Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors

Abstract

Purpose This first-in-human phase I trial assessed the safety, tolerability, and preliminary anti-tumor activity of apitolisib (GDC-0980), a dual inhibitor of class I phosphatidylinositol-3-(PI3K) and mammalian target of rapamycin (mTOR) kinases. Experimental Design Once-daily (QD) oral apitolisib was administered to patients with solid tumors for days 1-21 or 1-28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed. Results Overall, 120 patients were treated at doses between 2-70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40mg QD included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (one patient each) were G4 fasting hyperglycemia at 40 mg (21/28-schedule), and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28-schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the maximum tolerated dose (50 mg). Pharmacodynamic decreases in FDG-PET uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg QD. Evidence of single agent activity included ten RECIST partial responses (confirmed for peritoneal mesothelioma, PIK3CA mutant head- and-neck cancer, and three pleural mesotheliomas). Conclusion Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg QD 28/28-schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable anti-tumor activity was demonstrated.

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

“…The safety profile observed in patients receiving LY3023414 for prolonged period of time was similar as for the overall patient population supporting the longterm tolerability of LY3023414 at the RP2D. Upper gastrointestinal toxicity and fatigue has been previously reported as a common AE for other PI3K/mTOR dual inhibitors with a dosedependent safety profile (17). Potentially due to LY3023414's short half-life with intermittent target inhibition, rash and hyperglycemia were infrequently observed, which contrasts with the toxicity profiles of other PI3K/mTOR inhibitors that commonly report higher rates for these adverse events.…”

Autophagy: controlling cell fate in rheumatic diseases

“…For example, inhibition of AKT signalling combined with inhibi tion of mTOR signalling, using combinations of AKT and mTOR inhibitors or dual PI3K-AKT and mTOR inhibitors, might be of value in promoting autophagy in OA. Novel monospecific and dual inhibitors of AKT, PI3K, mTORC1 and mTORC2 have been tested, or are currently being tested, in clinical trials for the treat ment of breast and other cancers [209][210][211][212][213][214][215][216][217] . Dual PI3K and mTOR inhibitors, and dual mTORC1 and mTORC2 inhibitors, had similar safety and tolerability profiles within each class of compound as well as to allosteric mTORC inhibitors in earlyphase clinical trials in this setting.…”

“…Dual PI3K and mTOR inhibitors, and dual mTORC1 and mTORC2 inhibitors, had similar safety and tolerability profiles within each class of compound as well as to allosteric mTORC inhibitors in earlyphase clinical trials in this setting. The main safety concerns associated with these multispecific agents were dermatological, hyper glycaemic and inflammatory toxicities, which were dependent on dose, the stage of disease progression and previous treatment regimens [210][211][212][213][214][215][216][217] . Although transami nase levels, an indicator of liver damage, were increased in trials of one dual mTORC1-mTORC2 inhibitor (no longer being developed) 210,212 , this finding has not been replicated with other compounds 211,217 .…”

Novel systemic therapy against malignant pleural mesothelioma

“…gov NCT01655225). A phase I study evaluating safety and tolerability of apitolisib, a potent small molecule inhibit of PI3K and mTOR, reported a partial response in 2 out of 26 MPM patients (115). Recently, in vitro studies demonstrated that targeting MET and PI3Ks provides synergistic inhibition of MPM cell proliferation and migration, induction of apoptosis, and reduction in growth of an MPM patient derived xenograft mouse model (116), which provides a rationale for combinatorial therapy.…”