A phase I dose‐escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC‐223 in patients with advanced solid tumors or multiple myeloma

The mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1/mTORC2 inhibitor CC‐223 in patients with advanced cancer.

• Publication year

  2015

• Venue

  Cancer

• Publication date

  2015-07-15

• Fields of study

  Medicine

• Identifiers
  DOI 10.1002/cncr.29422PMID 26177599PMCID 4832308
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma.

  2014cited by this paper
• Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial.

  2014cited by this paper
• Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2

  2014cited by this paper
• Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy.

  2013cited by this paper
• Abstract C252: A phase 1, dose-escalation study of MLN0128, an investigational oral mammalian target of rapamycin complex 1/2 (mTORC1/2) catalytic inhibitor, in patients (pts) with advanced non-hematologic malignancies.

  2013cited by this paper
• Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors

  2013cited by this paper
• Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM)

  2013cited by this paper
• MLN0128 (INK128), an Investigational Oral Dual TORC1/2 Inhibitor, in Patients (pts) with Relapsed or Refractory Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), or Waldenstrom Macroglobulinemia (WM): Preliminary Results From a Phase 1 Dose-Escalation Study

  2012cited by this paper
• Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma

  2012cited by this paper
• 338 CC-223, a Selective mTOR Kinase Inhibitor, Potently Inhibits Proliferation of a Large Panel of Cancer Cell Lines in Vitro

  2012cited by this paper
• 337 The Discovery and Preclinical Characterization of CC-223, a Novel mTOR Kinase Inhibitor Under Clinical Investigation

  2012cited by this paper
• mTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs

  2010cited by this paper
• Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.

  2010cited by this paper
• Targeting the PI3K/Akt/mTOR Pathway – Beyond Rapalogs

  2010cited by this paper
• Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth.

  2009cited by this paper
• Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer.

  2009cited by this paper
• New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

  2009cited by this paper
• Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

  2009cited by this paper
• An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1*

  2009influential reference
• Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma

  2008cited by this paper
• Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.

  2008cited by this paper
• Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.

  2007cited by this paper
• International uniform response criteria for multiple myeloma

  2007cited by this paper
• International uniform response criteria for multiple myeloma

  2006cited by this paper
• mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.

  2006cited by this paper
• Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.

  2005cited by this paper
• Accelerated titration designs for phase I clinical trials in oncology.

  1997cited by this paper
• Annals of the New York Academy of Sciences Challenges in the Clinical Development of Pi3k Inhibitors

  year unknowncited by this paper

• Induction of Triple-Negative Breast Cancer Cell Death and Chemosensitivity Using mTORC2-Directed RNAi Nanomedicine

  2025cites this paper
• mTOR in radiotherapy of lung cancer: Mechanisms of radiation resistance and therapeutic implications (Review)

  2025cites this paper
• Kanser Tedavisinde PI3K/AKT/mTOR Yolunun Hedeflenmesi: Yeni Nesil mTOR İnhibitörlerine Güncel Bir Değerlendirme

  2025cites this paper
• Multicenter phase 1/2 study of onatasertib, a dual TORC1/2 inhibitor, combined with the PD-1 antibody toripalimab in advanced solid tumors

  2025cites this paper
• Chemically engineered mTOR-nanoparticle blockers enhance antitumour efficacy

  2024cites this paper
• Targeting mTOR signaling pathways in multiple myeloma: biology and implication for therapy

  2024cites this paper
• Mechanistic insights and the clinical prospects of targeted therapies for glioblastoma: a comprehensive review

  2024cites this paper
• Molecular targeted therapies for cutaneous squamous cell carcinoma: recent developments and clinical implications

  2024cites this paper
• The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches.

  2023cites this paper
• Phase I dose escalation study and pilot efficacy analysis of LXI-15029, a novel mTOR dual inhibitor, in Chinese subjects with advanced malignant solid tumors

  2023cites this paper
• Seizure reduction in TSC2‐mutant mouse model by an mTOR catalytic inhibitor

  2023cites this paper
• Identification of Promising Drug Candidates against Prostate Cancer through Computationally-Driven Drug Repurposing

  2023cites this paper
• Phase Ib study of combinations of avadomide (CC‐122), CC‐223, CC‐292, and rituximab in patients with relapsed/refractory diffuse large B‐cell lymphoma

  2022cites this paper
• Beyond controlling cell size: functional analyses of S6K in tumorigenesis

  2022cites this paper
• Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases

  2022cites this paper
• Phosphatidylinositol 3-kinase signaling inhibitors for treatment of multiple myeloma: From small molecules to microRNAs

  2021cites this paper
• Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling

  2021cites this paper
• Analytical Validation of Quantitative Pharmacodynamic Methods used in Clinical Cancer Studies

  2021cites this paper
• Hayatine inhibits amino acid-induced mTORC1 activation as a novel mTOR-Rag A/C interaction disruptor.

  2021cites this paper
• Targeting mTOR and Glycolysis in HER2-Positive Breast Cancer

  2021cites this paper
• UHPLC-MS/MS method to determine FP-208 in human plasma and its application to a pharmacokinetic study.

  2020cites this paper
• Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

  2020cites this paper
• Metformin enhances anti-cancer effects of cisplatin in meningioma through AMPK-mTOR signaling pathways

  2020cites this paper
• Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer

  2020cites this paper
• Novel PI3K/Akt/mTOR pathway inhibitors plus radiotherapy: Strategy for non-small cell lung cancer with mutant RAS gene.

  2020cites this paper
• Local Coverage Determination (LCD): Biomarker Testing for Neuroendocrine Tumors/Neoplasms (L37851)

  2020cites this paper
• Mitochondrial Perturbations Couple mTORC2 to Autophagy in C. elegans

  2019cites this paper
• mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy

  2019influential citation
• Cross Talk Networks of Mammalian Target of Rapamycin Signaling With the Ubiquitin Proteasome System and Their Clinical Implications in Multiple Myeloma.

  2019cites this paper
• A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial–Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer

  2019cites this paper
• An In silico Approach to Identify High Affinity Small Molecule Targeting m-TOR Inhibitors for the Clinical Treatment of Breast Cancer

  2019cites this paper
• The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax

  2019cites this paper
• DCZ0814 induces apoptosis and G0/G1 phase cell cycle arrest in myeloma by dual inhibition of mTORC1/2

  2019cites this paper
• Human BCR/ABL1 induces chronic myeloid leukemia-like disease in zebrafish

  2019cites this paper
• Emerging protein kinase inhibitors for the treatment of multiple myeloma

  2019cites this paper
• A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms

  2019cites this paper
• Mitochondrial Perturbations Couple mTORC2 to Autophagy in C. elegans.

  2019cites this paper
• PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases

  2019cites this paper
• mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

  2019cites this paper
• First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy

  2019influential citation
• CMAR_A_208720 10463..10476

  2019influential citation
• CMAR_A_194202 4797..4808

  2019cites this paper
• mTOR inhibition enhances efficacy of dasatinib in ABL-rearranged Ph-like B-ALL

  2018cites this paper
• ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer

  2018cites this paper
• Targeting the PI3K pathway in cancer: are we making headway?

  2018cites this paper
• Protein Targeting Chimeric Molecules Specific for Bromodomain and Extra-terminal Motif Family Proteins are Active Against Pre-Clinical Models of Multiple Myeloma

  2018cites this paper
• mTOR Inhibitors, with Special Focus on Temsirolimus and Similar Agents

  2018cites this paper
• Biological Aspects of mTOR in Leukemia

  2018cites this paper
• The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood‐brain barrier and increase seizure threshold in a mouse model of chronic epilepsy

  2018cites this paper
• Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways

  2018cites this paper
• The role of mTOR-mediated signaling in the regulation of cellular migration.

  2018cites this paper
• The structure of mTOR complexes at a glance

  2018cites this paper
• CC-223 inhibits human head and neck squamous cell carcinoma cell growth.

  2018cites this paper
• The next generation of PI3K-Akt-mTOR pathway inhibitors in breast cancer cohorts.

  2018cites this paper
• Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

  2017cites this paper
• CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair pathways and selectively inhibits ATM-deficient cell growth in vitro

  2017cites this paper
• mTOR Controls Mitochond rial Dynamics and Cell Survival via MTFP 1 Graphical Abstract Highlights

  2017cites this paper
• The Pathway in Human Disease.

  2017influential citation
• Inhibiting 4EBP1 in Glioblastoma

  2017cites this paper
• Discovery and Development of ATP-Competitive mTOR Inhibitors Using Computational Approaches.

  2017cites this paper
• mTOR function and therapeutic targeting in breast cancer.

  2017cites this paper
• mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1.

  2017cites this paper
• Renal Toxicities of Novel Agents Used for Treatment of Multiple Myeloma.

  2017cites this paper
• Uncoupling TORC2 from AGC kinases inhibits tumour growth

  2017cites this paper
• Preclinical study of CC223 as a potential anti-ovarian cancer agent

  2017cites this paper
• m‐TOR inhibitors and their potential role in haematological malignancies

  2017cites this paper
• Resistance to HER2-Targeted Therapy

  2017cites this paper
• The PI3K Pathway in Human Disease.

  2017influential citation
• Novel quinoline-derived mTOR inhibitors with remarkable enzymatic and cellular activities: design, synthesis and biological evaluation

  2016cites this paper
• Autophagy: controlling cell fate in rheumatic diseases

  2016cites this paper
• Targeting mTOR for the treatment of B cell malignancies.

  2016cites this paper
• Kinase inhibitors as potential agents in the treatment of multiple myeloma

  2016cites this paper
• Roles of mTOR complexes in the kidney: implications for renal disease and transplantation

  2016cites this paper
• Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer

  2016cites this paper
• The therapeutic potential of mTOR inhibitors in breast cancer.

  2016cites this paper
• CONCOMITANT TARGETING OF THE MTOR/MAPK PATHWAYS: NOVEL THERAPEUTIC STRATEGY IN SUBSETS OF NON-SMALL CELL LUNG CANCER

  2016cites this paper
• Mammalian‐target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the German MDS Study Group (D‐MDS)

  2016cites this paper
• mTORC1 and mTORC2 in cancer and the tumor microenvironment

  2016cites this paper
• Rapamycin and rapalogs : partial mTORC 1 inhibitors Mechanism of action

  2016cites this paper
• Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives

  2016influential citation
• RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors.

  2015cites this paper
• RICTOR Amplifi cation Defi nes a Novel Subset of Patients with Lung Cancer Who May Benefi t from Treatment with mTORC 1 / 2 Inhibitors

  2015cites this paper
• Inhibitors of mTOR pathway for cancer therapy, moving on from rapalogs to TORKinibs

  2015cites this paper
• Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115.

  2015cites this paper
• CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

  2015cites this paper
• Clinical Study Phase 1 study of mTORC 1 / 2 inhibitor sapanisertib ( TAK-228 ) in advanced solid tumours , with an expansion phase in renal , endometrial or bladder cancer

  year unknowncites this paper