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
Overview
- Phase
- Phase 1
- Intervention
- CC-223
- Conditions
- Multiple Myeloma
- Sponsor
- Celgene
- Enrollment
- 226
- Locations
- 16
- Primary Endpoint
- Maximum Observed Plasma Concentration (Cmax) of CC-223
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically-confirmed advanced solid tumor, Non-Hodgkin Lymphoma or multiple myeloma
- •Patients have not tolerated or progressed on standard therapy, and no further standard therapy is available
- •Archival and screening tumor biopsy
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (solid tumors), 0-2 (hematologic malignancy)
- •Adequate organ function
Exclusion Criteria
- •Prior systemic cancer-directed treatments or investigational drugs within 4 weeks or 5 half lives, whichever is shorter, prior to starting study drug or who have not recovered from side effects of such therapy. Subjects must have recovered from any effects of recent radiotherapy that might confound the safety evaluation of study drug
- •Symptomatic brain metastases (prior Rx and stable metastases are OK)
- •Acute or chronic liver or renal disease or pancreatitis
- •Diarrhea ≥ Grade 2, impaired GI absorption
- •Impaired cardiac function
- •Diabetes requiring Rx, glucose \>126 mg/dL, HbA1c ≥6.5%
- •Peripheral neuropathy ≥ Grade 2
- •Pulmonary fibrosis
- •Known HIV infection
- •Known chronic hepatitis B or C virus (HBV/HCV) infection, unless comorbidity in subjects with HCC
Arms & Interventions
CC-223
All patients will receive CC-223, but serial patient groups will receive different dose levels in Phase 1. The number of groups will be determined by the number of dose levels required to establish dose-limiting toxicity.
Intervention: CC-223
Outcomes
Primary Outcomes
Maximum Observed Plasma Concentration (Cmax) of CC-223
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
Cmax is defined as the maximum observed concentration (in plasma), obtained directly from the observed concentration versus time data. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.
Part A: Number of Participants With Dose-limiting Toxicities
Time Frame: From first dose up to 30 days after first dose
A dose-limiting toxicity was defined as: - ≥ Grade 3 (per Common Terminology Criteria for Adverse Events \[CTCAE\] Version 4) clinically relevant adverse event (AE) or laboratory abnormality suspected to be related to CC-223 that commenced within 30 days of first dose, except alopecia, Grade 3 rash of the acneiform or maculopapular type for \< 5 days, Grade 3 diarrhea or vomiting lasting \< 72 hours, repeated occurrence of Grade 3 hyperuricaemia in subjects with Grade 3 hyperuricemia at baseline, hyperglycemia, hematologic and liver function test (LFT) abnormalities due to disease progression. - Grade 2 fasting hyperglycemia lasting \> 14 days or ≥ Grade 3 lasting \> 4 days despite optimal medical treatment. - Hematological toxicities including febrile neutropenia, Grade 4 neutropenia or thrombocytopenia for \> 7 days, or Grade 3/4 thrombocytopenia with clinically significant bleeding. - Grade 4 LTFs - AE suspected to be CC-223 related necessitating dose reduction during cycle 1.
Part B: Progression Free Survival (PFS) Rate at 6 Months for GBM Participants
Time Frame: From first dose to 6 months
Progression free survival rate of GBM participants at 6 months is defined as the percentage of participants without progressive disease per Evaluation Criteria in Solid Tumors (RECIST) 1.1 6 months after starting study treatment. Progressive disease is defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Apparent Total Body Clearance (CL/F) of CC-223
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
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
Time Frame: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose
Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. VZ/F was not assessed following multiple dosing as the blood sampling schedule on Day 15 did not allow robust assessment of the terminal elimination rate constant.
Time to Maximum Concentration (Tmax) of CC-223
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
Tmax is defined as the time to Cmax, obtained directly from the observed concentration versus time data. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.
Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223
Time Frame: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose
Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. T1/2 was not assessed following multiple dosing as the blood sampling schedule on Day 15 did not allow robust assessment of the terminal elimination rate constant.
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223
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
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
Time Frame: 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
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
AUCinf is defined as the area under the concentration-time curve from Time 0 extrapolated to infinity. Plasma CC-223 was measured using validated chiral liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL. AUCinf was not assessed following multiple dosing as the blood sampling schedule on Day 15 did not allow robust assessment of the terminal elimination rate constant.
Secondary Outcomes
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Part A: Overall Response Rate(From first dose up to tumor response (approximately 11 months))
- Part B: Overall Response Rate(From first dose up to tumor response (approximately 36 months))
- 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)
- 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)
- 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)