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First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors
Robert McLeod1, Rajiv Kumar2, Dionysis Papadatos-Pastos2
1Cancer Research UK, London, United Kingdom.
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.
Insights
The novel ROCK-AKT inhibitor AT13148 showed antimetastatic and antiproliferative effects in preclinical models. However, dose-limiting toxicities and pharmacokinetic issues led to its discontinuation in clinical trials for solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- AT13148 is an oral dual inhibitor targeting ROCK and AKT kinases, belonging to the AGC kinase family.
- Preclinical studies indicated AT13148 possesses antimetastatic and antiproliferative properties relevant to cancer treatment.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AT13148 in patients with solid tumors.
- To determine the maximally tolerated dose (MTD) and assess preliminary efficacy signals of this novel kinase inhibitor.
Main Methods:
- A rolling six design was employed for dose escalation, with subsequent intrapatient dose escalation and biopsy cohorts added.
- AT13148 was administered orally three times weekly in 28-day cycles. Pharmacokinetic and pharmacodynamic analyses (p-GSK3β, p-cofilin, p-MLC2) were performed.
Main Results:
- Fifty-one patients were treated, with doses ranging from 5-300 mg. The MTD was determined to be 180 mg due to dose-limiting toxicities like hypotension and pneumonitis.
- At 180 mg, mean Cmax was 400 nmol/L and AUC was 13,000 nmol/L/hour. A ≥50% reduction in p-cofilin was observed in 3 of 8 post-treatment biopsies.
Conclusions:
- AT13148 was the first dual ROCK-AKT inhibitor tested in solid tumors, demonstrating potent inhibition but a narrow therapeutic index.
- Despite preclinical promise, pharmacokinetic challenges and tolerability issues led to the recommendation against further development of AT13148.
- Lessons learned from this trial inform the design and testing of multi-kinase inhibitors, particularly those targeting AGC kinases in cancer therapy.
