Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid and hematologic cancers.

Abstract

3006^ Background: The mammalian target of rapamycin (mTOR) signaling pathway is frequently activated in cancer. The mTOR kinase exists in two multi-protein complexes, TORC1 and TORC2, which drive key cellular metabolic and proliferative functions. TORC1-selective inhibitors can induce feedback upregulation of TORC2 and treatment resistance. CC-223 is an oral, potent, selective, ATP-competitive inhibitor of both TORC1 and TORC2, selected to address this escape mechanism. Methods: Subjects with advanced solid and hematologic cancers were enrolled using an accelerated (1+5) dose escalation design. CC-223 was administered orally once daily (QD) in 28 day cycles until disease progression. Safety, pharmacokinetic, pharmacodynamic and clinical endpoints were evaluated. Results: 28 subjects were treated across 5 dose levels: 7.5 (n=1), 15 (n=2), 30 (n=9), 45 (n=7) and 60 mg (n=8). The most common (> 20%) related adverse events (all grades) were fatigue (64%), nausea (50%), hyperglycemia and diarrhea (43% each), mucositis (39%), anorexia and vomiting (32% each) and rash (29%). Dose-limiting toxicity (all grade 3) occurred in 4 subjects: hyperglycemia (30 mg), rash (45 mg), fatigue (60mg), and mucositis (60 mg). The maximum tolerated dose (MTD) was 45 mg QD. Dose proportional exposure was observed with a terminal half life of 4 to 8 hrs (mean steady state Cmax 485 ng/mL, AUC0-24 2371 ngxhr/mL at 45 mg). Inhibition of TORC1 (pS6, p4EBP1) and TORC2 (pAKT) biomarkers in blood cells was characterized to be exposure-dependent and described by an Emax model. Near maximal inhibition of both TORC1 and TORC2 biomarkers was achieved at the peak concentrations of 30 or 45mg QD. Target inhibition was predicted to last 8 to 20 hours at 45mg QD. Tumor responses included: 1 partial response lasting 9 months (ER+ breast) and 7 subjects with stable disease (SD) lasting 8+ weeks (range 8 to 23.3). Conclusions: CC-223 was well tolerated with toxicities comparable to other drugs in this class. Evidence of TORC1/TORC2 pathway inhibition was observed as well as preliminary signals of anti-tumor activity, including one durable PR. Expansion cohorts in selected hematologic and solid tumors will evaluate CC-223 at the MTD of 45 mg QD.