Pharmacokinetics and Safety of PTC596, a Novel Tubulin‐Binding Agent, in Subjects With Advanced Solid Tumors

Abstract

PTC596 is a novel, orally bioavailable, small-molecule tubulin-binding agent that reduces B-cell-specific Moloney murine leukemia virus insertion site 1 activity and is being developed for the treatment of solid tumors. A phase 1, open-label, multiple-ascending-dose study was conducted to evaluate the pharmacokinetics and safety of the drug in subjects with advanced solid tumors. PTC596 was administered orally biweekly based on body weight. Dose escalation followed a modified 3 + 3 scheme using doses of 0.65, 1.3, 2.6, 5.2, 7.0, and 10.4 mg/kg. Following oral administration, PTC596 was rapidly absorbed, and between 0.65 and 7.0 mg/kg reached a maximum plasma concentration 2 to 4 hours after dosing. Area under the plasma concentration-time curve increased proportionally with body weight-adjusted doses. Maximum plasma concentration increased with dose, although the increase was less than dose proportional at dose levels >2.6 mg/kg. No accumulation occurred after multiple administrations up to 7.0 mg/kg. PTC596 had a terminal half-life ranging 12 to 15 hours at all doses except for the highest dose of 10.4 mg/kg, where the half-life was approximately 20 hours. Overall, PTC596 was well tolerated. The most frequently reported PTC596-related treatment-emergent adverse events were mild to moderate gastrointestinal symptoms, including diarrhea (54.8%), nausea (45.2%), vomiting (35.5%), and fatigue (35.5%). Only 1 patient treated with 10.4 mg/kg experienced dose-limiting toxicity of neutropenia and thrombocytopenia, both of which were reversible. Stable disease as best overall response was observed among 7 patients, with 2 patients receiving the study drug up to 16 weeks. These results support the further development of PTC596 for the treatment of solid tumors.

Preclinical and Early Clinical Development of PTC596, a Novel Small-Molecule Tubulin-Binding Agent

“…A 28-day phase I, open-label, first-in-human, safety and pharmacokinetic study of PTC596 as monotherapy was conducted in 31 patients with advanced solid tumors. This work has been described in more detail in another publication ( 39 ). The median age was 62.5 years (range 27 to 81 years) and approximately 60% were female.…”

“…This work has been described in more detail in another publication. 32 The median age was 62.5 years (range 27 to 81 years) and approximately 60% were female. Patients received eight doses per 4-week cycle schedule.…”

Inhibition of BMI-1 Induces Apoptosis through Downregulation of DUB3-Mediated Mcl-1 Stabilization

“…Therefore, PTC596 is more effective than PTC-209 for cancer therapy. Recently, PTC596 was newly discovered as a microtubule polymerization inhibitor that directly binds to tubulin [ 26 , 27 ]. Eberle-Singh and coworkers found that PTC596 induced mitotic arrest and apoptosis in multiple pancreatic ductal adenocarcinoma cell lines.…”

Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia

“…The IC50 levels of susceptible AML cells were in the range of physiologically relevant concentrations: Bimiralisib plasma levels were 2 μM in patients treated for solid tumors [ 32 ]; A-1331852 plasma levels were 2 μM in rat p.o. [ 33 ]; PTC-596 cmax ranged from 1 to 5 μM in patients with advanced tumors [ 34 ]; trametinib plasma levels were 20 nM in patients treated for BRAF melanoma [ 35 ]. Only for the STAT3 inhibitor C-188-9 the in vitro IC50 levels of AML cells exceeded the 2 μM plasma concentration determined in PDX mice [ 36 ].…”