Background: 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 data from a phase-1 study in patients with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or with BCR-ABL1T315I (NCT02885766) with ≥6 months therapy. 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 criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 patients were enrolled. 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 continuously. Median age was 50 years (range, 29-82 years). Median CML duration pre-study was 10 years (range, 0.3-23 years). All patients had baseline ECOG performance scores 0-1. Twelve patients had BCR-ABL1T315I. Patients were heavily pre-treated: 25 received ≥3 prior TKIs; 5 patients with BCR-ABL1T315I received 1 prior TKI. Interim analysis was conducted at follow-up of ≥6 months (cut-off date January 16th 2019). Therapy was ongoing in 17 patients at doses 200 mg (n=4), 300 mg (n=9), 400 mg (n=3) and 600 mg (n=1) with median duration of exposure of 7,4 (range, 4,6-26), 9,2 (range, 7,4-26), 9,2 (range, 8,3-9,2) and 9,2 months. Other patients discontinued because of progression (n=18), adverse events (n=6), consent withdrawal (n=4), participation in another study (n=3) or other reasons (n=3). The MTD was 600 mg with the grade-3 psoriasis-like skin lesions the DLT, which occurred during the first 28 days of treatment. Reversible grade-3 skin toxicity occurred in 11 patients at doses ≥400 mg. There were no other drug-related non-hematologic grade-3 toxicities except 1 grade-3 toxic hepatitis at 400 mg and there were no detectable effects on ankle-brachial index or vascular occlusive events. The best safety/efficacy dose was 300 mg/d with 6 of 11 patients achieving a major cytogenetic response (MCyR) and 4 of them - a major molecular response (MMR). Higher doses were less effective probably because of toxicity-related therapy interruptions and discontinuations. Five of 12 patients with BCR-ABL1T315I responded, 3 of which achieved a complete hematologic response and 4 achieved MCyR. Conclusion: PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1T315I responded. A pivotal study is beginning. Disclosures Turkina: Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Lomaia:Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant. Shukhov:Pfizer: Consultancy; Novartis: Consultancy. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shikhbabaeva:Novartis: Consultancy; Fusion Pharma: Consultancy. Shuvaev:Fusion Pharma: Consultancy; Novartis: Consultancy; Pfize: Honoraria; BMS: Consultancy. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Consultancy.

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; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: 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.

Background: Currently the main potential treatment for chronic myeloid leukemia (CML) blast phase (BP) are tyrosine kinase inhibitors. The aim of our study is to try to find any therapy in TKI resistant patients in CML BP. Material and methods: The patients were 5 male and one female (age range from 28 to 45 years old). 4 patients progressed to BP from chronic phase (CP), there was rapid progression from AP in other two pts (4 lymphoid, 1 myeloid, 1 undifferentiated). The pts were unresponsible to one or two second generation TKI treatment in BP (dasatinid, nilotinib). Two patients were also failed to respond to high dose cytarabine and methotrexate treatment after TKI failure. Chemotherapy «FLAG» (fludarabine, cytarabine high dose, G-CSF) was used to induce of CP. Results: Five of six pts achieved the second CP and deep response (1- CcyR, 3- MMR, and one BCR/ABL reduction to 0,371%).Two of these pts obtained deep response (CCyR, and bcr/abl reduction to 0.371% after unsuccessful treatment with dose mono cytarabine and methotrexat treatment. The response was short, the longest MMR duration is 48 days (patient is being prepared for ASCT). Conclusion: FLAG can induce deep molecular responses in BP pts resistant to TKIs. This regimen seems to be more effective than HDAC and HD MTX. The response is of short duration. Thus, in case of absence of relative sibling, haploidentical ASCT with unmanipulated bone marrow and posttransplantation cyclophosphamide could be the optimal treatment choice. The protocol for FLAG induced remission followed haploidentical ASCT is prepared. Disclosures No relevant conflicts of interest to declare.

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