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

• Published in: Annals of hematology Vol. 104; no. 5; pp. 2707 - 2715
• Main Authors: Turkina, Anna, Vinogradova, Olga, Lomaia, Elza, Shatokhina, Evgeniya, Shukhov, Oleg, Chelysheva, Ekaterina, Shikhbabaeva, Dzhariyat, Nemchenko, Irina, Petrova, Anna, Bykova, Anastasiya, Siordiya, Nadiya, Shuvaev, Vasily, Mikhailov, Ilya, Novikov, Fedor, Shulgina, Veronika, Hochhaus, Andreas, Ottmann, Oliver, Cortes, Jorge, Gale, Robert Peter, Chilov, Ghermes
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2025; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Benzamides; Female; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Hematology; Humans; Imidazoles - administration & dosage; Imidazoles - adverse effects; Imidazoles - therapeutic use; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Oncology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - therapeutic use; Pyrimidines; Toxicity; Young Adult; Vamotinib; Chronic myeloid leukaemia; Tyrosine kinase inhibitor; PF-114
• ISSN: 0939-5555; 1432-0584; 1432-0584
• DOI: 10.1007/s00277-025-06239-8

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 T315I . 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 T315I 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 T315I . 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 T315I 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.