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Characterization and first-in-human data of CLR457, an orally bioavailable pan-class I PI3-Kinase inhibitor

Harding, James J. , Bauer, Todd M., Tan, Daniel, Bedard, Philippe L. , Rodon, Jordi, Doi, Toshihiko, Schnell, Christian, Iyer, Varsha, Baffert, Fabienne, Radhakrishnan, Rajkumar, Fabre, Claire and Juric, Dejan (2018) Characterization and first-in-human data of CLR457, an orally bioavailable pan-class I PI3-Kinase inhibitor. Investigational new drugs. ISSN 1573-0646; 0167-6997


CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor.
Materials and Methods
CLR457 anti-tumor activity was characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and preliminary activity of CLR457. Successive cohorts of patients with advanced solid tumors having PI3K pathway activation received increasing doses of oral CLR457 according to a Bayesian escalation model.
CLR457 inhibited p110, p110β, p110 and p110γ with an IC50 of 89 ± 29 nM, 56 ± 35nM, 39 ± 10 nM and 230 nM ± 31nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. In the clinical study, 31 patients were treated at doses ranging from 5 to 100mg. DLTs included grade 3 hyperglycemia (1 at 100 mg) and rash (1 at 40 mg, 2 at 100 mg). Grade 3/4 toxicities were frequent (51.6%) and included rash, gastrointestinal toxicity, and fatigue. The MTD was not determined. CLR457 was rapidly absorbed with limited accumulation and demonstrated linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg). Disease stabilization (5 of 11, 45.5%), but not shrinkage, was observed at the 100 mg dose.
At pharmacologically active concentrations, CLR457 had poor tolerability with limited antitumor activity, thus clinical development was terminated. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K isoforms.

Item Type: Article
Date Deposited: 11 Sep 2018 00:45
Last Modified: 11 Sep 2018 00:45