Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of CUDC-427 When Given to Patients With Advanced and Refractory Solid Tumors or Lymphoma

• Subjects of ≥ 18 years of age.
• Histologically or cytologically confirmed diagnosis of advanced solid tumor or lymphoma that has progressed following standard therapy or for which there is no standard or curative therapy.
• Measurable or non-measureable disease.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Recovery to Grade 1 or baseline of any toxicity due to prior systemic treatments (excluding alopecia).
• Absolute neutrophil count 1,500/L; platelets 100,000/L; creatinine 1.5x upper limit of normal (ULN); total bilirubin 1.5x ULN; aspartate aminotransferase/ alanine aminotransferase (AST/ALT) 2.5x ULN; Tbili \</= ULN. For subjects with documented liver metastases, the AST/ALT may be 5x ULN.
• Life expectancy of at least 3 months.
• Subjects with adequately treated, stable brain metastases are eligible if symptomatically controlled on a stable dose of ≤ 10mg prednisone/day or its equivalent dose of steroids.
• Women of child bearing potential must have a negative serum or urine pregnancy test.
• Men and women of child bearing potential must agree to use adequate birth control from the time of screening through 30 days after the last dose of study drug.
• Able to provide written informed consent and to follow protocol requirements.

Exclusion Criteria:

• Systemic anticancer therapy within 3 weeks of study entry, except for nitrosoureas or mitomycin C (6 weeks). Subjects with prostate cancer receiving luteinizing hormone-releasing hormone (LHRH) hormonal therapy may be enrolled and continue on this therapy.
• Other investigational agents within 21 days prior to the first dose of study drug.
• Prior treatment with an antagonist of inhibitors of apoptosis proteins.
• History of chronic liver disease, hepatic cirrhosis, current cholestatic disease, active hepatic infection, non-alcoholic steatohepatitis (NASH), current alcohol or substance abuse (liver metastases due to disease under study are permitted).
• Pregnant or lactating/breast-feeding women.
• Ongoing treatment with chronic immunosuppressants.
• Known gastrointestinal condition that would interfere with swallowing or the oral absorption or tolerance of CUDC-427.
• Ongoing diarrhea defined as more than 1 watery stool/day.
• Infection requiring intravenous antibiotic therapy within 14 days prior to the first dose of study drug.

• Clinically significant cardiac history, such as:

  • Uncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis.
  • Previous history of QTc prolongation as a result of other medication that required discontinuation of that medication.
  • Congenital long QT syndrome or first degree relative with unexplained sudden death under 40 years of age.
  • QTc with Fridericia's (QTcF) correction that is unmeasurable or ≥ 480 msec on screening ECG. If a subject has a QTcF ≥ 480 sec on the screening ECG, the ECG may be repeated twice (at least 24 hour apart) and the mean QTcF from the three screening ECGs must be \< 480 msec in order for the subject to be eligible for the study.
  • Ejection fraction (EF) by ECHO \< 55% (abnormal values may be repeated x2 and the mean of the 3 tests used for determination)
  • Use of any concomitant medication (within 7 days of starting treatment) that may cause QTc prolongation, inducing Torsades de Pointes
• Unstable or clinically significant concurrent medical condition that would, in the opinion of the investigator, jeopardize the safety of a subject and/or their compliance with the protocol.
• Known human immunodeficiency virus (HIV) positive.
• Prior malignancy within 2 years except non-melanoma skin cancer and other in situ carcinomas that have been surgically treated with curative intent.