Study Assessing Safety, Pharmacokinetics and Efficacy of CC-223 With Either Erlotinib or Oral Azacitidine in Advanced Non-Small Cell Lung Cancer

Study Description

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Brief Summary:

The main purpose of this first study combining an investigational dual mTOR inhibitor, CC-223, with other agents (erlotinib or the investigational agent, oral azacitidine) is to establish a maximum tolerated dose level for each combination in order to evaluate their effects in future clinical trials for advanced non-small cell lung cancer.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Non-Small-Cell Lung; Non-Small Cell Lung Cancer	Drug: CC-223, erlotinib; Drug: CC-223, oral azacitidine	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	76 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A PHASE 1B, MULTI-CENTER, OPEN-LABEL STUDY OF THE MTOR KINASE INHIBITOR CC-223 IN COMBINATION WITH ERLOTINIB OR ORAL AZACITIDINE IN ADVANCED NON-SMALL CELL LUNG CANCER
Study Start Date :	May 2012
Actual Primary Completion Date :	December 2014
Actual Study Completion Date :	December 2014

Arms and Interventions

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Arm	Intervention/treatment
Experimental: CC-223/erlotinib concurrent; Cohorts will receive escalating continuous daily doses (15 mg and 30 mg) of CC-223 in capsules concurrently with at least two different daily dose levels of erlotinib tablets (100 mg and 150 mg) in 28-day cycles.	Drug: CC-223, erlotinib; Dose escalation: Combination doses start with 15 mg CC-223 and 100 mg erlotinib, or 15 mg CC-223 and 150 mg erlotinib, administered in 28-day cycles. Combination dose levels increase sequentially using predefined regimens until non-tolerated dose levels are established and a maximum tolerated dose combination has been identified for further study. Dose expansion: The maximum tolerated doses are evaluated further for evidence of preliminary efficacy
Experimental: CC-223/oral azacitidine concurrent; Cohorts will receive escalating continuous daily doses of CC-223 (15 mg and 30 mg) with one or more dose levels of oral azacitidine (200 mg or 300 mg, as two or three 100 mg tablets) administered on Day 1 to 21 of each 28-day cycle.	Drug: CC-223, oral azacitidine; Dose escalation: Combination doses start with 15 mg CC-223 and 200 mg oral azacitidine, administered in 28-day cycle. Combination dose levels increase sequentially using predefined regimens until non-tolerated dose levels are established and a maximum tolerated dose combination has been identified for further study. Dose expansion: The maximum tolerated doses are evaluated further for evidence of preliminary efficacy
Experimental: CC-223/oral azacitidine sequential; Cohorts will receive escalating continuous daily dose levels of CC-223 (15 mg and 30 mg) administered on Days 8 through 28 sequentially with one or more dose levels of of oral azacitidine (200 mg or 300 mg, as two or three 100 mg tablets) administered on Days 1 to 7 of each 28-day cycle	Drug: CC-223, oral azacitidine; Dose escalation: Sequential dosing starts with 200 mg of oral azacitidine administered on Days 1 through 7 of each 28-day cycle, followed by daily dose level of 15 mg CC-223 on Days 8 through 28. Combination dose levels increase sequentially using predefined regimens until non-tolerated dose levels are established and a maximum tolerated dose combination has been identified for further study. Dose expansion: The maximum tolerated doses are evaluated further for evidence of preliminary efficacy

Outcome Measures

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Primary Outcome Measures :

1. Adverse events [ Time Frame: Up to 24 months ]
   Number of participants with adverse events
2. MTD [ Time Frame: Up to 24 months ]
   Maximum tolerated dose (MTD)
3. PK-Cmax [ Time Frame: Up to 15 months ]
   Pk-Maximum observed concentration in plasma (Cmax)
4. PK-AUC [ Time Frame: Up to 15 months ]
   Area under the plasma concentration-time curve (AUC)
5. PK-Tmax [ Time Frame: Up to 15 months ]
   PK-Time to maximum concentration (Tmax)
6. PK-T1/2 [ Time Frame: Up to 15 months ]
   PK-Terminal half-life (T1/2)
7. PK-CL/F [ Time Frame: Up to 15 months ]
   PK-Apparent total body clearance (CL/F)
8. PK-Vz/F [ Time Frame: Up to 15 months ]
   PK-Apparent volume of distribution (Vz/F)

Secondary Outcome Measures :

1. mTORC1 and mTORC2 pathway biomarkers [ Time Frame: Up to 15 months. ]
   The effect of treatment on mTORC1 and mTORC2 pathway biomarkers in blood and tumor
2. CC-223 metabolite, M1 [ Time Frame: Up to 9 months ]
   CC-223 metabolite, M1, will be characterized
3. Tumor Response Rate [ Time Frame: Up to 24 months ]
   Tumor Response Rate using RECIST 1.1 (Eisenhauer, 2009)
4. Number of participants surviving without tumor progression [ Time Frame: Up to 24 months ]
   Number of participants surviving without tumor progression

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Men and women, 18 years or older, with histologically or cytologically-confirmed, Stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC) with tumor progression following at least one prior treatment regimen [(either chemotherapy or an Epidermal Growth Factor Receptor inhibitor (EGFR)] for advanced disease. There is no restriction on the number of prior treatment regimens allowed.
2. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 to 1.
3. Adequate organ function.
4. Adequate contraception (if appropriate).
5. Consent to retrieve archival tumor tissue.
6. Consent to repeated tumor biopsy (dose expansion phase).

Exclusion Criteria:

1. Prior systemic cancer-directed treatments or investigational drugs within 4 weeks or 5 half lives, whichever is shorter except erlotinib which may be continued with intervention in subjects allocated in Arm A.
2. Symptomatic central nervous system metastases.
3. Acute or chronic pancreatitis.
4. Persistent diarrhea or malabsorption > Grade 2, despite medical management.
5. Impaired cardiac function or significant cardiac disease.
6. Diabetes on active treatment, fasting blood glucose > 126 mg/dL, (glycated haemoglobin) HbA1c > 6.5%.
7. Known Human Immunodeficiency Virus (HIV), chronic hepatitis B or C infection.
8. Prior treatment with an investigational dual target of ripamycin 1 (TORC1)/ target of ripamycin 2 (TORC2), Phosphatidylinositol 3-Kinase (PI3K), or protein kinase B (Akt) inhibitor. Prior treatment with analogs of rapamycin (rapalogs) is allowed.
9. Major surgery < 2 weeks prior to starting study drugs. No specific wash out is required for radiotherapy. Subjects must have recovered from any effects of recent therapy that might confound the safety evaluation of study drug.
10. Pregnant or breastfeeding, inadequate contraception.
11. History of concurrent second malignancies requiring ongoing systemic treatment.

Contacts and Locations

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Locations

United States, California
Cedars Sinai Medical Center, Inflammatory Bowel Disease Center
Los Angeles, California, United States, 90048
University of California, San Francisco
San Francisco, California, United States, 9411
United States, New York
NYU School of Medicine
New York, New York, United States, 10016
United States, South Carolina
Cancer Center of the Carolinas
Greenville, South Carolina, United States, 29605
United States, Tennessee
Henry-Joyce Cancer Clinic
Nashville, Tennessee, United States, 37232-5505
United States, Texas
Mary Crowley Cancer Research Centers - Medical City
Dallas, Texas, United States, 75201
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Spain
Vall d´Hebron University Hospital
Barcelona, Spain, 08035
Hospital Virgen del RocíoServicio de Hematologia
Sevilla, Spain, 41013

Sponsors and Collaborators

Celgene Corporation

Investigators

Study Director:	Kristen Hege, MD	Celgene Corporation

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Celgene Corporation
ClinicalTrials.gov Identifier:	NCT01545947 History of Changes
Other Study ID Numbers:	CC-223-NSCL-001; 2011-005290-23 ( EudraCT Number )
First Posted:	March 7, 2012
Last Update Posted:	November 8, 2016
Last Verified:	November 2016

Keywords provided by Celgene Corporation:

Neoplasms; Pulmonary; Lung Cancer; Cancer of the Lung	Stage IIIB Non-Small Cell Lung Cancer; IV Non-Small Cell Lung Cancer; Non-Small Cell Lung Cancer

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic	Bronchial Neoplasms; Erlotinib Hydrochloride; Azacitidine; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites