Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid tumors.

Abstract

2606 Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with select advanced, refractory solid tumors, including NSCLC, HCC, NET, GBM and breast 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, including NSCLC (26), HCC (25), NET (23), breast (14), and GBM (13). Results from the NSCLC, HCC, and GBM cohorts are reported here; NET results are reported separately. The most common (> 20%) related adverse events (all grades) were fatigue, rash, stomatitis, hyperglycemia, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (1), pneumonitis (4), renal insufficiency (2) and pancreatitis (2). CC-223 dose reduction was required in > 50% of subjects with NSCLC and HCC, usually during cycle 1 or 2. Exposure-dependent TORC1 (p4EBP1) and TORC2 (pAKT) inhibition was observed across cohorts. mTOR pathway inhibition and/or decreased proliferation was demonstrated in paired tumor biopsies, but results were inconsistent. Reduction in glucose uptake (> 25% decrease in SUV) on PET imaging at day 15 was observed in 78% (14/18) of NSCLC and 69% (11/16) of HCC subjects. Partial tumor responses were observed in evaluable subjects with NSCLC (1/17; confirmed, treatment duration 36 weeks) and HCC (3/15; 1 confirmed, treatment duration 15 – 26 weeks). Disease control rate in the overall NSCLC cohort was 42% (11/26) and in the HCC cohort, 40% (10/25). GBM subjects underwent salvage resections on study and none were progression-free at 6 months. CC-223 was present in all (11/11) resected GBM tumors with plasma:tumor ratios of 16 - 77%, confirming transit across the blood-brain barrier. Conclusions: Encouraging signals of biomarker and clinical activity were observed in HCC and NSCLC. Due to the frequency of dose reductions, select additional cohorts will be enrolled at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.

A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms

“…The 45 mg CC-223 once daily was not well-tolerated in the NET cohort. Dose reductions were also reported for >50% of patients in tumor-specific cohorts of non-small cell lung cancer and hepatocellular carcinoma dosed at 45 mg [16]. Most dose reductions occurred during the first 1–2 cycles of treatment.…”

Distinct inhibitory effects on mTOR signaling by ethanol and INK128 in diffuse large B-cell lymphoma

“…Initial results have shown catalytic inhibitors having single-agent activity apparently higher than that seen with rapalogs. Clinical responses to TORKinibs have thus far been seen in patients with non-small cell lung cancer, hepatocellular carcinoma, and estrogen receptor positive breast cancer, with potential utility in diffuse large B-cell lymphoma [ 8 - 11 ].…”

Chemical and Structural Strategies to Selectively Target mTOR Kinase

“…The dihydropyrazino[2,3-b]pyrazin-2(1H)-one 49 has been included in a screening trial of innovative glioblastoma therapy [NCT02977780], while 50 has been assessed in different tumors including glioblastoma multiforme [NCT01177397]. [95] Chemical modifications on the triazine core led to inhibitors with specific targeting profiles and optimized brain penetration. While the dual PI3K/TORKi 4 showed negligible brain concentrations (B/P: 0.3, Figure 8d), [33] the dual PI3K/mTOR inhibitors 2 [32,96] and 5 [34] displayed excellent brain exposure (B/P: 1 and 1.67, Figure 8d and Figure 9c green circles).…”

“…The dihydropyrazino[2,3‐ b ]pyrazin‐2(1 H )‐one 49 has been included in a screening trial of innovative glioblastoma therapy [NCT02977780], while 50 has been assessed in different tumors including glioblastoma multiforme [NCT01177397]. [95] …”

“…Compound 46 was also found to inhibit the growth of glioblastomas in vitro and in vivo , [94] and the derivatives 49 and 50 obtained through medicinal chemistry investigations are currently in clinical trials. The dihydropyrazino[2,3‐ b ]pyrazin‐2(1 H )‐one 49 has been included in a screening trial of innovative glioblastoma therapy [NCT02977780], while 50 has been assessed in different tumors including glioblastoma multiforme [NCT01177397] [95] …”