Reference Detail

Ref Type

Journal Article

PMID

(32616501)

Authors

McLeod R, Kumar R, Papadatos-Pastos D, Mateo J, Brown JS, Garces AHI, Ruddle R, Decordova S, Jueliger S, Ferraldeschi R, Maiques O, Sanz-Moreno V, Jones P, Traub S, Halbert G, Mellor S, Swales KE, Raynaud FI, Garrett MD, Banerji U

Title

First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2020 Jul 02	4777-4784	Clin Cancer Res

URL

Abstract Text

AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity.The trial followed a rolling six design during dose escalation. An intrapatient dose escalation arm to evaluate tolerability and a biopsy cohort to study pharmacodynamic effects were later added. AT13148 was administered orally three days a week (Mon-Wed-Fri) in 28-day cycles. Pharmacokinetic profiles were assessed using mass spectrometry and pharmacodynamic studies included quantifying p-GSK3β levels in platelet-rich plasma (PRP) and p-cofilin and p-MLC2 levels in tumor biopsies.Fifty-one patients were treated on study. The safety of 5-300 mg of AT13148 was studied. Further, the doses of 120-180-240 mg were studied in an intrapatient dose escalation cohort. The dose-limiting toxicities included hypotension (300 mg), pneumonitis, and elevated liver enzymes (240 mg), and skin rash (180 mg). The most common side effects were fatigue, nausea, headaches, and hypotension. On the basis of tolerability, 180 mg was considered the maximally tolerated dose. At 180 mg, mean Cmax and AUC were 400 nmol/L and 13,000 nmol/L/hour, respectively. At 180 mg, ≥50% reduction of p-cofilin was observed in 3 of 8 posttreatment biopsies.AT13148 was the first dual potent ROCK-AKT inhibitor to be investigated for the treatment of solid tumors. The narrow therapeutic index and the pharmacokinetic profile led to recommend not developing this compound further. There are significant lessons learned in designing and testing agents that simultaneously inhibit multiple kinases including AGC kinases in cancer.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AT13148	AT13148	3	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AT13148		AT-13148\|AT 13148	AKT Inhibitor (Pan) - ATP competitive 7 PKA Inhibitor 2	AT13148 is a small molecule ATP-competitive inhibitor of AGC kinases including AKT1, AKT2, AKT3, p70S6K (RPS6KB1), PKA (PRKACA), ROCK1, ROCK2, RSK1, and SGK3, which results in decreased growth of tumor cells (PMID: 22781553, PMID: 25840982, PMID: 32616501).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References