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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Carcinoma, Non-Small-Cell Lung, Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: CC-223, erlotinib
* Drug: CC-223, oral azacitidine
* Drug: CC-223, oral azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Eastern Cooperative Oncology Group Performance Score of 0 to 1. Adequate organ function. Adequate contraception (if appropriate). Consent to retrieve archival tumor tissue. Consent to repeated tumor biopsy (dose expansion phase). Exclusion Criteria: 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. Symptomatic central nervous system metastases. Acute or chronic pancreatitis. Persistent diarrhea or malabsorption > Grade 2, despite medical management. Impaired cardiac function or significant cardiac disease. Diabetes on active treatment, fasting blood glucose > 126 mg/dL, HbA1c > 6.5%. Known Human Immunodeficiency Virus, chronic hepatitis B or C infection. Prior treatment with an investigational dual TORC1/TORC2, PI3K, or Akt inhibitor. Prior treatment with rapalogs is allowed. 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. Pregnant or breastfeeding, inadequate contraception. History of concurrent second malignancies requiring ongoing systemic treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-223/erlotinib concurrent<br>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<br>* 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<br>|
| Experimental: CC-223/oral azacitidine concurrent<br>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<br>* 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<br>|
| Experimental: CC-223/oral azacitidine sequential<br>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<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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