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1482 PF-114 in Patients Failing Prior Tyrosine Kinase-Inhibitor Therapy Including BCR::ABL1T315I

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research
Saturday, December 11, 2021, 5:30 PM-7:30 PM

Anna G. Turkina, Prof., MD1, Olga Vinogradova, MD2,3,4*, Elza Lomaia, MD, PhD5*, Evgeniya Shatokhina, MD, PhD6*, Oleg A. Shukhov, MD, PhD7*, Andrey Zaritskey5*, Ekaterina Yu. Chelysheva, MD, PhD8*, Dzhariyat Shikhbabaeva9*, Irina Nemchenko, MD, PhD10*, Anna Petrova, MD11*, Anastasiya Bykova, MD10*, Vasily Shuvaev, MD12,13, Nadia Siordia, MD14*, Jorge E. Cortes, MD15,16, Robert Peter Gale17, Michele Baccarani, MD18, Oliver Ottmann, MD, FRCPath19, Ilya Mikhailov20*, Fedor Novikov, PhD21*, Veronika Shulgina, PhD, MD21* and Ghermes Chilov, PhD22*

1National Research Center for Hematology, Moscow, Russia
2Hematology Center of Botkin Hospital, Moscow, Russian Federation
3Dmitry Rogachev National Research Center of Pediatric Hematology/Oncology and Immunology, Moscow, Russian Federation
4Pirogov Russian National Research Medical University, Moscow, Russian Federation
5Almazov National Medical Research Centre, St. Petersburg, Russian Federation
6Central State Medical Academy, Affairs of the President of Russian Federation, Moscow, Russian Federation
7National Research Center for Hematology, Russian Federation, Moscow, Russia
8Moscow, AZ
9Hematological Moscow City Center, Botkin City Clinical Hospital, Moscow, Russian Federation
10National Research Center for Hematology, Moscow, Russian Federation
11Moscow, Russia
12City Clinical Hospital n.a. V.V. Veresaev of the Moscow Department of Healthcare, Moscow, Russian Federation
13Federal State Budget Institution “Russian Scientific-Research Institute of Hematology and Transfusiology of Federal Medical-Biological Agency”, St. Petersburg, Russia
14Institute of Hematology, Almazov National Medical Research Centre, St. Petersburg, Russian Federation
15Georgia Cancer Center Augusta University, Augusta, GA
16Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
17Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
18Institute of Hematology "L. & A. Seràgnoli", St. Orsola University Hospital, Bologna, Italy
19Cardiff University, Cardiff, United Kingdom
20Fusion Pharma, Moscow, Russian Federation
21Fusion Pharma LLC, Moscow, Russian Federation
22Fusion Pharma, LLC, Moscow, Russia

Background: Not everyone with CML responds optimally to TKI-therapy, especially those with BCR::ABL1T315I. PF-114 is a 4th-generation 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 study (NCT02885766).

Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic and molecular response criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03.

Results: 51 subjects (5 with accelerated phase CML, 46 – with chronic CML), 23 males, were studied. Daily doses were 50-600 mg/d given once daily continuously. Median age was 50 y (range, 29-82 y). Median CML duration pre-study was 10 y (range, 0.3-23 y). 16 subjects had BCR::ABL1T315I. 25 subjects received ≥ 3 prior TKIs. Median follow-up was ≥ 31 mo and median exposure, 6 mo (range, 0.4-52). Therapy was ongoing in 7 subjects at study termination. Others discontinued because of progression (n = 20), AEs (n = 2), consent withdrawal (n = 5), entry into another study (n = 3) or other reasons (n = 14). The MTD was 600 mg with the grade-3 psoriasis-like skin AE as the DLT. There were no vascular occlusive events or deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 15 of 44 subjects, complete cytogenetic response (CCyR) in 11 of 50 subjects and major molecular response (MMR) in 8 of 51 subjects. Median duration of CHR was 12 mo and has not been reached for MCyR, CCyR and MMR. The best safety/efficacy dose was 300 mg/d with 6 of 9 subjects achieving a MCyR, 5, a CCyR and 4, MMR. 5 of 16 subjects with BCR::ABL1T315I responded, including 4 achieving a MCyR, 2, a CCyR and 1, a MMR. 2 of 6 subjects failing ponatinib achieved a CHR.

Conclusion: PF-114 was safe and effective in subjects failing ≥ 2 TKIs and those with BCR::ABL1T315I including those failing ponatinib. The PF-114 dose for further study is 300 mg/d.

Disclosures: Turkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Vinogradova: Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Chelysheva: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pharmstandart: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Cortes: Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Baccarani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ottmann: Fusion: Honoraria; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria. Mikhailov: Fusion Pharma: Current Employment. Novikov: Fusion Pharma: Current Employment. Shulgina: Fusion Pharma: Current Employment. Chilov: Fusion Pharma: Current Employment.

*signifies non-member of ASH