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 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.

Abstract: CC‐223 inhibits both mTORC1 and mTORC2, a feature thought to increase the efficiency of mTOR pathway suppression that distinguishes this agent from rapamycin and its analogs that primarily target mTORC1 alone. In a phase 1 study of patients with advanced solid tumors or multiple myeloma, CC‐223 was tolerable with manageable toxicities, and treatment was associated with early signs of disease control, including tumor regression.

Abstract: Purpose: mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it. Experimental Design: We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology—DNA Encoded Antibody Libraries—was used to identify mechanisms of resistance. Results: Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2–induced cell death. Conclusions: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it. Clin Cancer Res; 19(20); 5722–32. ©2013 AACR.

Abstract: Background: CC-122 is a first in class PPMTM pleiotropic pathway modifier compound with multiple biological activities including potent anti-proliferative activity against B lineage cells, anti-angiogenic activity and immunomodulatory effects. CC-122 binds cereblon, and promotes ubiquitination of lymphoid transcription factors Ikaros and Aiolos, leading to their subsequent degradation resulting in activation of T cells. The immunological properties of CC-122 including effects on T cell subset number in vivo and T cell cytokine production ex vivo was explored in subjects with advanced aggressive non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) enrolled in a Phase 1b trial (NCT01421524) at 3 mg QD and 4 and 5 mg 5/7 days dosed in 28 day cycles until disease progression. Methods: As of June 25, 2015, 76 total DLBCL and MM subjects were enrolled in the expansion phase of the study. Assessments for T cell subset numbers were performed at screening (baseline), cycle 1 day 15 (C1D15), cycle 1 day 22, cycle 2 day 15 and cycle 2 day 22 by flow cytometric immunophenotyping of fresh whole blood. Ex vivo whole blood T cell activation as measured by IL-2, IL-6, IFNg and GM-CSF cytokine production was performed using the anti-CD3 TruCulture Assay. Changes from baseline were evaluated using the t test with p 〈 0.05 considered significant. Results: T cell subsets which were significantly changed are shown in italics in Table 1. In MM subjects (n=19-21) and DLBCL subjects (n=30-31), CC-122 treatment significantly expanded several T cell activator and memory T cell subsets while decreasing naïve T cells. A single dose of CC-122 on C1D1 activated T cells as measured in an ex vivo T cell activation assay in MM subjects (n=6-13) and DLBCL subjects (n=5-12) (Table 2). In addition, we evaluated potential correlations of clinical outcome with baseline biomarker and biomarker changes upon CC-122 treatment. Table 1. MM n=19-21 NHL n=30-31 T cell Parameter Phenotype Baseline cells/mm3 Median % Change at C1D15 from Baseline P Baseline cells/mm3 Median % Change at C1D15 from Baseline P Total T cells ABS CD3+ 636.9 17.733 0.24747 522.94 43.83 0.03638 Total T helper ABS CD3+/CD4+/CD8- 275.38 18.333 0.07812 238.96 13.428 0.09893 T helper Activated ABS CD3+/CD4+/CD8-/HLA-DR+ 62.34 105.769 0.00238 57.11 78.571 0.01567 T helper Total Naïve ABS CD3+/CD4+/CD8-/45RA+/45RO- 69.07 -54.545 0.0038 47.94 -47.841 0.03159 T helper Effector CD62L+ ABS CD3+/CD4+/CD8-/45RA+/62L+ 117.62 0 0.16621 93.74 -6 0.14611 T helper Effector CD62L- ABS CD3+/CD4+/CD8-/45RA+/62L- 21.38 -25.862 0.15196 28.44 -20.161 0.08548 T helper Total Memory ABS CD3+/CD4+/CD8-/45RA-/45RO+ 137.93 41.176 0.05373 119.15 36 0.01915 T helper Central Memory ABS CD3+/CD4+/CD8-/45RA-/62L+ 91.9 47.451 0.01953 75.74 37.143 0.01275 T helper Effector Memory ABS CD3+/CD4+/CD8-/45RA-/62L- 44.17 18.147 0.17768 41.07 19.375 0.04749 Total T cytotoxic ABS CD3+/CD4-/CD8+ 334.07 18.044 0.27499 265.7 43.823 0.0127 T cytotoxic Activated ABS CD3+/CD4-/CD8+ /HLA-DR+ 176.76 100 0.20781 121.3 96.454 0.00686 T cytotoxic Total Naïve ABS CD3+/CD4-/CD8+ /45RA+/45RO- 173.69 -35.714 0.15126 116.04 -32.667 0.89774 T cytotoxic Effector CD62L+ ABS CD3+/CD4-/CD8+ /45RA+/62L+ 127.28 20.727 0.24151 93.43 17.419 0.09599 T cytotoxic Effector CD62L- ABS CD3+/CD4-/CD8+ /45RA+/62L- 151.72 -14.286 0.28394 120.98 -18.301 0.18068 T cytotoxic Total Memory ABS CD3+/CD4-/CD8+ /45RA-/45RO+ 55.03 167.402 0.26292 54.13 184.615 0.01034 T cytotoxic Central Memory ABS CD3+/CD4-/CD8+ /45RA-/62L+ 26.83 160.417 0.00013 18.78 264.087 0.00169 T cytotoxic Effector Memory ABS CD3+/CD4-/CD8+ /45RA-/62L- 28.14 133.333 0.00107 32.59 100 0.01939 Table 2. MM n=6-13 NHL n=5-12 Cytokine Baseline cells/mm3 Median % Change from Baseline P Baseline cells/mm3 Median % Change from Baseline P IL-2 98.71 603.509 0.01329 104.5 437.194 0.01761 IL-6 131.84 124.108 0.03426 99.64 21.68 0.2692 GM-CSF 90.24 636.207 0.06608 212.96 144.601 0.16744 IFNg 271.85 404.98 0.0056 554.64 162.451 0.03024 Conclusions: CC-122 significantly increases the proportion of several cytotoxic and helper T cells subsets while decreasing naïve T cells in both DLBCL and MM subjects. CC-122 also significantly activates T cells ex vivo as measured by cytokine production. These results indicate that CC-122 is a potent modulator of T cell numbers and activation and this may serve as rationale for combinations with other immunotherapies. Disclosures Gandhi: Celgene: Employment, Equity Ownership. Off Label Use: CC-122 is a first in class PPM(TM) pleiotropic pathway modifier with multiple biological activities against B lineage cells. Vincent:Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Carpio:Celgene: Research Funding. Stoppa:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gharibo:Celgene: Research Funding. Damian:Celgene: Research Funding. Rasco:Celgene: Research Funding; Asana BioSciences, LLC: Research Funding. Ysebaert:Celgene: Research Funding. Cordoba:Celgene: Research Funding. Edenfield:Celgene: Research Funding. Pinto:Celgene Corporation: Honoraria; Takeda: Honoraria, Research Funding; Spectrum: Honoraria. López-Martín:Celgene: Research Funding. Sancho:Celgene: Research Funding. Panizo:Janssen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Celgene: Research Funding. Wei:Celgene: Employment, Equity Ownership. Hagner:Celgene: Employment, Equity Ownership. Waldman:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene: Employment.

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.

Abstract: 8522 Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2 complexes. 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 advanced DLBCL, MM and select solid tumors were enrolled in parallel 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, 35 subjects were enrolled including DLBCL (21) and MM (14). Results in solid tumor cohorts are reported separately. The most common ( 〉 20%) related adverse events (all grades) were fatigue, hyperglycemia, rash, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (2), pneumonitis (1), renal insufficiency (2), pancreatitis (1) and thrombocytopenia (1). CC-223 dose reduction was required in 9 subjects (27%), usually during cycle 1 or 2, and 4 additional subjects with DLBCL dropped out during cycle 1 due to toxicity. Systemic exposure was similar between the two tumor cohorts and was associated with inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers in blood cells. Reduction in glucose uptake (32 – 98% decrease) on PET imaging at day 15 was observed in 7/7 DLBCL subjects with results currently available. Three of 17 evaluable subjects with DLBCL had partial responses (PR) after 2 cycles; two with rapid and near complete regression ( 〉 90%) of target lesions by CT and PET with PR confirmed and treatment ongoing at 6 and 8 cycles. Both had failed multiple prior treatment regimens (5 and 3, respectively), including autologous stem cell transplant (ASCT). No responses were observed in 10/14 evaluable subjects with MM although 2 subjects have prolonged stable disease (SD) with treatment ongoing at 12 and 14 cycles. Conclusions: Encouraging signals of biomarker and clinical activity were observed in DLBCL, including two near complete responses, which are ongoing. Due to dose reductions and interruptions, a starting dose of 30 mg QD is recommended for future studies. Clinical trial information: NCT01177397.

Abstract: Introduction: A variety of chemically diverse drugs are known to alter cardiac repolarization and to produce sudden cardiac death. Current regulatory guidelines therefore require the characterization of a new drug's effect on cardiac repolarization, and in particular, the effects on the QTc interval in a thorough QT/QTc study (ICH E14 Guidance, 2005). QTc studies are usually performed with healthy volunteers but may be performed in the targeted patient (pt) population if the toxicity profile of a drug precludes its use in healthy individuals. Early-phase oncology dose-escalation studies generally include pharmacokinetic/pharmacodynamic (PK/PD) evaluations from relatively large pt populations, which could provide a robust data set for concurrent cardiac safety evaluation. We have combined these approaches and present the results from a first-in-human phase 1 study of CC-223, a potent and selective dual inhibitor of mechanistic target of rapamycin (mTOR) kinases. Patients and Methods: Adult (aged 〉 18 years) pts with histologically confirmed advanced non-Hodgkin lymphoma, multiple myeloma, or advanced, unresectable solid tumors who had progressed on (or were unable to tolerate) standard therapy or for whom standard therapy does not exist were eligible. The dose of CC-223, administered orally, ranged from 7.5 to 60.0 mg/day in 28-day continuous cycles. PK blood samples and corresponding triplicate electrocardiograms (ECG) were collected at 2 time points: predose and 1.5-3 hours after the dose in cycle 2. ECG analysis was performed on all pts who received ≥ 1 dose of CC-223 with baseline and on-treatment ECG results available. The primary cardiac assessment was the by time point change from baseline for cardiac interval duration measurements, including heart rate (HR), PR interval, QRS duration, and QTcF interval (QT interval corrected for HR using the Fridericia formula). Secondary analyses included a time-averaged central tendency analysis, analysis of morphology and measurement outliers, and PK/PD analysis of the relationship between the plasma concentration of CC-223 and its M1 metabolite vs QTcF change from baseline. Results: As of April 1, 2013, 158 pts met the requirements for inclusion in the ECG analysis, and of those, 149 were also included in the PK/PD analysis. The data revealed no effect of CC-223 on cardiac interval duration measurements. The by time point analyses of HR, PR, QRS, and QTcF demonstrated no clinically significant ECG effects of CC-223 during cycle 1 or subsequent cycles. The time-averaged central tendency analyses also demonstrated only small changes in cardiac interval duration. For QTcF, the time-averaged mean change from baseline was −18.5 to −1.0 ms in cycle 1 and −8.7 to 7.3 ms in subsequent cycles. There were few nonspecific ECG morphological findings and few measurement outliers. The PK/PD analysis showed no evidence of any significant exposure-effect relationship between CC-223 or the M1 metabolite and QTcF (Figure). The estimated QTcF change at the maximum concentration (Cmax) of 354 ng/mL for CC-223 was −0.2 ms, with an upper 1-sided 95% CI of 1.2 ms, and the estimated QTcF change at Cmaxof 1532 ng/mL for the M1 metabolite was 0.4 ms, with an upper 1-sided 95% CI of 1.8 ms. Adverse events (AEs) related to cardiac function included 2 reports of ventricular arrhythmias; neither event was serious, both resolved while the pts were on study, and neither were considered study drug related. Conclusions: The QTcF intervals and PK/PD relationships for CC-223 and its active metabolite revealed no significant effect on cardiac repolarization or other ECG parameters. This study used a robust data set in pts, avoided potential AE exposure in healthy volunteers, and had the additional benefit of fulfilling the QTc study requirement for new drugs by the Food and Drug Administration. As such, combining a phase 1 study with the required QTc analysis can be an improved, cost-effective approach for assessing cardiac safety during early drug development. Disclosures Kleiman: Celgene Corporation: Consultancy. Chopra:Celgene: Employment, Equity Ownership. Hans:Celgene Corporation: Consultancy. Hege:Celgene Corporation: Employment, Equity Ownership. James:Celgene Corporation: Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. O'Mara:Celgene Corporation: Employment, Equity Ownership.

Abstract: Introduction: PIK3CA and PTEN are among the top five most frequently mutated genes in breast cancer. Activating mutation of PIK3CA or loss of function mutation in PTEN leads to constitutive activation of AKT and mTOR driving multiple downstream metabolic and proliferative pathways important to oncogenesis. There is also cross-talk between the PI3K/AKT/mTOR pathway and ER signaling and activation of the PI3K/AKT/mTOR pathway is associated with resistance to endocrine therapy. CC-223 is a potent and selective ATP-competitive mTOR kinase inhibitor, targeting both TORC1 and TORC2 complexes. Results: Pre-clinically, CC-223 potently inhibits the growth of breast cancer cell lines with GI50 values below 1 uM in 38 of 43 lines. Luminal-derived cell lines are more sensitive to CC-223 than basal-derived lines. Within the luminal subset, ER+, HER2+, PIK3CA mutant, or wild-type TP53 cell lines are more sensitive to CC-223; PTEN loss is not associated with increased CC-223 sensitivity. During the dose escalation part of the phase I clinical trial, 3 pts with breast cancer were enrolled. One pt with HR+/Her2- breast cancer had a durable PR (31 weeks). An expansion cohort of HR+/Her2- breast cancer enrolled 17 pts at a CC-223 dose of 45 mg QD in 28-day cycles and 13 pts were evaluable for tumor response. Deep sequencing of tumors for multiple cancer-related genes was performed. The most common ( & gt; 20%) related adverse events (all grades) reported in the breast cancer cohort were nausea, stomatitis, fatigue, anorexia, diarrhea, vomiting, hyperglycemia, rash, and thrombocytopenia. Exposure-dependent TORC1 (p4EBP1) and TORC2 (pAKT) inhibition was observed in blood cells; analysis of paired tumor biopsies is ongoing. Reduction in glucose uptake ( & gt; 25% decrease in SUV) on PET imaging at day 15 was observed in 4 of 8 patients with PET imaging data currently available. Three pts demonstrated RECIST PR in target lesions (one categorized as PD due to a new bone lesion); PIK3CA mutations were present in all 3 subjects. Of the two additional pts with PIK3CA mutations, one had SD & gt; 6 months. The one PIK3CA mutated subject with PD at first restaging had a concurrent p53 mutation. Additional genetic abnormalities in mTOR and related pathways in subjects with target lesion PR involved PTEN, Rictor, and IGFR1 genes. Six subjects had SD after 2 cycles, with minor target lesion regression (0 to -30%) in 5 of 6, and with SD & gt; 24 weeks in 1 of 6. Conclusion: The safety profile of CC-223 is typical for drugs targeting the mTOR pathway. Preclinical and clinical data support the activity of CC-223 in HR+ positive breast cancer, particularly in tumors with PIK3CA mutations. Breast Cancer Accrual: Cedars-Sinai (Mita): 4; SCRIL (Arkenau): 4; IGR (Varga): 4; SCRI (Bendell): 3 (all Part A); Moffitt (Mahipal): 2; UCSF (Munster): 1; JSOM (Paz-Ares): 1; ICR (DeLord): 1. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A68. Citation Format: Monica M. Mita, Hendrik-Tobias Arkenau, Johanna C. Bendell, Pamela N. Munster, Amit Mahipal, Jean-Pierre Delord, Luis G. Paz-Ares, Jean-Charles Soria, Shuichan Xu, Tam Tran, Tao Shi, Xiaoling Wu, Rajesh Chopra, Kristen Hege, Andrea Varga. Activity of the TORC 1/2 kinase inhibitor, CC-223, in hormone receptor positive (HR+) breast cancer cell lines and patients (pts) with genetically characterized HR+ breast cancer in a Phase I clinical trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A68.

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.