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<p>Vamotinib (PF-114) is a 3rd -generation, ATP-competitive oral tyrosine kinase inhibitor (TKI) active against wild-type and mutated <i>BCR::ABL1</i> isoforms including <i>BCR::ABL1</i><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 <i>BCR::ABL1</i><sup>T315I</sup> were enrolled. Subjects received vamotinib, 50–750&#xa0;mg/d, continuously. Median exposure was 6 months (range, &lt; 1–52 months). Median CML duration pre-study was 10 years (range, &lt; 1–23 years). 27 subjects received ≥ 3 prior TKIs and 16 had <i>BCR::ABL1</i><sup>T315I</sup>. The MTD was 600&#xa0;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&#xa0;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 <i>BCR::ABL1</i><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&#xa0;mg/d.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年4月29日

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  • Anna Turkina,
  • Olga Vinogradova,
  • Elza Lomaia,
  • Evgeniya Shatokhina,
  • Oleg Shukhov,
  • Ekaterina Chelysheva,
  • Dzhariyat Shikhbabaeva,
  • Irina Nemchenko,
  • Anna Petrova,
  • Anastasiya Bykova,
  • Nadiya Siordiya,
  • Vasily Shuvaev,
  • Ilya Mikhailov,
  • Fedor Novikov,
  • Veronika Shulgina,
  • Andreas Hochhaus,
  • Oliver Ottmann,
  • Jorge Cortes,
  • Robert Peter Gale,
  • Ghermes Chilov

摘要

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::ABL1T315I. 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::ABL1T315I 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::ABL1T315I. 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::ABL1T315I 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.