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

• Safety [ Time Frame: From the time of informed consent, throughout dosing period and for 21 days after the last dose of CC-223 ] [ Designated as safety issue: Yes ]
  To determine the safety profile and dose-limiting toxicity of CC-223 using NCI CTCAE v4.
• Pharmacokinetics [ Time Frame: Throughout the first cycle (30 days) through to the first day of Cycle 2. ] [ Designated as safety issue: No ]
  Standard variables (eg. Cmax, AUC, half-life) to define the PK profile for single and multiple doses of oral CC-223.

• Pharmacodynamics [ Time Frame: Throughout the first cycle (30 days) through to the first day of Cycle 2. ] [ Designated as safety issue: No ]
  Phosphorylation inhibition changes by levels of S6, 4EBP (for mTORC1) and AKT (for mTORC2) in circulating granulocytes, and tumor tissue (when available).
• Efficacy [ Time Frame: Every 2-3 months until proof of tumor progression ] [ Designated as safety issue: No ]
  Tumor response rates using appropriate objective criteria for various malignancies

• Pharmacodynamics [ Time Frame: Throughout the first cycle (30 days) through to the first day of Cycle 2. ] [ Designated as safety issue: No ]
  Phosphorylation inhibition changes by levels of S6, 4EBP (for mTORC1) and AKT (for mTORC2) in circulating granulocytes, and tumor tissue (when available).
• Efficacy [ Time Frame: Every two months until proof of tumor progression ] [ Designated as safety issue: No ]
  Tumor response rates and duration using objective criteria appropriate for type of tumor evaluated (eg. RECIST)

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.

Initially, patients will be treated with oral CC-223 for one month. During this time, various tests (involving blood and urine collections, ECGs, etc) will be performed. Those whose tumors stabilize or regress may continue receiving treatment for as long as they benefit from CC-223. Different dose levels of CC-223 will be tested in a dose-rising study design.

• 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

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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