Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia

Vamotinib (PF-114) is a 3rd -generation, ATP-competitive oral tyrosine kinase inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1<sup>T315I</sup>. We present final results of a phase-1 vamotinib dose-escalation study to identify maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) followed by expansion cohorts. 51 subjects with chronic myeloid leukaemia (CML) failing ≥ 1 2nd generation TKI or with BCR::ABL1<sup>T315I</sup> were enrolled. Subjects received vamotinib, 50-750 mg/d, continuously. Median exposure was 6 months (range, < 1-52 months). Median CML duration pre-study was 10 years (range, < 1-23 years). 27 subjects received ≥ 3 prior TKIs and 16 had BCR::ABL1<sup>T315I</sup>. The MTD was 600 mg with the Grade-3 psoriasis-like skin toxicity as the DLT. There were no vascular occlusive events nor deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 14 of 44 subjects, complete cytogenetic response (CCyR) in 10 of 50 and major molecular response (MMR) in 7 of 51 subjects who did not have a CHR, MCyR, CCyR or MMR at enrollment. The best safety/efficacy dose was 300 mg with MCyR achieved in 6 of 7 subjects, CCyR in 5 of 9 and MMR in 4 of 9 subjects who did not have a MCyR, CCyR or MMR at enrollment. 5 of 16 subjects with BCR::ABL1<sup>T315I</sup> responded including 3 achieving a CHR, 3, a MCyR, and 1,a CCyR. 2 of 5 subjects failing ponatinib achieved a CHR. Vamotinib dose for further phase-3 study is 300 mg/d.

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Publication Details

Journal
Annals of Hematology
Published
2025-04-29
DOI
https://doi.org/10.1007/s00277-025-06239-8
Citations
3
Primary Topic
Chronic Myeloid Leukemia Treatments
Type
article
Field-Weighted Citation Impact
5.31

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article

Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia

Anna Turkina, Ekaterina Chelysheva, Irina Nemchenko, Jörge E. Cortes et al.
3 citations
Annals of Hematology
Chronic Myeloid Leukemia Treatments
5.31
article

Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia

Anna Turkina, Ekaterina Chelysheva, Irina Nemchenko, Jörge E. Cortes, Ghermes G. Chilov, Olga Vinogradova, Andreas Hochhaus, Veronika Shulgina, Fedor N. Novikov, I. А. Mikhailov, Oleg Shukhov, Oliver G. Ottmann, Vasily Shuvaev, Elza Lomaia, Е. А. Шатохина, Robert Peter Gale, Анна Петрова, Dzhariyat Shikhbabaeva, Nadiya Siordiya, Anastasiya Bykova
article en
3 citations

Abstract

Vamotinib (PF-114) is a 3rd -generation, ATP-competitive oral tyrosine kinase inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1<sup>T315I</sup>. We present final results of a phase-1 vamotinib dose-escalation study to identify maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) followed by expansion cohorts. 51 subjects with chronic myeloid leukaemia (CML) failing ≥ 1 2nd generation TKI or with BCR::ABL1<sup>T315I</sup> were enrolled. Subjects received vamotinib, 50-750 mg/d, continuously. Median exposure was 6 months (range, < 1-52 months). Median CML duration pre-study was 10 years (range, < 1-23 years). 27 subjects received ≥ 3 prior TKIs and 16 had BCR::ABL1<sup>T315I</sup>. The MTD was 600 mg with the Grade-3 psoriasis-like skin toxicity as the DLT. There were no vascular occlusive events nor deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 14 of 44 subjects, complete cytogenetic response (CCyR) in 10 of 50 and major molecular response (MMR) in 7 of 51 subjects who did not have a CHR, MCyR, CCyR or MMR at enrollment. The best safety/efficacy dose was 300 mg with MCyR achieved in 6 of 7 subjects, CCyR in 5 of 9 and MMR in 4 of 9 subjects who did not have a MCyR, CCyR or MMR at enrollment. 5 of 16 subjects with BCR::ABL1<sup>T315I</sup> responded including 3 achieving a CHR, 3, a MCyR, and 1,a CCyR. 2 of 5 subjects failing ponatinib achieved a CHR. Vamotinib dose for further phase-3 study is 300 mg/d.

Annals of HematologyVol. 104(5)
Lomonosov Moscow State University (RU), Federal Almazov North-West Medical Research Centre (RU), Augusta University Health (US), Moscow City Hospital No 29 (RU), N.D. Zelinsky Institute of Organic Chemistry (RU), Russian Medical Academy of Continuous Professional Education (RU), Medical Radiological Research Center (RU), Botkin Hospital (RU), Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology (RU), National Research Center for Hematology Russian Academy of Medical Sciences (RU), City Clinical Hospital (RU), Jena University Hospital (DE), National Medical Research Center of Cardiology (RU), Federal State Budgetary Institution "Center for Expertise and Quality Control of Medical Care" (RU), Imperial College London (GB), Cardiff University (GB)
National Institute for Health and Care Research, Università di Bologna
Good health and well-being
Openalex Percentile: Top 5%
Chronic Myeloid Leukemia Treatments
5.31
DOIOpen Access PDFOpenAlex
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