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

Abstract

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-GSK3b 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.

Rho GTPase signaling in cancer progression and dissemination

“…CCT129254 showed reduction in melanoma metastatic burden (468). Interestingly, strong anti-tumour effects of AT13148 were clear for pancreatic, breast, prostate and uterus cancer (468)(469)(470) and progressed into clinical testing (NCT01585701) (471). This trial involved 56 patients with solid tumours -mostly advanced CRC, with multiple metastasis-who previously received standard-ofcare treatment.…”

Cancer-Associated Fibroblasts: Implications for Cancer Therapy

“…Furthermore, several clinical trials investigating the activity of molecules that inhibit downstream signalling of IL6-, namely ROCK and STAT3 inhibitors, have been undertaken. A dual ROCK-AKT inhibitor, AT13148, was tested in phase I, but failed to show a safe profile [ 221 ]. The STAT3 inhibitor, AZD9150, was well tolerated in a phase I clinical trial [ 222 ] and an investigation of its efficacy is undergoing.…”

Role of Rho in Salt-Sensitive Hypertension

“…Although 180 mg was the maximum tolerated dose of the drug, post-treatment biopsies of 3 of 8 patients showed a decrease of more than 50% in p-cofilin. In the end, AT13148 was not recommended for further development due to its narrow therapeutic potential area [167]. This study may serve as a reminder that systemic administration of broad-spectrum, potent AGC inhibitors can have various and strong adverse effects.…”

“…AT13148, an oral AGC kinase inhibitor, is a potent inhibitor of ROCKI/II and Akt kinases and has been shown to inhibit cancer metastasis and growth in preclinical studies. In the first human clinical trial with AT13148 in 51 patients with solid tumors, dose-limiting toxicities included hypotension (300 mg), pneumonia, elevated liver enzymes (240 mg), and skin rash (180 mg), and the most common side effects were fatigue, nausea, headache, and hypotension [167]. In other words, dose-limiting toxicities were mainly due to ROCK inhibition (hypotension and headache) and not Akt inhibition (hyperglycemia and rash).…”