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

NCT01177397 | Completed Phase 1 Results

• 1 other identifier: CC-223-ST-001
• Study Type: interventional
• Target: 226
• Locations: 4 countries
• Sites: 16

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.

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

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (14)

• 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 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 by Tumor Cohort

  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

  Cycle 1 Day 1: 1.5 hours post-dose and Day 15: 1.5 hours post-dose

Study Arms (1)

CC-223

EXPERIMENTAL

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

Interventions

CC-223 DRUG

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.

CC-223

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Celgene: lead

Study Sites (16)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

UCLA Neuro-Oncology Program

Los Angeles, California, 90095, United States

Location

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

San Francisco, California, 94115, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Mayo Clinic Cancer Clinical Studies Unit

Rochester, Minnesota, 55905, United States

Location

Billings Clinic

Billings, Montana, 59102, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

NYU Cancer Institute - Bellevue Hospital

New York, New York, 10016, United States

Location

Sarah Cannon Research Institute Drug Development Unit

Nashville, Tennessee, 37203, United States

Location

Mary Crowley Medical Research Center

Dallas, Texas, 75201, United States

Location

Institut Claudius Regaud

Toulouse, 31052, France

Location

Institut Gustave Roussy Faculte de Medecine Paris Sud Service de pneumologie

Villejuif, 94800, France

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Hospital Universitario Virgen Del Rocio

Seville, 41013, Spain

Location

Sarah Cannon Research Institute UK

London, W1G 6AD, United Kingdom

Location

UCL Cancer Institute

London, WC1E 6BT, United Kingdom

Location

MeSH Terms

Conditions

Multiple Myeloma; Lymphoma, Large B-Cell, Diffuse; Glioblastoma; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung

Interventions

CC-223

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Lymphatic Diseases; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Adenocarcinoma; Carcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trails@bms.com

Please email

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2010
• First Posted: August 9, 2010
• Study Start: July 20, 2010
• Primary Completion: November 15, 2016
• Study Completion: December 9, 2016
• Last Updated: December 13, 2022
• Results First Posted: November 15, 2022

Record last verified: 2022-12

Locations

ES (2); US (10); GB (2); FR (2)