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