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790 Phase-1 Study of PF-114 Mesylate in CML Failing Prior Tyrosine Kinase-Inhibitor Therapy

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Therapy: TFR Failure, Resistance, and New Drug Development
Hematology Disease Topics & Pathways:
Diseases, Biological, Adult, CML, Therapies, Study Population, Myeloid Malignancies, TKI
Monday, December 3, 2018: 3:30 PM
Room 6E (San Diego Convention Center)

Anna G Turkina, Prof., MD1, Olga Vinogradova, MD, PhD2*, Elza Lomaia, MD3*, Evgeniya Shatokhina, MD, PhD4*, Oleg Shukhov, MD, PhD5*, Ekaterina Chelysheva, MD, PhD6*, Irina Nemchenko, MD, PhD1*, Anna Petrova, MD5*, Anastasiya Bykova, MD1*, Andrey Zaritskey, MD, PhD7*, Nadia Siordia, MD8*, Dzhariyat Shikhbabaeva2*, Vasily Shuvaev, MD 9, Jorge E. Cortes, MD10, Robert Peter Gale11, Michele Baccarani, MD12, Oliver G. Ottmann, MD13, Ilya Mikhailov14*, Fedor Novikov, PhD15*, Veronika Shulgina, PhD, MD15* and Ghermes Chilov, PhD16*

1National Research Center for Hematology, Moscow, Russian Federation
2Hematological Moscow City Center, Botkin City Clinical Hospital, Moscow, Russian Federation
3Federal Almazov North-West Medical Research Centre, Saint-Petersburg, Russian Federation
4Central State Medical Academy, Affairs of the President of Russian Federation, Moscow, Russian Federation
5National Research Center for Hematology, Moscow, Russia
6National Research Center for Hematology, Moscow, AZ
7Federal Almazov North-West Medical Research Centre, St Petersburg, Russian Federation
8Federal Almazov North-West Medical Research Centre, Saint-petersburg, Russian Federation
9Federal State Budget Institution “Russian Scientific-Research Institute of Hematology and Transfusiology of Federal Medical-Biological Agency”, Saint-Petersburg, Russian Federation
10Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
11Haematology Research Center, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom
12Institute of Hematology "L. and A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, Bologna, Italy
13Department of Haematology, Cardiff University, Cardiff, United Kingdom
14Fusion Pharma, Moscow, Russian Federation
15Fusion Pharma LLC, Moscow, Russian Federation
16Fusion Pharma, LLC, Moscow, Russia

Background: PF-114 mesylate is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCRABL1 isoforms including those with a BCRABL1T315I. We present data from a phase-1 study in subjects with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or who have BCRABL1T315I (NCT02885766).

Methods: 3+3 dose-escalation design to determine maximum tolerated dose (MTD) followed by expanded cohorts for doses ≤MTD. The primary objective was to determine the MTD and identify dose-limiting toxicities (DLTs) during cycle 1 (28 days). Secondary objectives included safety and anti-CML activity based on hematological, cytogenetic, and molecular criteria. Adverse events (AEs) were assessed and graded using NCI-CTCAE v4.03.

Results: 51 subjects were enrolled as of June 26, 2018. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given on a continuous QD schedule. Median age was 50 years (range, 29-82 years). Median interval from diagnosis to study-entry was 10 years (range, 0-23 years). Subjects had baseline ECOG performance scores <2. 13 subjects were reported to have BCRABL1T315I. Subjects were heavily pre-treated: 25 had received ≥3 prior TKIs; 5 subjects with BCRABL1T315I received 1 prior TKI. 600 mg was identified as the MTD with 1 of 6 subjects experiencing a DLT at this dose (Gr 3 psoriasis-like skin lesion). Similar grade-3 skin lesions were also identified at the dose of 750 mg in 2 subjects and at 400 mg in 1 subject. Therapy is ongoing in 23 subjects at doses 200, 300 and 400 mg with median duration of exposure of 5 (range, 1-21), 3 (range, 1-12) and 4 (range, 1-19) cycles. Other subjects discontinued because of progression (n=16), AEs (n=6) or other reasons (n=6). The most common of non-hematologic toxicity was skin toxicity, which was common at doses of ≥400 mg. Grade-3 skin toxicity occurred in 3 subjects on daily dose 750 mg, 4 subjects on dose 600 mg, 1 patient on dose 500 mg and 3 subjects on dose 400 mg. Skin lesions resolved rapidly upon drug discontinuation and topical therapy. No other drug related non-hematologic grade-3 toxicities except a single case of grade-3 hepatitis on dose 400 mg were observed. No deterioration of ankle-brachial index or vascular occlusive events were observed. A complete hematologic response was achieved in 8 of 19 evaluable subjects including 3 of 8 with BCRABL1T315I. Major cytogenetic response was achieved in 6 of 21 evaluable subjects including 3 of 7 with BCRABL1T315I. Major molecular response was achieved in 2 of 18 subjects completing ≥13 cycles. Most cytogenetic and molecular responses were achieved at doses 200 and 300 mg which were well-tolerated and will be considered for the phase-2 study.

Conclusion: MTD of PF-114 is 600 mg with skin toxicity as the DLT. The best safety/efficacy ratio was seen at doses of 200 and 300 mg which are being studied in expanded cohorts and soon in a phase-2 study.

Disclosures: Turkina: Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations. Shukhov: Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Chelysheva: Bristol Myers Squibb: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations ; Novartis: Other: provided consultations and performed lectures. Cortes: Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Ottmann: Novartis: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Fusion Pharma: Consultancy, Research Funding. Mikhailov: Fusion Pharma: Employment. Novikov: Fusion Pharma: Employment. Shulgina: Fusion Pharma: Employment. Chilov: Fusion Pharma: Employment.

*signifies non-member of ASH