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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: CC-223


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-223<br>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. | Drug: CC-223<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From first dose up to 30 days after first dose | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 0 to 24 hours post-dose on Day -1 and Day 15 | 
| 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. | 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 | 
| 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. | Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose | 
| 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. | 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 | 
| 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. | Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose | 
| 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. | From first dose to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose | 
| 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. | Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose | 
| 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. | Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose | 
| 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). | Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose | 
| 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). | Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose | 
| 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. | Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose | 
| 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. | Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose | 
| 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. | Up to Cycle 1 Day 15 3 hours post dose | 
| 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. | From first dose up to tumor response (approximately 11 months) | 
| 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. | From first dose up to tumor response (approximately 36 months) | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 0 to 24 hours post-dose on Day -1 and Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid malignant neoplasms,Non-Hodgkin Lymphoma,, Multiple Myeloma