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Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid and hematologic cancers.
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2012
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Torc2 BiomarkersPathologyPharmacotherapyTumor BiologyMolecular PharmacologyOral Torc1/torc2 InhibitorDose Proportional ExposureOncologyMetronomic TherapyCancer Cell BiologyHematologic CancersAnti-cancer AgentMtor Kinase ExistsRadiation OncologyCancer ResearchMolecular OncologyCancer TreatmentPharmacologyMedicine
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 C max 485 ng/mL, AUC 0-24 2371 ng x hr/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 E max 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.