A Trial of Oral 5-azacitidine in Combination With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Virally Mediated Cancers and Liposarcoma

This is a two part, single-institution, open-label, Phase I dose-escalation study of oral 5-azacitidine in combination with intravenous (IV) romidepsin. Part 1 of the study is a traditional 3 + 3 dose escalation study designed to evaluate the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, pharmacokinetic (PK) profiles, and pharmacodynamic profiles of increasing doses of orally administered 5-azacitidine in combination with a constant dose of IV romidepsin. Part 2 is an expansion cohort study for the preliminary evaluation of efficacy in the treatment of virally mediated cancers and liposarcoma once the MTD has been determined. PK and PD data will also be collected for these subjects.

• Plasma samples will be obtained, prior and during treatment, to assess the methylation status of free tumor DNA circulating in the blood
• Archival tissue will be obtained on all participants for future correlative studies, such as baseline gene expression, methylation patterns.
• Participants with accessible, biopsiable tumors will also undergo pre-treatment and post-treatment (~cycle 2D1) biopsies for correlative studies in the expansion cohort.

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 HPV+ nasopharyngeal cancer, HPV+ cervical cancer or liposarcoma (for 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 ≤ 1
• 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