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

Primary Purpose

Multiple Myeloma, Diffuse Large B-Cell Lymphoma, Glioblastoma Multiforme

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
CC-223
Sponsored by
Celgene
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring Advanced solid malignant neoplasms,Non-Hodgkin Lymphoma,, Multiple Myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Cedars-Sinai Medical Center
  • UCLA Neuro-Oncology Program
  • University of California, San Francisco Hellen Diller Family Comprehensive Cancer Center
  • Moffitt Cancer Center
  • Mayo Clinic Cancer Clinical Studies Unit
  • Billings Clinic
  • Hackensack University Medical Center
  • NYU Cancer Institute - Bellevue Hospital
  • Sarah Cannon Research Institute Drug Development Unit
  • Mary Crowley Medical Research Center
  • Institut Claudius Regaud
  • Institut Gustave Roussy Faculte de Medecine Paris Sud Service de pneumologie
  • Hospital Universitario de Salamanca
  • Hospital Universitario Virgen Del Rocio
  • Sarah Cannon Research Institute UK
  • UCL Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CC-223

Arm Description

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.

Outcomes

Primary Outcome Measures

Part A: Number of Participants With Dose-limiting Toxicities
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.
Maximum Observed Plasma Concentration (Cmax) of CC-223
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.
Time to Maximum Concentration (Tmax) of CC-223
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.
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223
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
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
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.
Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223
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.
Apparent Total Body Clearance (CL/F) of CC-223
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
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.
Part B: Progression Free Survival (PFS) Rate at 6 Months for GBM Participants
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.

Secondary Outcome Measures

Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells
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
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 A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes
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 by Tumor Cohort
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 B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by 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 B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort
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 B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by 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 B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type
Tumor tissue biopsies were performed at Baseline and on Day 15 3 hours post dose. Levels of pS6RP were quantified using immunohistochemical (IHC) methods.
Part A: Overall Response Rate
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
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.
Maximum Observed Concentration (Cmax) of Metabolite M1
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.
Time to Maximum Concentration (Tmax) of Metabolite M1
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.
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1
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.
Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1
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.

Full Information

First Posted
August 5, 2010
Last Updated
December 9, 2022
Sponsor
Celgene
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1. Study Identification

Unique Protocol Identification Number
NCT01177397
Brief Title
Study to Assess Safety, Pharmacokinetics, and Efficacy of Oral CC-223 for Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma or Multiple Myeloma
Official Title
A Phase 1/2, Multi-Center, Open-Label, Dose Finding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the mTOR Kinase Inhibitor CC-223 Administered Orally to Subjects With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Multiple Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
July 20, 2010 (Actual)
Primary Completion Date
November 15, 2016 (Actual)
Study Completion Date
December 9, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Celgene

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma, Diffuse Large B-Cell Lymphoma, Glioblastoma Multiforme, Hepatocellular Carcinoma, Non-Small Cell Lung Cancer, Neuroendocrine Tumors of Non-Pancreatic Origin, Hormone Receptor-Positive Breast Cancer
Keywords
Advanced solid malignant neoplasms,Non-Hodgkin Lymphoma,, Multiple Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
226 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CC-223
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
CC-223
Intervention Description
Part A: (closed to enrollment) Dose level starts with 7.5mg daily taken by mouth in cycles of 28 days. Level increases for different patient cohorts in 100% or 50% increments until optimal dose level is established for further study. Treatment continues for as long as patient benefits (i.e., until disease progression or unacceptable toxicity). Part B: (closed to enrollment) Optimal dose is administered in 28 day cycles until disease progression.
Primary Outcome Measure Information:
Title
Part A: Number of Participants With Dose-limiting Toxicities
Description
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.
Time Frame
From first dose up to 30 days after first dose
Title
Maximum Observed Plasma Concentration (Cmax) of CC-223
Description
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.
Time Frame
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
Title
Time to Maximum Concentration (Tmax) of CC-223
Description
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.
Time Frame
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
Title
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223
Description
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.
Time Frame
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
Title
Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223
Description
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.
Time Frame
0 to 24 hours post-dose on Day -1 and Day 15
Title
Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) For CC-223
Description
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.
Time Frame
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
Title
Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223
Description
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.
Time Frame
Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose
Title
Apparent Total Body Clearance (CL/F) of CC-223
Description
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.
Time Frame
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
Title
Apparent Volume of Distribution (Vz/F) of CC-223
Description
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 Frame
Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose
Title
Part B: Progression Free Survival (PFS) Rate at 6 Months for GBM Participants
Description
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.
Time Frame
From first dose to 6 months
Secondary Outcome Measure Information:
Title
Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells
Description
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.
Time Frame
Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose
Title
Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells
Description
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.
Time Frame
Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose
Title
Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes
Description
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.
Time Frame
Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose
Title
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort
Description
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).
Time Frame
Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
Title
Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose
Description
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).
Time Frame
Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
Title
Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort
Description
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.
Time Frame
Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
Title
Part B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by Dose
Description
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.
Time Frame
Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
Title
Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type
Description
Tumor tissue biopsies were performed at Baseline and on Day 15 3 hours post dose. Levels of pS6RP were quantified using immunohistochemical (IHC) methods.
Time Frame
Up to Cycle 1 Day 15 3 hours post dose
Title
Part A: Overall Response Rate
Description
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.
Time Frame
From first dose up to tumor response (approximately 11 months)
Title
Part B: Overall Response Rate
Description
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 Frame
From first dose up to tumor response (approximately 36 months)
Title
Maximum Observed Concentration (Cmax) of Metabolite M1
Description
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.
Time Frame
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
Title
Time to Maximum Concentration (Tmax) of Metabolite M1
Description
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.
Time Frame
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
Title
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1
Description
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.
Time Frame
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
Title
Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1
Description
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.
Time Frame
0 to 24 hours post-dose on Day -1 and Day 15

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
Cedars-Sinai Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
UCLA Neuro-Oncology Program
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of California, San Francisco Hellen Diller Family Comprehensive Cancer Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Mayo Clinic Cancer Clinical Studies Unit
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Billings Clinic
City
Billings
State/Province
Montana
ZIP/Postal Code
59102
Country
United States
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
NYU Cancer Institute - Bellevue Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Sarah Cannon Research Institute Drug Development Unit
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Mary Crowley Medical Research Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75201
Country
United States
Facility Name
Institut Claudius Regaud
City
Toulouse Cedex
ZIP/Postal Code
31052
Country
France
Facility Name
Institut Gustave Roussy Faculte de Medecine Paris Sud Service de pneumologie
City
Villejuif
ZIP/Postal Code
94800
Country
France
Facility Name
Hospital Universitario de Salamanca
City
Salamanca
ZIP/Postal Code
37007
Country
Spain
Facility Name
Hospital Universitario Virgen Del Rocio
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Facility Name
Sarah Cannon Research Institute UK
City
London
ZIP/Postal Code
W1G 6AD
Country
United Kingdom
Facility Name
UCL Cancer Institute
City
London
ZIP/Postal Code
WC1E 6BT
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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