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

Celgene226 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

226

Conditions

Multiple Myeloma Diffuse Large B-Cell Lymphoma Glioblastoma Multiforme Hepatocellular Carcinoma

Interventions

CC-223DRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (16)

Cedars-Sinai Medical Center

Los Angeles, California, United States

UCLA Neuro-Oncology Program

Los Angeles, California, United States

University of California, San Francisco Hellen Diller Family Comprehensive Cancer Center

San Francisco, California, United States

Moffitt Cancer Center

Tampa, Florida, United States

Mayo Clinic Cancer Clinical Studies Unit

Rochester, Minnesota, United States

Billings Clinic

Billings, Montana, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

NYU Cancer Institute - Bellevue Hospital

New York, New York, United States

Sarah Cannon Research Institute Drug Development Unit

Nashville, Tennessee, United States

Mary Crowley Medical Research Center

Dallas, Texas, United States

...and 6 more locations

Outcomes

Primary Outcomes

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

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

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

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

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

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

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

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

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

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

Secondary Outcomes

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

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

Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes

Phosphorylated AKT is a biomarker for inhibition of the mammalian target of rapamycin complex 2 (mTORC2). Phosphorylated AKT was measured in stimulated monocytes via flow cytometry. The raw measurements were expressed as median fluorescence intensity (MFI). MFI values were normalized against calibration beads using a linear regression transformation carried out on a log-log scale and reported as equivalent reference fluorophores (ERF). The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Results were not available for the single subject treated in the 7.5-mg dose group and for one of the two subjects treated in the 15-mg dose group.

Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort

Phosphorylated 4E-BP1 is a biomarker for inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Phosphorylated 4E-BP1 was measured in stimulated monocytes via flow cytometry. MFI values were determined and converted to molecules of equivalent fluorescence label (MEFL) by normalizing against calibration beads. The biomarker evaluable population included all subjects who took at least one dose of study drug and had at least one non-missing pharmacodynamic (PD) assessment. Data is reported by T-cell subsets known as clusters of differentiation (CD).

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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

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

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

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