Clinical trial NCT01177397: Study to Assess Safety, Pharmacokinetics, and Efficacy of Oral CC-223 for Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma or Multiple Myeloma
Official title: A Phase 1/2, Multi-Center, Open-Label, Dose Finding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the mTOR Kinase Inhibitor CC-223 Administered Orally to Subjects With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Diffuse Large B-Cell Lymphoma
Glioblastoma Multiforme
Hepatocellular Carcinoma
Non-Small Cell Lung Cancer
Neuroendocrine Tumors of Non-Pancreatic Origin
Hormone Receptor-Positive Breast Cancer
Keywords: Advanced solid malignant neoplasms,Non-Hodgkin Lymphoma,
Multiple Myeloma
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2010-08-09
Enrollment: 226
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* Histologically-confirmed advanced solid tumor, Non-Hodgkin Lymphoma or multiple myeloma
* Patients have not tolerated or progressed on standard therapy, and no further standard therapy is available
* Archival and screening tumor biopsy
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (solid tumors), 0-2 (hematologic malignancy)
* Adequate organ function

Exclusion Criteria:

* Prior systemic cancer-directed treatments or investigational drugs within 4 weeks or 5 half lives, whichever is shorter, prior to starting study drug or who have not recovered from side effects of such therapy. Subjects must have recovered from any effects of recent radiotherapy that might confound the safety evaluation of study drug
* Symptomatic brain metastases (prior Rx and stable metastases are OK)
* Acute or chronic liver or renal disease or pancreatitis
* Diarrhea ≥ Grade 2, impaired GI absorption
* Impaired cardiac function
* Diabetes requiring Rx, glucose \>126 mg/dL, HbA1c ≥6.5%
* Peripheral neuropathy ≥ Grade 2
* Pulmonary fibrosis
* Known HIV infection
* Known chronic hepatitis B or C virus (HBV/HCV) infection, unless comorbidity in subjects with HCC
* Pregnant, inadequate contraception
* Most concurrent second malignancies

Primary outcomes:
measure: Part A: Number of Participants With Dose-limiting Toxicities
timeFrame: From first dose up to 30 days after first dose
measure: Maximum Observed Plasma Concentration (Cmax) of CC-223
timeFrame: 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
measure: Time to Maximum Concentration (Tmax) of CC-223
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for CC-223
timeFrame: 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
measure: Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for CC-223
timeFrame: 0 to 24 hours post-dose on Day -1 and Day 15
measure: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) For CC-223
timeFrame: 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
measure: Part A: Terminal Elimination Phase Half-Life (T1/2) of CC-223
timeFrame: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose
measure: Apparent Total Body Clearance (CL/F) of CC-223
timeFrame: 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
measure: Apparent Volume of Distribution (Vz/F) of CC-223
timeFrame: Cycle 1 Day -1: pre-dose, 0.5, 1, 1.5, 3, 5, 8, 24 and 48 hours post-dose
measure: Part B: Progression Free Survival (PFS) Rate at 6 Months for GBM Participants
timeFrame: From first dose to 6 months
Secondary outcomes:
measure: Part A: Percent Change From Baseline in Levels of Phosphorylated Ribosomal Protein S6 (pS6RP) in Stimulated B Cells
timeFrame: Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose
measure: Part A: Percent Change From Baseline in Levels of Phosphorylated Elongation I Initiation Binding Protein (p4E-BP1) in Stimulated T Cells
timeFrame: Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose
measure: Part A: Percent Change From Baseline in Levels of Phosphorylated Protein Kinase B (pAKT) in Stimulated Monocytes
timeFrame: Cycle 1 Day -1: 3 hours post-dose and Day 15: 1.5 hours post-dose
measure: Part B: Percent Change From Baseline in p4E-BP1 in Monocytes by Tumor Cohort
timeFrame: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
measure: Part B: Percent Change From Baseline in p4E-BP1 in Monocytes in the HCC and NET Cohorts by Dose
timeFrame: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
measure: Part B: Percent Change From Baseline in Levels of pAKT in Monocytes by Tumor Cohort
timeFrame: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
measure: Part B: Percent Change From Baseline in Levels of pAKT in Monocytes in the HCC and NET Cohorts by Dose
timeFrame: Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose
measure: Part B: Percent Change From Baseline in pS6RP Levels in Tumor Tissue by Tumor Type
timeFrame: Up to Cycle 1 Day 15 3 hours post dose
measure: Part A: Overall Response Rate
timeFrame: From first dose up to tumor response (approximately 11 months)
measure: Part B: Overall Response Rate
timeFrame: From first dose up to tumor response (approximately 36 months)
measure: Maximum Observed Concentration (Cmax) of Metabolite M1
timeFrame: 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
measure: Time to Maximum Concentration (Tmax) of Metabolite M1
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUCt) for Metabolite M1
timeFrame: 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
measure: Area Under the Concentration Time-Curve From 0-24 Hours After a Dose (AUC0-24) for Metabolite M1
timeFrame: 0 to 24 hours post-dose on Day -1 and Day 15
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Neuro-Oncology Program
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco Hellen Diller Family Comprehensive Cancer Center
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Rochester
country: United States
facility: Mayo Clinic Cancer Clinical Studies Unit
state: Minnesota
city: Billings
country: United States
facility: Billings Clinic
state: Montana
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: NYU Cancer Institute - Bellevue Hospital
state: New York
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Drug Development Unit
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Medical Research Center
state: Texas
city: Toulouse Cedex
country: France
facility: Institut Claudius Regaud
city: Villejuif
country: France
facility: Institut Gustave Roussy Faculte de Medecine Paris Sud Service de pneumologie
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Del Rocio
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
city: London
country: United Kingdom
facility: UCL Cancer Institute
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: