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

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

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.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Non-Small-Cell Lung; Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: CC-223, erlotinib; Drug: CC-223, oral azacitidine; Drug: CC-223, oral azacitidine

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men and women, 18 years or older, with histologically or cytologically-confirmed, Stage IIIB/IV Non-Small Cell Lung Cancer with tumor progression following at least one prior treatment regimen (either chemotherapy or an Epidermal Growth Factor Receptor inhibitor) for advanced disease. There is no restriction on the number of prior treatment regimens allowed.
2. Eastern Cooperative Oncology Group 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, HbA1c > 6.5%.
7. Known Human Immunodeficiency Virus, chronic hepatitis B or C infection.
8. Prior treatment with an investigational dual TORC1/TORC2, PI3K, or Akt inhibitor. Prior treatment with 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / 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 erlotonib, 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; 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
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: 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; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Number of participants with adverse events	Up to 24 months
MTD	Maximum tolerated dose (MTD)	Up to 24 months
PK-Cmax	Pk-Maximum observed concentration in plasma (Cmax)	Up to 15 months
PK-AUC	Area under the plasma concentration-time curve (AUC)	Up to 15 months
PK-Tmax	PK-Time to maximum concentration (Tmax)	Up to 15 months
PK-T1/2	PK-Terminal half-life (T1/2)	Up to 15 months
PK-CL/F	PK-Apparent total body clearance (CL/F)	Up to 15 months
PK-Vz/F	PK-Apparent volume of distribution (Vz/F)	Up to 15 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Celgene

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2012
• Primary Completion (ACTUAL): December 11, 2014
• Study Completion (ACTUAL): December 11, 2014

Study Registration Dates

• First Submitted: March 2, 2012
• First Submitted That Met QC Criteria: March 2, 2012
• First Posted (ESTIMATE): March 7, 2012

Study Record Updates

• Last Update Posted (ACTUAL): November 12, 2019
• Last Update Submitted That Met QC Criteria: November 7, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Lung Cancer; Non-Small Cell Lung Cancer; Neoplasms; Pulmonary; Stage IIIB Non-Small Cell Lung Cancer; Cancer of the Lung; IV Non-Small Cell Lung Cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Azacitidine
• Other Study ID Numbers: CC-223-NSCL-001; 2011-005290-23 (EUDRACT_NUMBER)