A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors

Abstract

Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257.

Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells

“…Similarly, uprosertib treatment has been shown to cause dosedependent hyperglycaemia and reduced glucose uptake in patients with gynaecological malignancies. 22,23 Glucose carbon entry into the TCA cycle via PDH was also inhibited by uprosertib, consistent with previous work that suggests a direct interaction between PDH subunit B and AKT1 and that silencing of AKT1 could reduce PDH flux from 13 C labelled glucose. 35 By contrast exogenous lactate incorporation into citrate was maintained in cells treated with uprosertib.…”

“…Clinical reports indicate that uprosertib treatment as a monotherapy is primarily associated with tumour growth inhibition and stable disease at the recommended phase II dose (75 mg) in patients with solid tumours. 22 Since lactate concentrations and acidity are often elevated in the tumour microenvironment, the cytostatic response to uprosertib in the presence of lactic acid in our experimental system potentially mimics the stable disease response that has been observed in patients. Glycolysis inhibition occurred upon treatment with uprosertib in the presence and absence of lactic acid supplementation.…”

“…Clinical investigations combining uprosertib with the MEK inhibitor trametinib in several cancers types have been underway, however, similar studies in multiple myeloma, melanoma and cervical cancer have revealed no clinical benefits of this combination. [43][44][45][46] Although uprosertib treatment as a monotherapy has been well tolerated, 22,23 the adverse toxicity profile of phase II combination studies has been deemed unacceptable, thus, uprosertib is not currently under further development. 46 Since we have demonstrated that enhanced OXPHOS in the presence of lactic acid is related to uprosertib resistance, and previous reports highlight that resistance to MEK combination therapies also corresponds with enhanced OXPHOS, 41 this metabolic phenotype should be considered as a possible contributor to the lack of clinical efficacy observed during phase II trials with uprosertib.…”

The Akt pathway in oncology therapy and beyond (Review)

“…The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in a phase I, open-label study in patients with solid tumors. Uprosertib was safe and well-tolerated, most treatment-related adverse events were low grade and included diarrhea, fatigue, vomiting and decreased appetite ( 160 ).…”

Recent Advance of Akt Inhibitors in Clinical Trials

“…Similarly, clinical trials with GSK2141795 and MEK inhibitor GSK1120212 shows that 93% inhibition of tumor growth in the pancreatic cancer tumor model, which is much more effective than the drug alone. In addition, combination with Bortezomib and Dexamethasone of multiple Myeloma in the phase I clinical trial has also been completed (NCT01428492), showed an overall response rate of 41% . GSK2141795 is not in active development lately.…”