Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in nonpancreatic neuroendocrine tumors (NET).

Abstract

e15004 Background: Clinical activity of everolimus, an allosteric TORC1-selective inhibitor, has been established in pancreatic NET. CC-223 is an ATP-competitive inhibitor of the mTOR kinase, inhibiting both TORC1 and TORC2 complexes. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with non-pancreatic NET and selected other tumors were enrolled in expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 101 solid tumor subjects have been treated. Preliminary results from the NET cohort (n=23) are reported here. Subjects with non-pancreatic tumors of gut origin with progression within 12 months and receiving ongoing treatment with somatostatin analogs (SSA) were eligible. The majority of tumors were of midgut origin with liver metastases; 9 subjects had refractory carcinoid syndrome despite SSA use. The most common (> 20%) related adverse events (all grades) were stomatitis, diarrhea, fatigue, anorexia, nausea and rash. In addition, related serious adverse events included one case of transient dehydration/renal insufficiency (1). CC-223 dose reduction to 30 or 15 mg was required in 57% of subjects, usually during cycle 1 or 2, but thereafter treatment was well tolerated. Inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers was confirmed in blood cells. Reduction in glucose uptake (> 25% change in SUV) on PET imaging at day 15 was observed in 54% (7/13) subjects. All evaluable subjects (n=10) reported stable disease (SD) with treatment ongoing at up to 9 cycles (median 6; range 4 – 9). Although not prospectively collected, 6 subjects with refractory carcinoid syndrome reported complete resolution of flushing (5) or improvement in diarrhea (1). Symptom improvement generally occurred within the first week of dosing and persisted despite dose reduction in 5 subjects. Conclusions: Encouraging signals of biomarker and clinical activity were observed in NET including prolonged SD and symptomatic improvement in subjects with refractory carcinoid syndrome. Due to the frequency of early dose reductions, the NET cohort will be explored further at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.