male ,Oncology ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Immunology ,Population ,Fusion Proteins, bcr-abl ,Phases of clinical research ,Antineoplastic Agents ,Biochemistry ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Clinical endpoint ,Humans ,Prospective cohort study ,education ,Protein Kinase Inhibitors ,Aged ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,education.field_of_study ,Dose-Response Relationship, Drug ,business.industry ,Ponatinib ,Imidazoles ,Cell Biology ,Hematology ,Middle Aged ,Dose-ranging study ,3. Good health ,Pyridazines ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Relative risk ,Leukemia, Myeloid, Chronic-Phase ,Cohort ,Female ,business - Abstract
In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.
- Published
- 2021
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