A Trial of Oral 5-azacitidine in Combination With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Non-small Cell Lung Cancer

Inclusion Criteria:

• Understand and voluntarily sign informed consent form (ICF).
• Age ≥ 18 years at time of signing ICF.
• Adhere to study visit schedule and other protocol requirements.
• Histologically or cytologically confirmed metastatic or unresectable solid tumor (phase I dose escalation), OR NSCLC (expansion cohort).
• Failed at least one previous chemotherapy regimen for metastatic disease if standard therapies exist.
• Measurable disease per RECIST 1.1
• Life expectancy ≥ 12 weeks
• No previous cancer therapy ≥ 4 weeks.
• ECOG performance status ≤ 2

• Laboratory test results:

  • Absolute neutrophil count ≥ 1500/mm³
  • Platelet ≥ 100,000/mm³
  • Serum creatinine levels < 1.5 X ULN OR creatinine clearance >60 mL/min/1.73 m2 for subjects with creatinine levels > institutional normal
  • Serum bilirubin ≤ 1.5 times the upper limit of the normal range for the laboratory (ULN).
  • AST (SGOT) and ALT (SGPT) ≤ to 2.5 x ULN
• Disease free of prior malignancies ≥ 5 years (except currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast).
• Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment with 5-azacitidine. All men/women of childbearing potential must use acceptable methods of birth control throughout the study.

Exclusion Criteria:

• Serious medical conditions, laboratory abnormality, or psychiatric illness that would prevent the subject from signing ICF.
• Pregnant or breastfeeding women. (Lactating women must agree not to breast feed while taking 5-azacitidine).
• Conditions, including laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret study data.
• Chemotherapy, radiotherapy, or experimental drug or therapy ≤ 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to enrollment or adverse events < grade 1 due to agents administered >4 weeks earlier except for stable grade 2 neuropathy.
• No other concomitant investigational agents.
• Known or suspected hypersensitivity to 5-azacitidine, romidepsin, mannitol or other agents used in this study.
• Uncontrolled brain metastases.
• Known positive for HIV, infectious hepatitis, type B or C.
• Uncontrolled intercurrent illness
• Known GI disorders precluding oral administration of 5-azacitidine.

• Known cardiac abnormalities such as:

  • Congenital long QT syndrome
  • QTc interval ≥ 500 milliseconds;
  • Myocardial infarction ≤6 months of C1D1. Subjects with a history of myocardial infarction between 6-12 months prior to C1D1 who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate;
  • Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min);
  • Symptomatic coronary artery disease (CAD), e.g., angina. In any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
  • Screening ECG showing evidence of cardiac ischemia (ST depression, depression of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
  • Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction <40% by MUGA scan or <50% by echocardiogram and/or MRI;
  • Known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);
  • Hypertrophic cardiomegaly or restrictive cardiomyopathy;
  • Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria; or
  • Cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers)
• Patients taking drugs leading to significant QT prolongation
• Concomitant use of CYP3A4 inhibitors