Study to Assess Safety, Pharmacokinetics, and Efficacy of Oral CC-223 for Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma or Multiple Myeloma

Phase 1

Completed

Conditions: Diffuse Large B-Cell Lymphoma
Multiple Myeloma
Non-Small Cell Lung Cancer
Hepatocellular Carcinoma
Neuroendocrine Tumors of Non-Pancreatic Origin
Hormone Receptor-Positive Breast Cancer
Glioblastoma Multiforme

Interventions: Drug: CC-223

Registration Number: NCT01177397

Lead Sponsor: Celgene

Brief Summary: The main purpose of this first human study with CC-223 is to assess the safety and action of a new class of experimental drug (dual mTOR inhibitors) in patients with advanced tumors unresponsive to standard therapies and to determine the appropriate dose and tumor type for later-stage clinical trials.

Detailed Description: Initially, patients will be treated with oral CC-223 for one month. During this time, various tests (involving blood and urine collections, ECGs, etc) will be performed. Those whose tumors stabilize or regress may continue receiving treatment for as long as they benefit from CC-223. Different dose levels of CC-223 will be tested in a dose-rising study design.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 226

Inclusion Criteria

Histologically-confirmed advanced solid tumor, Non-Hodgkin Lymphoma or multiple myeloma
Patients have not tolerated or progressed on standard therapy, and no further standard therapy is available
Archival and screening tumor biopsy
Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (solid tumors), 0-2 (hematologic malignancy)
Adequate organ function

Exclusion Criteria

Prior systemic cancer-directed treatments or investigational drugs within 4 weeks or 5 half lives, whichever is shorter, prior to starting study drug or who have not recovered from side effects of such therapy. Subjects must have recovered from any effects of recent radiotherapy that might confound the safety evaluation of study drug
Symptomatic brain metastases (prior Rx and stable metastases are OK)
Acute or chronic liver or renal disease or pancreatitis
Diarrhea ≥ Grade 2, impaired GI absorption
Impaired cardiac function
Diabetes requiring Rx, glucose >126 mg/dL, HbA1c ≥6.5%
Peripheral neuropathy ≥ Grade 2
Pulmonary fibrosis
Known HIV infection
Known chronic hepatitis B or C virus (HBV/HCV) infection, unless comorbidity in subjects with HCC
Pregnant, inadequate contraception
Most concurrent second malignancies

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CC-223	CC-223	All patients will receive CC-223, but serial patient groups will receive different dose levels in Phase 1. The number of groups will be determined by the number of dose levels required to establish dose-limiting toxicity.

Primary Outcome Measures

Name	Time	Method
Maximum Observed Plasma Concentration (Cmax) of CC-223	Cycle 1 Day 1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose	Cmax is defined as the maximum observed concentration (in plasma), obtained directly from the observed concentration versus time data. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.
Part A: Number of Participants With Dose-limiting Toxicities	From first dose up to 30 days after first dose	A dose-limiting toxicity was defined as: - ≥ Grade 3 (per Common Terminology Criteria for Adverse Events \[CTCAE\] Version 4) clinically relevant adverse event (AE) or laboratory abnormality suspected to be related to CC-223 that commenced within 30 days of first dose, except alopecia, Grade 3 rash of the acneiform or maculopapular type for \< 5 days, Grade 3 diarrhea or vomiting lasting \< 72 hours, repeated occurrence of Grade 3 hyperuricaemia in subjects with Grade 3 hyperuricemia at baseline, hyperglycemia, hematologic and liver function test (LFT) abnormalities due to disease progression. - Grade 2 fasting hyperglycemia lasting \> 14 days or ≥ Grade 3 lasting \> 4 days despite optimal medical treatment. - Hematological toxicities including febrile neutropenia, Grade 4 neutropenia or thrombocytopenia for \> 7 days, or Grade 3/4 thrombocytopenia with clinically significant bleeding. - Grade 4 LTFs - AE suspected to be CC-223 related necessitating dose reduction during cycle 1.
Part B: Progression Free Survival (PFS) Rate at 6 Months for GBM Participants	From first dose to 6 months	Progression free survival rate of GBM participants at 6 months is defined as the percentage of participants without progressive disease per Evaluation Criteria in Solid Tumors (RECIST) 1.1 6 months after starting study treatment. Progressive disease is defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Apparent Total Body Clearance (CL/F) of CC-223	Cycle 1 Day 1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose	CL/F is defined as the apparent total body clearance when dosed orally, calculated as Dose/AUCinf. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.
Apparent Volume of Distribution (Vz/F) of CC-223	Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose	Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. VZ/F was not assessed following multiple dosing as the blood sampling schedule on Day 15 did not allow robust assessment of the terminal elimination rate constant.
Time to Maximum Concentration (Tmax) of CC-223	Cycle 1 Day 1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose	Tmax is defined as the time to Cmax, obtained directly from the observed concentration versus time data. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.
Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223	Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose	Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. T1/2 was not assessed following multiple dosing as the blood sampling schedule on Day 15 did not allow robust assessment of the terminal elimination rate constant.
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223	Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose	Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.
Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223	0 to 24 hours post-dose on Day -1 and Day 15	AUC0-24 is defined as the area under the concentration-time curve from Time 0 to 24 hours after a dose. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.
Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) For CC-223	Cycle 1 Day 1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose	AUCinf is defined as the area under the concentration-time curve from Time 0 extrapolated to infinity. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. AUCinf was not assessed following multiple dosing as the blood sampling schedule on Day 15 did not allow robust assessment of the terminal elimination rate constant.

Secondary Outcome Measures

Name	Time	Method
Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes	Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose	Phosphorylated AKT is a biomarker for inhibition of the mammalian target of rapamycin complex 2 (mTORC2). Phosphorylated AKT was measured in stimulated monocytes via flow cytometry. The raw measurements were expressed as median fluorescence intensity (MFI). MFI values were normalized against calibration beads using a linear regression transformation carried out on a log-log scale and reported as equivalent reference fluorophores (ERF). The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Results were not available for the single subject treated in the 7.5-mg dose group and for one of the two subjects treated in the 15-mg dose group.
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose	Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose	Phosphorylated 4E-BP1 is a biomarker for inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Phosphorylated 4E-BP1 was measured in stimulated monocytes via flow cytometry. MFI values were determined and converted to molecules of equivalent fluorescence label (MEFL) by normalizing against calibration beads. The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Data is reported by T-cell subsets known as clusters of differentiation (CD).
Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells	Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose	Phosphorylated S6RP is a biomarker for inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Phosphorylated S6RP was measured in stimulated B cells via flow cytometry. The raw measurements were expressed as median fluorescence intensity (MFI). MFI values were normalized against calibration beads using a linear regression transformation carried out on a log-log scale and reported as equivalent reference fluorophores (ERF). The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Results were not available for the single subject treated in the 7.5-mg dose group and for one of the two subjects treated in the 15-mg dose group.
Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells	Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose	Phosphorylated 4E-BP1 is a biomarker for inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Phosphorylated 4E-BP1 was measured in stimulated T cells via flow cytometry. The raw measurements were expressed as median fluorescence intensity (MFI). MFI values were normalized against calibration beads using a linear regression transformation carried out on a log-log scale and reported as equivalent reference fluorophores (ERF). The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Results were not available for the single subject treated in the 7.5-mg dose group and for one of the two subjects treated in the 15-mg dose group.
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort	Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose	Phosphorylated 4E-BP1 is a biomarker for inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Phosphorylated 4E-BP1 was measured in stimulated monocytes via flow cytometry. MFI values were determined and converted to molecules of equivalent fluorescence label (MEFL) by normalizing against calibration beads. The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Data is reported by T-cell subsets known as clusters of differentiation (CD).
Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1	0 to 24 hours post-dose on Day -1 and Day 15	AUC0-24 is defined as the area under the concentration-time curve from Time 0 to 24 hours after a dose. Plasma metabolite M1 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 10.0 ng/mL.
Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort	Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose	Phosphorylated AKT is a biomarker for inhibition of the mammalian target of rapamycin complex 2 (mTORC2). Phosphorylated AKT was measured in stimulated monocytes via flow cytometry. MFI values were determined and converted to molecules of equivalent fluorescence label (MEFL) by normalizing against calibration beads. The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment.
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1	Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose	AUCt is defined as the area under the concentration-time curve from Time 0 to the time of the last quantifiable concentration. Plasma metabolite M1 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 10.0 ng/mL.
Part B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by Dose	Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose	Phosphorylated AKT is a biomarker for inhibition of the mammalian target of rapamycin complex 2 (mTORC2). Phosphorylated AKT was measured in stimulated monocytes via flow cytometry. MFI values were determined and converted to molecules of equivalent fluorescence label (MEFL) by normalizing against calibration beads. The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment.
Part A: Overall Response Rate	From first dose up to tumor response (approximately 11 months)	Tumor response was based on Investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for solid tumors (NSCLC, HCC, NET, and HRPBC), and the International Working Group Criteria (IWC) for DLBCL. Overall Response Rate is defined as the percentage of participants with a best overall response of complete response or partial response. Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. In Part A, participants with MM and participants with GBM were not evaluated for tumor response.
Part B: Overall Response Rate	From first dose up to tumor response (approximately 36 months)	Tumor response was based on Investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for solid tumors (NSCLC, HCC, NET, and HRPBC), International Working Group Criteria (IWC) for DLBCL, and the International Myeloma Working Group (IMWG) criteria for MM. For GBM, Responses Assessment for Neuro-Oncology Working Group (RANO) criteria were used for tumor response, using the post resection MRI scan as the baseline. Overall Response Rate is defined as the percentage of participants with a best overall response of complete response or partial response. Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time to Maximum Concentration (Tmax) of Metabolite M1	Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose	Tmax is defined as the time to Cmax, obtained directly from the observed concentration versus time data. Plasma metabolite M1 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 10.0 ng/mL.
Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type	Up to Cycle 1 Day 15 3 hours post dose	Tumor tissue biopsies were performed at Baseline and on Day 15 3 hours post dose. Levels of pS6RP were quantified using immunohistochemical (IHC) methods.
Maximum Observed Concentration (Cmax) of Metabolite M1	Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose and Day 15: pre-dose, 0.5, 1, 1.5, 3, 5, and 8 hours post-dose	Cmax is defined as the maximum observed concentration (in plasma), obtained directly from the observed concentration versus time data. Plasma metabolite M1 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 10.0 ng/mL.

Trial Locations

Locations (16): Cedars-Sinai Medical Center
🇺🇸
Los Angeles, California, United States
UCLA Neuro-Oncology Program
🇺🇸
Los Angeles, California, United States
Billings Clinic
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Billings, Montana, United States
NYU Cancer Institute - Bellevue Hospital
🇺🇸
New York, New York, United States
Institut Claudius Regaud
🇫🇷
Toulouse Cedex, France
Mary Crowley Medical Research Center
🇺🇸
Dallas, Texas, United States
Institut Gustave Roussy Faculte de Medecine Paris Sud Service de pneumologie
🇫🇷
Villejuif, France
Hospital Universitario de Salamanca
🇪🇸
Salamanca, Spain
Sarah Cannon Research Institute UK
🇬🇧
London, United Kingdom
Hospital Universitario Virgen Del Rocio
🇪🇸
Sevilla, Spain
UCL Cancer Institute
🇬🇧
London, United Kingdom
Hackensack University Medical Center
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Hackensack, New Jersey, United States
University of California, San Francisco Hellen Diller Family Comprehensive Cancer Center
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San Francisco, California, United States
Moffitt Cancer Center
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Tampa, Florida, United States
Mayo Clinic Cancer Clinical Studies Unit
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Rochester, Minnesota, United States
Sarah Cannon Research Institute Drug Development Unit
🇺🇸
Nashville, Tennessee, United States