Phase 3 Clinical Trial of 300 mg Vamotinib Directly Compared with High-Dose Imatinib in Chronic Myeloid Leukemia Patients in Chronic Phase with Failure of Standard-Dose Imatinib: Interim Analysis

BACKGROUND. Resistance and intolerance to treatment for Ph+ chronic myeloid leukemia (CML) after failure of imatinib therapy remain an issue in clinical oncohematology. Vamotinib (former name PF-114) is a domestic innovative third-generation BCR::ABL1-tyrosine kinase inhibitor (TKI). Previous pre-clinical studies and a phase 1 clinical trial demonstrated the efficacy and safety of this drug in Ph+ CML therapy, also in patients with resistance and/or intolerance to second-generation TKIs as well as with T315I mutation.

AIM. To study vamotinib efficacy and safety profile compared with high-dose imatinib in terms of the major molecular response (MMR) rate after 12-month treatment in CML patients in chronic phase (CP).

MATERIALS & METHODS. The present phase 3 trial is prospective, randomized, open-label, multi-center, and international (Russia and India). CML patients in CP with 400 mg or 600 mg imatinib resistance were randomized into the high-dose imatinib (600 mg or 800 mg) and 300 mg vamotinib groups. After imatinib therapy failure, patients could switch to vamotinib treatment.

RESULTS. The trial enrolled 180 patients (89 in vamotinib and 91 in imatinib groups); interim analysis was carried out after 12 months of therapy. The primary endpoint was reached: superiority of vamotinib was demonstrated in terms of MMR rate (47.2 % vs. 12.1 % on imatinib; p < 0.001). Vamotinib is distinguished by a favorable safety profile; the number of patients with adverse events (AEs) grade 3/4 was 11 in vamotinib vs. 8 in imatinib groups. The most prevalent AE on vamotinib therapy was cutaneous toxicity; hematologic toxicity was not characteristic, no vascular occlusions were observed.

CONCLUSION. The interim analysis after 12 months therapy with vamotinib showed that it holds promise for the treatment of CP CML patients with 400 mg or 600 mg imatinib resistance.

• A.G. Turkina National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 https://orcid.org/0000-0001-9947-2371 (unauthenticated)
• O. Yu. Vinogradova SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284 https://orcid.org/0000-0002-3669-0141 (unauthenticated)
• Е.G. Lomaia VA Almazov National Medical Research Center, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341 https://orcid.org/0000-0003-3290-7961 (unauthenticated)
• B.A. Bakirov Bashkir State Medical University, 3 Lenina ul., Ufa, Republic of Bashkortostan, Russian Federation, 450008 https://orcid.org/0000-0002-3297-1608 (unauthenticated)
• N.M. Kalimulina UZI 4D Clinic, 107 Kalinina pr-t, Pyatigorsk, Russian Federation, 357500
• T.V. Shelekhova VI Razumovskii Saratov State Medical University, 112 Bolshaya Kazachya ul., Saratov, Russian Federation, 410012 https://orcid.org/0000-0002-4737-7695 (unauthenticated)
• I.L. Davydkin Samara State Medical University, 89 Chapaevskaya ul., Samara, Russian Federation, 443099 https://orcid.org/0000-0002-4318-4247 (unauthenticated)
• T.I. Pospelova Novosibirsk State Medical University, 52 Krasnyi pr-t, Novosibirsk, Russian Federation, 630091 https://orcid.org/0000-0002-1261-5470 (unauthenticated)
• O.A. Shukhov National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 https://orcid.org/0000-0001-5393-0816 (unauthenticated)
• E.Yu. Chelysheva National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 https://orcid.org/0000-0001-6423-1789 (unauthenticated)
• V.A. Shuvaev NMRC of Radiology, 4 Koroleva ul., Obninsk, Kaluga Region, Russian Federation, 249036 https://orcid.org/0000-0003-3536-0770 (unauthenticated)
• S. Lavana Marudhar Hospital, A 93-99 Khatipura, Jaipur, India, 302012
• V. Khushoo All India Institute of Medical Sciences, sector 20, plot 2, Nagpur, India, 441108
• S. Apte Sahyadri Super Speciality Hospital, Pune, India, 400058
• T.K. Dolai Nil Ratan Sircar Medical College & Hospital, 138 A.J.C. Bose road, Kolkata, India, 700014
• R.K. Sahoo Kailash Cancer Hospital & Research Centre, Muni Seva Ashram, Goraj, Vadodara, India, 391760
• Germes Grigorevich Chilov Fusion Pharma, 5 Nobelya ul., Moscow, Russian Federation, 121205

1. Hehlmann R, Lauseker M, Saussele S, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017;31(11):2398–406. doi: 10.1038/leu.2017.253. DOI: https://doi.org/10.1038/leu.2017.253
2. Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35(2):440–53. doi: 10.1038/s41375-020-01111-2. DOI: https://doi.org/10.1038/s41375-020-01111-2
3. Туркина А.Г., Лазарева О.В., Челышева Е.Ю. и др. Результаты терапии больных хроническим миелолейкозом по данным российской части международного многоцентрового популяционного исследования Eutos Population-Based Study (EUTOS-PBS). Гематология и трансфузиология. 2019;64(2):106–21. doi: 10.35754/0234-5730-2019-64-2-106-121. [Turkina A.G., Lazareva O.V., Chelysheva E.Yu., et al. Treatment outcomes in patients with chronic myeloid leukemia according to the Russian part of the EUTOS population-based study. Russian journal of hematology and transfusiology. 2019;64(2):106–21. doi: 10.35754/0234-5730-2019-64-2-106-121. (In Russ)] DOI: https://doi.org/10.35754/0234-5730-2019-64-2-106-121
4. Ассоциация содействия развитию гематологии, трансфузиологии и трансплантации костного мозга «Национальное гематологическое общество», Национальное общество детских гематологов, онкологов. Клинические рекомендации «Хронический миелоидный лейкоз». 2024. (электронный документ) Доступно по: https://cr.minzdrav.gov.ru/view-cr/889_1. Ссылка активна на 01.10.2025 г. [Association for the Advancement of Hematology, Transfusiology, and Bone Marrow Transplantation “National Society of Hematologists”, National Society of Pediatric Hematologists and Oncologists. Clinical Guidelines “Chronic Myeloid Leukemia”. 2024. (Internet) Available from: https://cr.minzdrav.gov.ru/view-cr/889_1. Accessed 01.10.2025. (In Russ)]
5. Deininger MW, Kopecky KJ, Radich JP, et al. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol. 2014;164(2):223–32. doi: 10.1111/bjh.12618. DOI: https://doi.org/10.1111/bjh.12618
6. Hehlmann R, Lauseker M, Jung-Munkwitz S, et al. Tolerability-Adapted Imatinib 800 mg/d Versus 400 mg/d Versus 400 mg/d Plus Interferon-α in Newly Diagnosed Chronic Myeloid Leukemia. J Clin Oncol. 2011;29(12):1634–42. doi: 10.1200/JCO.2010.32.0598. DOI: https://doi.org/10.1200/JCO.2010.32.0598
7. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study. J Clin Oncol. 2009;28(3):424–30. doi: 10.1200/JCO.2009.25.3724. DOI: https://doi.org/10.1200/JCO.2009.25.3724
8. Iurlo A, Cattaneo D, Bucelli C, Breccia M. Dose optimization of tyrosine kinase inhibitors in chronic myeloid leukemia: a new therapeutic challenge. J Clin Med. 2021;10(3):515. doi: 10.3390/jcm10030515. DOI: https://doi.org/10.3390/jcm10030515
9. Овсянникова Е.Г., Давыдкин И.Л., Попов Е.А. и др. Эффективность дазатиниба в качестве второй линии терапии хронического миелолейкоза. Эффективная фармакотерапия. 2013;24:56–9. [Ovsyannikova E.G., Davydkin I.L., Popov E.A., et al. Efficacy of dasatinib as second-line therapy for chronic myeloid leukemia. Effektivnaya farmakoterapiya. 2013;24:56–9. (In Russ)]
10. Soverini S, Hocchaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118(5):1208–15. doi: 10.1182/blood-2010-12-326405. DOI: https://doi.org/10.1182/blood-2010-12-326405
11. Loscocco F, Visani G, Galimberti S, et al. BCR-ABL Independent Mechanisms of Resistance in Chronic Myeloid Leukemia. Front Oncol. 2019;9:939. doi: 10.3389/fonc.2019.00939. DOI: https://doi.org/10.3389/fonc.2019.00939
12. Zhang X, Liu B, Huang J, et al. A predictive model for therapy failure in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy. Blood. 2024;144(18):1951–61. doi: 10.1182/blood.2024024761. DOI: https://doi.org/10.1182/blood-2024-205710
13. Kantarjian HM, Jabbour E, Deininger M, et al. Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia. Am J Hematol. 2022;97(11):1419–26. doi: 10.1002/ajh.26686. DOI: https://doi.org/10.1002/ajh.26686
14. Гурьянова М.А., Казей В.И., Шухов О.А. и др. Промежуточные результаты российского проспективного многоцентрового клинического исследования READIT-2020 (снижение дозы ингибиторов тирозинкиназ при ХМЛ, концентрация иматиниба/нилотиниба в плазме, сохранение молекулярного ответа, лекарственная токсичность). Клиническая онкогематология. 2024;17(4):347–59. doi: 10.21320/2500-2139-2024-17-4-347-359. [Gurianova М.А., Kazey V.I., Shukhov O.A., et al. Interim Results of the Russian Prospective Multi-Center Clinical Trial READIT-2020 (Reduction of Tyrosine Kinase Inhibitor Doses in CML Patients, Plasma Imatinib/Nilotinib Concentrations, Sustaining Molecular Response, and Drug Toxicity). Clinical oncohematology. 2024;17(4):347–59. doi: 10.21320/2500-2139-2024-17-4-347-359. (In Russ)] DOI: https://doi.org/10.21320/2500-2139-2024-17-4-347-359
15. Ломаиа Е.Г., Лазорко Н.С., Саламатова Е. и др. Хронический миелолейкоз — до и после применения иматиниба (часть II): обзор научной литературы и практические рекомендации. Онкогематология. 2009;3:40–56. [Lomaia E.G., Lazorko N.S., Salamatova E., et al. Chronic myeloid leukemia — before and after imatinib (part II): literature review and practical recommendations. Onkogematologiya. 2009;3:40–56. (In Russ)]
16. Mian AA, Rafiei A, Haberbosch I, et al. PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation. Leukemia. 2015;29(5):1104–14. doi: 10.1038/leu.2014.326. DOI: https://doi.org/10.1038/leu.2014.326
17. Ivanova ES, Tatarskiy VV, Yastrebova MA, et al. PF-114, a novel selective inhibitor of BCRABL tyrosine kinase, is a potent inducer of apoptosis in chronic myelogenous leukemia cells. Int J Oncol. 2019;55(1):289–97. doi: 10.3892/ijo.2019.4801. DOI: https://doi.org/10.3892/ijo.2019.4801
18. Singh AP, Glennon MS, Umbarkar P, et al. Ponatinib-induced cardiotoxicity: delineating the signalling mechanisms and potential rescue strategies. Cardiovasc Res. 2019;115(5):966–77. doi: 10.1093/cvr/cvz006. DOI: https://doi.org/10.1093/cvr/cvz006
19. Turkina A, Vinogradova O, Lomaia E, et al. Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia. Ann Hematol. 2025;104(5):2707–15. doi: 10.1007/s00277-025-06239-8. DOI: https://doi.org/10.1007/s00277-025-06239-8
20. Aichberger KJ, Herndlhofer S, Schernthaner G-H, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol. 2011;86(7):533–9. doi: 10.1002/ajh.22037. DOI: https://doi.org/10.1002/ajh.22037
21. Fernando F, Sol Andres M, Claudiani S, et al. Cardiovascular events in CML patients treated with nilotinib: validation of the HFA-ICOS baseline risk score. Cardiooncology. 2024;10(1):42. doi: 10.1186/s40959-024-00245-x. DOI: https://doi.org/10.1186/s40959-024-00245-x
22. Januzzi JL, Garasic JM, Kasner SE, et al. Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee. J Hematol Oncol. 2022;15(1):1. doi: 10.1186/s13045-021-01221-z. DOI: https://doi.org/10.1186/s13045-022-01239-x
23. Cortes JE, De Souza CA, Ayala M, et al. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol. 2016;3(12):e581–e591. doi: 10.1016/S2352-3026(16)30167-3. DOI: https://doi.org/10.1016/S2352-3026(16)30167-3
24. Kantarjian H, Pasquini R, Hamerschalk N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109(12):5143–50. doi: 10.1182/blood-2006-11-056028. DOI: https://doi.org/10.1182/blood-2006-11-056028
25. Kantarjian H, Pasquini R, Levy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer. 2009;115(18):4136–47. doi: 10.1002/cncr.24504. DOI: https://doi.org/10.1002/cncr.24504
26. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;(34):966–84. doi: 10.1038/s41375-020-0776-2. DOI: https://doi.org/10.1038/s41375-020-0776-2
27. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84. doi: 10.1182/blood-2013-05-501569. DOI: https://doi.org/10.1182/blood-2013-05-501569
28. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540–6. doi: 10.1182/blood-2007-03-080689. DOI: https://doi.org/10.1182/blood-2007-03-080689
29. Gambacort-Passerini C, Brummendorf TH, Kim D-W, et al. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: minimum 24-month follow-up. Am J Hematol. 2014;89(7):732–42. doi: 10.1002/ajh.23728. DOI: https://doi.org/10.1002/ajh.23728
30. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica. 2018;103(8):1298–307. doi: 10.3324/haematol.2017.171249. DOI: https://doi.org/10.3324/haematol.2017.171249