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
Conditions
Keywords
Advanced solid malignant neoplasms,Non-Hodgkin Lymphoma,, Multiple Myeloma
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.
Interventions
DRUGCC-223
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.
Sponsors
Celgene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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. |
| 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. |
| 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 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 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 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). |
| 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 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. |
| 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 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. |
| 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. |
Countries
France, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: CC-223 7.5 mg Participants received a single dose of 7.5 mg CC-223 on Day -1, then daily dosing of 7.5 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator. | 1 |
| Part A: CC-223 15 mg Participants received a single dose of 15 mg CC-223 on Day -1, then daily dosing of 15 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator. | 2 |
| Part A: CC-223 30 mg Participants received a single dose of 30 mg CC-223 on Day -1, then daily dosing of 30 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator. | 9 |
| Part A: CC-223 45 mg Participants received a single dose of 45 mg CC-223 on Day -1, then daily dosing of 45 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator. | 9 |
| Part A: CC-223 60 mg Participants received a single dose of 60 mg CC-223 on Day -1, then daily dosing of 60 mg CC-223 for 28 days beginning on Day 1. Participants received subsequent cycles consisting of 28-day continuous dosing without rest between cycles for as long as they derived benefit from treatment as judged by the investigator. | 7 |
| Part B: Non-small Cell Lung Cancer (NSCLC) Participants with NSCLC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator. | 26 |
| Part B: Glioblastoma Multiforme (GBM) Participants with GBM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator. | 13 |
| Part B: Hepatocellular Carcinoma (HCC) Participants with HCC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator. | 53 |
| Part B: Neuroendocrine Tumor (NET) Participants with NET received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator. | 47 |
| Part B: Diffuse Large B-cell Lymphoma (DLBCL) Participants with DLBCL received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator. | 28 |
| Part B: Multiple Myeloma (MM) Participants with MM received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator. | 14 |
| Part B: Hormone Receptor Positive Breast Cancer (HRPBC) Participants with HRPBC received CC-223 at a starting dose of 45 mg/day (reduced to 30 mg/day after protocol Amendment 9) orally once a day in 28-day cycles for as long as they derived benefit from treatment as judged by the investigator. | 17 |
| Total | 226 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 2 | 0 | 12 | 1 | 14 | 8 | 6 | 3 | 7 |
| Overall Study | Death | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 5 | 2 | 1 | 0 | 0 |
| Overall Study | Disease progression | 1 | 2 | 5 | 5 | 4 | 10 | 10 | 21 | 18 | 12 | 10 | 8 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Other reasons | 0 | 0 | 1 | 0 | 1 | 1 | 2 | 6 | 10 | 8 | 0 | 2 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 1 | 2 | 0 | 5 | 9 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Part A: CC-223 7.5 mg | Part A: CC-223 15 mg | Part A: CC-223 30 mg | Part A: CC-223 45 mg | Part A: CC-223 60 mg | Part B: Non-small Cell Lung Cancer (NSCLC) | Part B: Glioblastoma Multiforme (GBM) | Part B: Hepatocellular Carcinoma (HCC) | Part B: Neuroendocrine Tumor (NET) | Part B: Diffuse Large B-cell Lymphoma (DLBCL) | Part B: Multiple Myeloma (MM) | Part B: Hormone Receptor Positive Breast Cancer (HRPBC) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.0 years | 54.5 years STANDARD_DEVIATION 10.61 | 53.8 years STANDARD_DEVIATION 11.57 | 46.0 years STANDARD_DEVIATION 12.86 | 49.9 years STANDARD_DEVIATION 11.65 | 62.8 years STANDARD_DEVIATION 10.72 | 55.6 years STANDARD_DEVIATION 9.46 | 60.0 years STANDARD_DEVIATION 11.41 | 62.6 years STANDARD_DEVIATION 9.87 | 53.9 years STANDARD_DEVIATION 14.51 | 60.4 years STANDARD_DEVIATION 10 | 53.9 years STANDARD_DEVIATION 7.79 | 58.2 years STANDARD_DEVIATION 11.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants | 2 Participants | 4 Participants | 2 Participants | 1 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 2 Participants | 9 Participants | 9 Participants | 7 Participants | 20 Participants | 12 Participants | 44 Participants | 45 Participants | 22 Participants | 6 Participants | 11 Participants | 188 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 5 Participants | 0 Participants | 2 Participants | 6 Participants | 5 Participants | 22 Participants |
| Race Asian | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 10 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 20 Participants |
| Race Black or African American | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 9 Participants |
| Race Missing | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 5 Participants | 0 Participants | 2 Participants | 6 Participants | 5 Participants | 22 Participants |
| Race Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race White | 1 Participants | 2 Participants | 7 Participants | 7 Participants | 6 Participants | 20 Participants | 12 Participants | 31 Participants | 43 Participants | 24 Participants | 8 Participants | 10 Participants | 171 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 6 Participants | 5 Participants | 6 Participants | 12 Participants | 5 Participants | 10 Participants | 28 Participants | 11 Participants | 6 Participants | 17 Participants | 108 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 3 Participants | 4 Participants | 1 Participants | 14 Participants | 8 Participants | 43 Participants | 19 Participants | 17 Participants | 8 Participants | 0 Participants | 118 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 | 2 / 9 | 3 / 9 | 1 / 7 | 10 / 26 | 3 / 13 | 24 / 53 | 2 / 47 | 5 / 28 | 2 / 14 | 4 / 17 |
| other Total, other adverse events | 1 / 1 | 2 / 2 | 8 / 9 | 9 / 9 | 7 / 7 | 26 / 26 | 13 / 13 | 53 / 53 | 47 / 47 | 28 / 28 | 14 / 14 | 17 / 17 |
| serious Total, serious adverse events | 0 / 1 | 0 / 2 | 4 / 9 | 4 / 9 | 2 / 7 | 15 / 26 | 6 / 13 | 29 / 53 | 23 / 47 | 17 / 28 | 6 / 14 | 11 / 17 |
Outcome results
Primary
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.
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
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: CC-223 7.5 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day 15 | 25.1 L/h | — |
| Part A: CC-223 7.5 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day -1/1 | 21.2 L/h | — |
| Part A: CC-223 15 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day 15 | 39.2 L/h | Geometric Coefficient of Variation 88.8 |
| Part A: CC-223 15 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day -1/1 | 39.7 L/h | Geometric Coefficient of Variation 49.7 |
| Part A: CC-223 30 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day -1/1 | 24.3 L/h | Geometric Coefficient of Variation 38.9 |
| Part A: CC-223 30 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day 15 | 20.8 L/h | Geometric Coefficient of Variation 41.4 |
| Part A: CC-223 45 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day -1/1 | 26.6 L/h | Geometric Coefficient of Variation 41.8 |
| Part A: CC-223 45 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day 15 | 21.6 L/h | Geometric Coefficient of Variation 29.3 |
| Part A: CC-223 60 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day 15 | 20.3 L/h | Geometric Coefficient of Variation 106.2 |
| Part A: CC-223 60 mg | Apparent Total Body Clearance (CL/F) of CC-223 | Day -1/1 | 28.9 L/h | Geometric Coefficient of Variation 111.4 |
Primary
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.
Time frame: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: CC-223 7.5 mg | Apparent Volume of Distribution (Vz/F) of CC-223 | 235 L | — |
| Part A: CC-223 15 mg | Apparent Volume of Distribution (Vz/F) of CC-223 | 192 L | Geometric Coefficient of Variation 3.7 |
| Part A: CC-223 30 mg | Apparent Volume of Distribution (Vz/F) of CC-223 | 195 L | Geometric Coefficient of Variation 36.7 |
| Part A: CC-223 45 mg | Apparent Volume of Distribution (Vz/F) of CC-223 | 186 L | Geometric Coefficient of Variation 27.1 |
| Part A: CC-223 60 mg | Apparent Volume of Distribution (Vz/F) of CC-223 | 236 L | Geometric Coefficient of Variation 107.5 |
Primary
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.
Time frame: 0 to 24 hours post-dose on Day -1 and Day 15
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: CC-223 7.5 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day -1 | 319 ng*h/mL | — |
| Part A: CC-223 7.5 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day 15 | 299 ng*h/mL | — |
| Part A: CC-223 15 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day -1 | 379 ng*h/mL | Geometric Coefficient of Variation 45.2 |
| Part A: CC-223 15 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day 15 | 383 ng*h/mL | Geometric Coefficient of Variation 88.8 |
| Part A: CC-223 30 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day -1 | 1144 ng*h/mL | Geometric Coefficient of Variation 36.5 |
| Part A: CC-223 30 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day 15 | 1443 ng*h/mL | Geometric Coefficient of Variation 41.4 |
| Part A: CC-223 45 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day 15 | 2082 ng*h/mL | Geometric Coefficient of Variation 29.3 |
| Part A: CC-223 45 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day -1 | 1497 ng*h/mL | Geometric Coefficient of Variation 45.5 |
| Part A: CC-223 60 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day -1 | 2031 ng*h/mL | Geometric Coefficient of Variation 96.3 |
| Part A: CC-223 60 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223 | Day 15 | 2954 ng*h/mL | Geometric Coefficient of Variation 106.2 |
Primary
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.
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
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: CC-223 7.5 mg | Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) For CC-223 | Day -1/1 | 353 ng*h/mL | — |
| Part A: CC-223 15 mg | Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) For CC-223 | Day -1/1 | 378 ng*h/mL | Geometric Coefficient of Variation 49.7 |
| Part A: CC-223 30 mg | Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) For CC-223 | Day -1/1 | 1234 ng*h/mL | Geometric Coefficient of Variation 38.9 |
| Part A: CC-223 45 mg | Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) For CC-223 | Day -1/1 | 1694 ng*h/mL | Geometric Coefficient of Variation 41.8 |
| Part A: CC-223 60 mg | Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) For CC-223 | Day -1/1 | 2074 ng*h/mL | Geometric Coefficient of Variation 111.4 |
Primary
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.
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
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: CC-223 7.5 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day -1/Day 1 | 318 ng*h/mL | — |
| Part A: CC-223 7.5 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day 15 | 179 ng*h/mL | — |
| Part A: CC-223 15 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day 15 | 282 ng*h/mL | Geometric Coefficient of Variation 100.7 |
| Part A: CC-223 15 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day -1/Day 1 | 347 ng*h/mL | Geometric Coefficient of Variation 60.2 |
| Part A: CC-223 30 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day 15 | 1016 ng*h/mL | Geometric Coefficient of Variation 39.2 |
| Part A: CC-223 30 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day -1/Day 1 | 1204 ng*h/mL | Geometric Coefficient of Variation 37.8 |
| Part A: CC-223 45 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day -1/Day 1 | 1493 ng*h/mL | Geometric Coefficient of Variation 54.3 |
| Part A: CC-223 45 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day 15 | 1351 ng*h/mL | Geometric Coefficient of Variation 45 |
| Part A: CC-223 60 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day 15 | 1900 ng*h/mL | Geometric Coefficient of Variation 93.5 |
| Part A: CC-223 60 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223 | Day -1/Day 1 | 2080 ng*h/mL | Geometric Coefficient of Variation 100.8 |
Primary
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 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
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: CC-223 7.5 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day -1 | 45.8 ng/mL | — |
| Part A: CC-223 7.5 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day 15 | 50.8 ng/mL | — |
| Part A: CC-223 15 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day 15 | 92.0 ng/mL | Geometric Coefficient of Variation 162.6 |
| Part A: CC-223 15 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day -1 | 97.4 ng/mL | Geometric Coefficient of Variation 57.5 |
| Part A: CC-223 30 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day 15 | 293 ng/mL | Geometric Coefficient of Variation 38.8 |
| Part A: CC-223 30 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day -1 | 188 ng/mL | Geometric Coefficient of Variation 41.8 |
| Part A: CC-223 45 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day -1 | 269 ng/mL | Geometric Coefficient of Variation 65.7 |
| Part A: CC-223 45 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day 15 | 417 ng/mL | Geometric Coefficient of Variation 61.6 |
| Part A: CC-223 60 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day 15 | 480 ng/mL | Geometric Coefficient of Variation 88.9 |
| Part A: CC-223 60 mg | Maximum Observed Plasma Concentration (Cmax) of CC-223 | Day -1 | 319 ng/mL | Geometric Coefficient of Variation 70 |
Primary
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.
Time frame: From first dose up to 30 days after first dose
Population: All treated participants in Part A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: CC-223 7.5 mg | Part A: Number of Participants With Dose-limiting Toxicities | 0 Participants |
| Part A: CC-223 15 mg | Part A: Number of Participants With Dose-limiting Toxicities | 0 Participants |
| Part A: CC-223 30 mg | Part A: Number of Participants With Dose-limiting Toxicities | 1 Participants |
| Part A: CC-223 45 mg | Part A: Number of Participants With Dose-limiting Toxicities | 1 Participants |
| Part A: CC-223 60 mg | Part A: Number of Participants With Dose-limiting Toxicities | 2 Participants |
Primary
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.
Time frame: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: CC-223 7.5 mg | Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223 | 7.68 Hours | — |
| Part A: CC-223 15 mg | Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223 | 3.35 Hours | Geometric Coefficient of Variation 54.1 |
| Part A: CC-223 30 mg | Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223 | 5.57 Hours | Geometric Coefficient of Variation 38.4 |
| Part A: CC-223 45 mg | Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223 | 4.86 Hours | Geometric Coefficient of Variation 25.9 |
| Part A: CC-223 60 mg | Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223 | 5.64 Hours | Geometric Coefficient of Variation 16.7 |
Primary
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.
Time frame: From first dose to 6 months
Population: All treated participants in Part B with GBM without progression per RECIST 1.0 at 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: CC-223 7.5 mg | Part B: Progression Free Survival (PFS) Rate at 6 Months for GBM Participants | 0 Percentage of participants |
Primary
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.
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
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: CC-223 7.5 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day -1/1 | 1.00 Hours |
| Part A: CC-223 7.5 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day 15 | 1.50 Hours |
| Part A: CC-223 15 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day -1/1 | 1.25 Hours |
| Part A: CC-223 15 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day 15 | 2.00 Hours |
| Part A: CC-223 30 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day -1/1 | 1.55 Hours |
| Part A: CC-223 30 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day 15 | 1.28 Hours |
| Part A: CC-223 45 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day 15 | 1.63 Hours |
| Part A: CC-223 45 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day -1/1 | 3.00 Hours |
| Part A: CC-223 60 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day -1/1 | 1.50 Hours |
| Part A: CC-223 60 mg | Time to Maximum Concentration (Tmax) of CC-223 | Day 15 | 1.58 Hours |
Secondary
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.
Time frame: 0 to 24 hours post-dose on Day -1 and Day 15
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: CC-223 7.5 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 1 | 2712 ng*h/mL | — |
| Part A: CC-223 7.5 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 15 | 6401 ng*h/mL | — |
| Part A: CC-223 15 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 1 | 3207 ng*h/mL | Geometric Coefficient of Variation 82.5 |
| Part A: CC-223 15 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 15 | 4388 ng*h/mL | Geometric Coefficient of Variation 133.8 |
| Part A: CC-223 30 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 1 | 12328 ng*h/mL | Geometric Coefficient of Variation 39.4 |
| Part A: CC-223 30 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 15 | 27389 ng*h/mL | Geometric Coefficient of Variation 48.5 |
| Part A: CC-223 45 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 15 | 30823 ng*h/mL | Geometric Coefficient of Variation 38.3 |
| Part A: CC-223 45 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 1 | 14107 ng*h/mL | Geometric Coefficient of Variation 26.9 |
| Part A: CC-223 60 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 1 | 16926 ng*h/mL | Geometric Coefficient of Variation 89.2 |
| Part A: CC-223 60 mg | Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1 | Day 15 | 33070 ng*h/mL | Geometric Coefficient of Variation 101.6 |
Secondary
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.
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
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: CC-223 7.5 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 1 | 4583 ng*h/mL | — |
| Part A: CC-223 7.5 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 15 | 6401 ng*h/mL | — |
| Part A: CC-223 15 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 1 | 3788 ng*h/mL | Geometric Coefficient of Variation 121.2 |
| Part A: CC-223 15 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 15 | 4388 ng*h/mL | Geometric Coefficient of Variation 133.8 |
| Part A: CC-223 30 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 1 | 18964 ng*h/mL | Geometric Coefficient of Variation 45.1 |
| Part A: CC-223 30 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 15 | 27389 ng*h/mL | Geometric Coefficient of Variation 48.5 |
| Part A: CC-223 45 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 15 | 30823 ng*h/mL | Geometric Coefficient of Variation 38.3 |
| Part A: CC-223 45 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 1 | 19938 ng*h/mL | Geometric Coefficient of Variation 30.1 |
| Part A: CC-223 60 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 1 | 23702 ng*h/mL | Geometric Coefficient of Variation 98.1 |
| Part A: CC-223 60 mg | Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1 | Day 15 | 33070 ng*h/mL | Geometric Coefficient of Variation 101.6 |
Secondary
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 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
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: CC-223 7.5 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day -1 | 143 ng/mL | — |
| Part A: CC-223 7.5 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day 15 | 363 ng/mL | — |
| Part A: CC-223 15 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day -1 | 284 ng/mL | Geometric Coefficient of Variation 64.6 |
| Part A: CC-223 15 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day 15 | 357 ng/mL | Geometric Coefficient of Variation 139.8 |
| Part A: CC-223 30 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day -1 | 729 ng/mL | Geometric Coefficient of Variation 40.3 |
| Part A: CC-223 30 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day 15 | 1681 ng/mL | Geometric Coefficient of Variation 34.5 |
| Part A: CC-223 45 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day 15 | 2061 ng/mL | Geometric Coefficient of Variation 23.1 |
| Part A: CC-223 45 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day -1 | 1002 ng/mL | Geometric Coefficient of Variation 37.2 |
| Part A: CC-223 60 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day -1 | 1174 ng/mL | Geometric Coefficient of Variation 86 |
| Part A: CC-223 60 mg | Maximum Observed Concentration (Cmax) of Metabolite M1 | Day 15 | 1946 ng/mL | Geometric Coefficient of Variation 78.9 |
Secondary
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.
Time frame: From first dose up to tumor response (approximately 11 months)
Population: Participants who received treatment in Part A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: CC-223 7.5 mg | Part A: Overall Response Rate | 0 Percentage of participants |
| Part A: CC-223 15 mg | Part A: Overall Response Rate | 0 Percentage of participants |
| Part A: CC-223 30 mg | Part A: Overall Response Rate | 11.1 Percentage of participants |
| Part A: CC-223 45 mg | Part A: Overall Response Rate | 0 Percentage of participants |
| Part A: CC-223 60 mg | Part A: Overall Response Rate | 0 Percentage of participants |
Secondary
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.
Time frame: Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose
Population: All biomarker evaluable participants who received treatment in Part A.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: CC-223 15 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells | Day 15 1.5 hours post-dose | -14.4 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells | Day -1 3 hours post-dose | -20.7 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells | Day 15 1.5 hours post-dose | -61.1 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells | Day -1 3 hours post-dose | -44.0 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells | Day -1 3 hours post-dose | -55.7 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells | Day 15 1.5 hours post-dose | -54.8 Percent change in p4E-BP1 |
| Part A: CC-223 60 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells | Day -1 3 hours post-dose | -44.3 Percent change in p4E-BP1 |
| Part A: CC-223 60 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells | Day 15 1.5 hours post-dose | -46.4 Percent change in p4E-BP1 |
Secondary
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.
Time frame: Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose
Population: All biomarker evaluable participants who received treatment in Part A.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: CC-223 15 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes | Day -1 3 hours post-dose | -26.9 Percent change in pAKT |
| Part A: CC-223 15 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes | Day 15 1.5 hours post-dose | 58.3 Percent change in pAKT |
| Part A: CC-223 30 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes | Day 15 1.5 hours post-dose | -70.5 Percent change in pAKT |
| Part A: CC-223 30 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes | Day -1 3 hours post-dose | -56.5 Percent change in pAKT |
| Part A: CC-223 45 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes | Day -1 3 hours post-dose | -59.7 Percent change in pAKT |
| Part A: CC-223 45 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes | Day 15 1.5 hours post-dose | -55.8 Percent change in pAKT |
| Part A: CC-223 60 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes | Day -1 3 hours post-dose | -48.4 Percent change in pAKT |
| Part A: CC-223 60 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes | Day 15 1.5 hours post-dose | -45.7 Percent change in pAKT |
Secondary
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.
Time frame: Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose
Population: All biomarker evaluable participants who received treatment in Part A.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: CC-223 15 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells | Day -1 3 hours post-dose | -19.4 Percent change |
| Part A: CC-223 15 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells | Day 15 1.5 hours post-dose | 174.0 Percent change |
| Part A: CC-223 30 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells | Day 15 1.5 hours post-dose | -59.0 Percent change |
| Part A: CC-223 30 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells | Day -1 3 hours post-dose | -73.6 Percent change |
| Part A: CC-223 45 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells | Day 15 1.5 hours post-dose | -80.5 Percent change |
| Part A: CC-223 45 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells | Day -1 3 hours post-dose | -79.8 Percent change |
| Part A: CC-223 60 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells | Day -1 3 hours post-dose | -76.6 Percent change |
| Part A: CC-223 60 mg | Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells | Day 15 1.5 hours post-dose | -69.3 Percent change |
Secondary
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.
Time frame: From first dose up to tumor response (approximately 36 months)
Population: Participants who received treatment in Part B reported by tumor cohort
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: CC-223 7.5 mg | Part B: Overall Response Rate | 3.8 Percentage of participants |
| Part A: CC-223 15 mg | Part B: Overall Response Rate | 0 Percentage of participants |
| Part A: CC-223 30 mg | Part B: Overall Response Rate | 5.7 Percentage of participants |
| Part A: CC-223 45 mg | Part B: Overall Response Rate | 6.4 Percentage of participants |
| Part A: CC-223 60 mg | Part B: Overall Response Rate | 10.7 Percentage of participants |
| Part B: Non-small Cell Lung Cancer (NSCLC) | Part B: Overall Response Rate | 0 Percentage of participants |
| Part B: Multiple Myeloma (MM) | Part B: Overall Response Rate | 11.8 Percentage of participants |
Secondary
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.
Time frame: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
Population: All biomarker evaluable participants who received treatment in Part B.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 1 1.5 hours post-dose | -68.1 Percent change in pAKT |
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 15 1.5 hours post-dose | -76.1 Percent change in pAKT |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 1 1.5 hours post-dose | -28.0 Percent change in pAKT |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 15 1.5 hours post-dose | -34.1 Percent change in pAKT |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 15 1.5 hours post-dose | -84.1 Percent change in pAKT |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 1 1.5 hours post-dose | -55.5 Percent change in pAKT |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 1 1.5 hours post-dose | -70.3 Percent change in pAKT |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 15 1.5 hours post-dose | -52.2 Percent change in pAKT |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 1 1.5 hours post-dose | -54.3 Percent change in pAKT |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 15 1.5 hours post-dose | -88.6 Percent change in pAKT |
| Part B: Non-small Cell Lung Cancer (NSCLC) | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 15 1.5 hours post-dose | -52.9 Percent change in pAKT |
| Part B: Non-small Cell Lung Cancer (NSCLC) | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 1 1.5 hours post-dose | -78.8 Percent change in pAKT |
| Part B: Multiple Myeloma (MM) | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort | Day 1 1.5 hours post-dose | -53.8 Percent change in pAKT |
Secondary
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.
Time frame: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
Population: All biomarker evaluable participants who received treatment in Part B.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose | -55.5 Percent change in pAKT |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose | -84.1 Percent change in pAKT |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose | -70.3 Percent change in pAKT |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose | -52.2 Percent change in pAKT |
Secondary
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).
Time frame: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
Population: All biomarker evaluable participants who received treatment in Part B.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD91+ | -39.4 Percent change in p4E-BP1 |
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD91+ | -22.4 Percent change in p4E-BP1 |
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD14+ | -28.7 Percent change in p4E-BP1 |
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD14+ | -61.3 Percent change in p4E-BP1 |
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD19+ | -15.3 Percent change in p4E-BP1 |
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD19+ | -0.3 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD91+ | -20.0 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD19+ | -48.0 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD14+ | -17.3 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD14+ | -58.1 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD3+ | -23.5 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD19+ | -44.3 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD3+ | -38.9 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD91+ | -24.7 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD19+ | -51.1 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD91+ | -49.4 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD14+ | -39.1 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD3+ | -51.8 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD19+ | -39.4 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD3+ | -50.0 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD14+ | -11.7 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD3+ | -61.6 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD3+ | -58.7 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD14+ | -44.5 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD19+ | -44.5 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD14+ | -74.1 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD91+ | -24.5 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD19+ | -27.3 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD91+ | -6.9 Percent change in p4E-BP1 |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD19+ | -12.0 Percent change in p4E-BP1 |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD3+ | -63.3 Percent change in p4E-BP1 |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD3+ | -58.4 Percent change in p4E-BP1 |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD14+ | -49.4 Percent change in p4E-BP1 |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD14+ | -35.8 Percent change in p4E-BP1 |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD19+ | -44.8 Percent change in p4E-BP1 |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD91+ | -43.0 Percent change in p4E-BP1 |
| Part B: Non-small Cell Lung Cancer (NSCLC) | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD91+ | -24.9 Percent change in p4E-BP1 |
| Part B: Non-small Cell Lung Cancer (NSCLC) | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD91+ | -24.8 Percent change in p4E-BP1 |
| Part B: Multiple Myeloma (MM) | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 1,1.5 hours post-dose - CD91+ | -51.4 Percent change in p4E-BP1 |
| Part B: Multiple Myeloma (MM) | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort | Day 15, 1.5 hours post-dose - CD91+ | 19.6 Percent change in p4E-BP1 |
Secondary
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).
Time frame: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
Population: All biomarker evaluable participants who received treatment in Part B.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose - CD3+ | -28.3 Percent change in p4E-BP1 |
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose - CD3+ | -34.0 Percent change in p4E-BP1 |
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose - CD14+ | -22.1 Percent change in p4E-BP1 |
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose - CD14+ | -58.1 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose - CD14+ | -28.4 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose - CD14+ | 7.0 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose - CD3+ | -52.8 Percent change in p4E-BP1 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose - CD3+ | 20.0 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose - CD14+ | -8.7 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose - CD14+ | -25.6 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose - CD3+ | -39.7 Percent change in p4E-BP1 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose - CD3+ | -40.4 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose - CD3+ | -70.2 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose - CD3+ | -70.6 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 15 1.5 hours post-dose - CD14+ | -47.4 Percent change in p4E-BP1 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose | Day 1 1.5 hours post-dose - CD14+ | -36.6 Percent change in p4E-BP1 |
Secondary
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.
Time frame: Up to Cycle 1 Day 15 3 hours post dose
Population: All biomarker evaluable participants who received treatment in Part B.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part A: CC-223 7.5 mg | Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type | 22 Percent change in pS6RP | Full Range -37 |
| Part A: CC-223 15 mg | Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type | -36 Percent change in pS6RP | Full Range -36 |
| Part A: CC-223 30 mg | Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type | -19 Percent change in pS6RP | Full Range -37 |
| Part A: CC-223 45 mg | Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type | -30 Percent change in pS6RP | Full Range -30 |
| Part A: CC-223 60 mg | Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type | -21 Percent change in pS6RP | Full Range -43 |
| Part B: Multiple Myeloma (MM) | Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type | -15 Percent change in pS6RP | Full Range -17 |
Secondary
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.
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
Population: All treated participants with available pharmacokinetic data in Part A.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: CC-223 7.5 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 1 | 8.00 Hours |
| Part A: CC-223 7.5 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 15 | 1.50 Hours |
| Part A: CC-223 15 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 1 | 2.28 Hours |
| Part A: CC-223 15 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 15 | 3.25 Hours |
| Part A: CC-223 30 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 1 | 6.51 Hours |
| Part A: CC-223 30 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 15 | 1.58 Hours |
| Part A: CC-223 45 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 15 | 1.71 Hours |
| Part A: CC-223 45 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 1 | 5.00 Hours |
| Part A: CC-223 60 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 1 | 5.00 Hours |
| Part A: CC-223 60 mg | Time to Maximum Concentration (Tmax) of Metabolite M1 | Day 15 | 3.00 Hours |