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

• Adverse events [ Time Frame: Up to 24 months ] [ Designated as safety issue: Yes ]
  Number of participants with adverse events
• MTD [ Time Frame: Up to 24 months ] [ Designated as safety issue: Yes ]
  Maximum tolerated dose (MTD)
• PK-Cmax [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  Pk-Maximum observed concentration in plasma (Cmax)
• PK-AUC [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  Area under the plasma concentration-time curve (AUC)
• PK-Tmax [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  PK-Time to maximum concentration (Tmax)
• PK-T1/2 [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  PK-Terminal half-life (T1/2)
• PK-CL/F [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  PK-Apparent total body clearance (CL/F)
• PK-Vz/F [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  PK-Apparent volume of distribution (Vz/F)

• Number of participants with adverse events [ Time Frame: Up to 24 months ] [ Designated as safety issue: Yes ]
  Number of participants with adverse events
• Maximum tolerated dose (MTD) [ Time Frame: Up to 24 months ] [ Designated as safety issue: Yes ]
  Maximum tolerated dose (MTD)
• PK-Maximum observed concentration in plasma (Cmax) [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  Pk-Maximum observed concentration in plasma (Cmax)
• PK-Area under the plasma concentration-time curve (AUC) [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  Area under the plasma concentration-time curve (AUC)
• PK-Time to maximum concentration (Tmax) [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  PK-Time to maximum concentration (Tmax)
• PK-Terminal half-life (T1/2) [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  PK-Terminal half-life (T1/2)
• PK-Apparent total body clearance (CL/F) [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  PK-Apparent total body clearance (CL/F)
• PK-Apparent volume of distribution (Vz/F) [ Time Frame: Up to 15 months ] [ Designated as safety issue: No ]
  PK-Apparent volume of distribution (Vz/F)

• mTORC1 and mTORC2 pathway biomarkers [ Time Frame: Up to 15 months. ] [ Designated as safety issue: No ]
  The effect of treatment on mTORC1 and mTORC2 pathway biomarkers in blood and tumor
• CC-223 metabolite, M1 [ Time Frame: Up to 9 months ] [ Designated as safety issue: No ]
  CC-223 metabolite, M1, will be characterized
• Tumor Response Rate [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
  Tumor Response Rate using RECIST 1.1 (Eisenhauer, 2009)
• Number of participants surviving without tumor progression [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
  Number of participants surviving without tumor progression

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.

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

• Drug: CC-223

  Dose escalation: Combination doses start with either 15 mg CC-223 and 100 mg erlotinib, or 15 mg CC-223 and 200 mg oral azacitidine, 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: Each combination, in maximum tolerated doses, is evaluated further in three cohorts for evidence of preliminary efficacy.

• Drug: Erlotinib

  Dose escalation: Combination doses start with either 15 mg CC-223 and 100 mg erlotinib, or 15 mg CC-223 and 200 mg oral azacitidine, 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: Each combination, in maximum tolerated doses, is evaluated further in three cohorts for evidence of preliminary efficacy.

• Drug: Oral azacitidine concurrent

  Dose escalation: Combination doses start with either 15 mg CC-223 and 100 mg erlotinib, or 15 mg CC-223 and 200 mg oral azacitidine, 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: Each combination, in maximum tolerated doses, is evaluated further in three cohorts for evidence of preliminary efficacy.

• Drug: oral azacitidine sequential

  Dose escalation: Combination doses start with either 15 mg CC-223 and 100 mg erlotinib, or 15 mg CC-223 and 200 mg oral azacitidine, 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: Each combination, in maximum tolerated doses, is evaluated further in three cohorts for evidence of preliminary efficacy.

• Experimental: CC-223/erlotinib
  Cohorts will receive escalating continuous daily doses (15 mg, 30 mg, and 45 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.
  Interventions:

  • Drug: CC-223
  • Drug: Erlotinib
• Experimental: CC-223/oral azacitidine concurrent
  Cohorts will receive escalating continuous daily doses of CC-223 (15 mg, 30 mg, and 45 mg) concurrently 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.
  Interventions:

  • Drug: CC-223
  • Drug: Oral azacitidine concurrent
• Experimental: CC-223/oral azacitidine sequential
  Cohorts will receive escalating daily dose levels of CC-223 (15 mg, 30 mg, and 45 mg) administered on Days 8 to 28 after one or more dose levels 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
  Interventions:

  • Drug: CC-223
  • Drug: oral azacitidine sequential

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.