A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND METHODS: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. RESULTS: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. CONCLUSIONS: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER: NCT02525068.

Cyclosporin A causes a hypermetabolic state and hypoxia in the liver: prevention by dietary glycine.

Acute cyclosporin A (CsA) treatment inhibits mitochondrial respiration, yet effects of chronic treatment remain unclear. Accordingly, the effects of chronic CsA on oxygen metabolism in perfused rat liver and isolated mitochondria were investigated. Basal rates of oxygen uptake of around 120 micromol/g/h in isolated perfused livers from vehicle-treated controls were elevated about 1.6-fold by chronic CsA treatment. In the presence of ammonium chloride, a substrate for urea synthesis, oxygen uptake was about 150 micromol/g/h and was increased about 1.7-fold by CsA, indicating that chronic CsA treatment causes a robust hypermetabolic state in the liver. In isolated mitochondria, state 3 rates of oxygen uptake were increased about 1.6-fold by chronic CsA treatment. Since significant increases in oxygen consumption could cause hypoxia, the hypoxia marker pimonidazole was given. Pimonidazole binding in the liver was increased about 3-fold by chronic CsA. Moreover, intracellular calcium in Kupffer cells isolated from vehicle-treated rats was not altered by CsA addition; however, in cells isolated from chronic CsA-treated rats, CsA increased intracellular calcium about 15-fold and prostaglandin E(2) (PGE(2)) production 3.5-fold. Importantly, dietary glycine (5%) largely blocked chronic CsA-induced activation of Kupffer cells, blunted production of PGE(2), prevented the hypermetabolic state, and minimized tissue hypoxia. Taken together, it is concluded that chronic CsA treatment causes a hypermetabolic state leading to hypoxia and injury to the liver. It is hypothesized that CsA activates Kupffer cells and increases production of PGE(2), which alters mitochondria leading to a hypermetabolic state. Glycine inhibits activation of Kupffer cells thus preventing liver injury.