First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors.
Date
2020-09-15Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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 C max 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. CONCLUSIONS: 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.
Collections
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Clinical PD Biomarker Group
Clinical Pharmacology – Adaptive Therapy
Language
eng
Date accepted
2020-06-30
License start date
2020-09
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (18), pp. 4777 - 4784
Publisher
AMER ASSOC CANCER RESEARCH