PF-114 Mesylate, a Novel Third Generation ATP-Competitive BCR-ABL Tyrosine Kinase Inhibitor: First Safety and Efficacy Data from a Phase I Study in Patients with CML with Failure of Prior TKI Therapy
Authors: Turkina Anna G , Shukhov Oleg , Chelysheva Ekaterina , Nemchenko Irina , Petrova Anna , Bykova Anastasiya , Zaritskey Andrey , Lomaia Elza , Shuvaev Vasily , Novikov Fedor , Shulgina Veronika , Chilov Ghermes 
Published: April 2021

Abstract
Background: PF-114 mesylate is a novel third generation oral tyrosine kinase inhibitor (TKI) that blocks native and mutated Bcr-Abl isoforms, including the gatekeeper mutant T315I, which is uniformly resistant to all approved first- and second generation TKIs. At the present time extensive pre-clinical studies of PF-114, including mechanism of action, kinase profiling, in vitro and in vivo efficacy, safety pharmacology, ADME, and toxicology studies in mice, rats and dogs have been completed and supported initiation of phase I clinical trial of PF-114 mesylate in patients with chronic or accelerated phase Ph+ CML who are resistant to at least one of the second generation TKIs or intolerant to previous treatment with TKIs or who have T315I mutation in the BCR-ABL gene (NCT02885766).
Methods: The trial represents a classical 3+3 design of dose escalation till the maximum tolerated dose (MTD) followed by the expanded cohorts planned for dose(s) below the MTD. The total expected enrollment is 44 patients. Escalating doses of single-agent PF-114 mesylate were administered orally on a continuous once daily (QD) dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to study the dose-limiting toxicities (DLTs) occurring in cycle 1 of treatment and determine the MTD. Secondary objectives included safety, anti-CML activity (based on hematologic, cytogenetic, and molecular assessments), pharmacodynamic and pharmacogenetic properties. Adverse events (AEs) were assessed and graded according to NCI-CTCAE v4.03.
Results: At data cutoff, 4-dose cohorts - 50 mg, 100 mg, 200 mg and 400 mg have completed cycle 1 and 500 mg cohort has started cycle 1 of treatment. Overall 18 patients (8 males) had been treated at the following QD doses: 50 mg (n = 1), 200 mg (n = 5), 400 mg (n = 11), 500 mg (n = 1), and the MTD has not yet been reached. A total of 7 patients with T315I mutation were included into the trial thus far. Median age was 50.5 years (range, 32-66 years). Median time from diagnostics to treatment was 11.5 years (range, 16-1 years) All patients had baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated; 9 (50%) had received ≥ 3 prior TKIs, 6 (33%) had received 2 prior TKIs and 3 (17%) patients with T315I had received 1 prior TKI. In 11 patients, treatment is ongoing at doses 200-500 mg QD, with median duration of exposure of 8 months (range, 2-12 months), and 7 patients discontinued (disease progression [n = 5], AEs [n = 2]). Preliminary data suggest PF-114 pharmacokinetics is dose-proportional. At the end of cycle 1 of study therapy, no drug-related adverse events greater than grade 1 in severity were observed in patients treated at the 50 mg, 100 mg and 200 mg dose levels. At the dose of 400 mg QD, a single DLT case of grade 3 erythematous rash was observed. Most common grade 2/3 AEs on 400 mg QD were dermatologic toxicity (4/11), neutropenia (1/11). No deterioration of the ankle-brachial index (ABI), which is being prospectively measured, or vascular occlusive events were observed so far. The patient with recurrent pleural effusions on previous treatment with dasatinib did not reveal effusions after 11 cycle of therapy; the patient with ischemic stroke on previous treatment with nilotinib did not reveal cardio-vascular events after 9 cycles. To date, no SAEs have been reported. Overall, during the period of 3 cycles, major cytogenetic response (CyR) have been obtained in 4 of 11 patients who completed 3 cycles (2 cases of complete CyR in and 2 cases of partial CyR). Of those patients who revealed cytogenetic response two patients have T315I mutation. Pharmacodynamic and pharmacogenetic assessments are underway.
Conclusion: PF-114 mesylate exhibits antitumor activity in a heavily pretreated subgroup of patients with resistant forms of CML including cases with T315I mutation. The evaluation of the safety profile continues. The dose escalation stage of the current phase 1 study continues, while the including of patients into the expanded cohorts with doses below the MTD has already started.

Disclosures
Chelysheva: Fusion Pharma LLC: Consultancy. Nemchenko: Fusion Pharma LLC: Consultancy. Zaritskey: Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau. Shuvaev: Fusion Pharma LLC: Consultancy. Novikov: Fusion Pharma LLC: Employment. Shulgina: Fusion Pharma LLC: Employment. Chilov: Fusion Pharma LLC: Employment, Patents & Royalties.