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Azacitidine and Romidepsin in Treating Patients with Relapsed or Refractory Lymphoid Malignancies

Trial Status: Active

This phase I / II trial studies the side effects and best dose of azacitidine when given together with romidepsin and to see how well they work in treating patients with lymphoid malignancies that have come back or do not respond to treatment. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Romidepsin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with romidepsin may be an effective treatment for lymphoid malignancies.

Inclusion Criteria

  • Phase I: Patients must have histologically confirmed relapsed or refractory non-Hodgkin lymphoma or Hodgkin lymphoma (World Health Organization [WHO] criteria), with no accepted curative options
  • Phase II: Patients with untreated, relapsed or refractory T-cell lymphoma, including patients with central nervous system (CNS) involvement or lymphomatous meningitis are allowed on study
  • Exploratory Cohort: Patients with histologically confirmed relapsed or refractory germinal center (GC)-derived B-Cell lymphoma (diffuse large B-cell [DLBCL] and follicular lymphoma [FL]) defined by the WHO and Hans criteria with no accepted curative options
  • There is no upper limit for the number of prior therapies; patients may have relapsed after prior autologous or allogeneic stem cell transplant
  • Evaluable disease in the Phase I, and measurable disease for the Phase II
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count >= 1,000/dL
  • Platelets >= 75,000 total (>= 50,000 if bone marrow involvement)
  • Bilirubin =< 1.5 X institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 X institutional upper limit of normal
  • Serum creatinine within normal institutional limits OR creatinine clearance >= 50 mL/min/for patients with creatinine levels above institutional normal
  • Negative urine or serum pregnancy test for females of childbearing potential
  • All females of childbearing potential must use an effective barrier method of contraception (either an intrauterine contraceptive device [IUDC] or double barrier method using condoms or a diaphragm plus spermicide) during the treatment period and for at least 1 month thereafter; male subjects should use a barrier method of contraception during the treatment period and for at least 3 months thereafter; female subjects should avoid the use of estrogen-containing contraceptives, since romidepsin may reduce the effectiveness of estrogen-containing contraceptives
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Prior therapy * Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier * Systemic steroids that have not been stabilized (>= 5 days) to the equivalent of =< 10 mg/day prednisone prior to the start of the study drugs * No other concurrent investigational agents are allowed
  • History of allergic reactions to oral 5-azacitidine or romidepsin
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women
  • Nursing women
  • Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix); patients whose lymphoma has transformed from a less aggressive histology remain eligible
  • Patients known to be human immunodeficiency virus (HIV)-positive
  • Patients with active hepatitis A, hepatitis B, or hepatitis C infection
  • Concomitant use of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors
  • Any known cardiac abnormalities such as: * Congenital long QT syndrome * Corrected QT (QTc) interval >= 500 milliseconds * Patients taking drugs leading to significant QT prolongation * Myocardial infarction within 6 months of course 1 day 1 (C1D1); (subjects with a history of myocardial infarction between 6 and 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 electrocardiogram (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 Canadian class II-IV; 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 * An ECG recorded at screening showing evidence of cardiac ischemia (ST depression of >= 2 mm, measured from isoelectric line to the ST segment); if in any doubt, the 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 multigated acquisition (MUGA) scan or < 50% by echocardiogram and/or MRI; * A 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 from prior treatment or other causes * 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 * Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers)


Moffitt Cancer Center
Contact: Lubomir Sokol

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE
Contact: Owen O'Connor
Phone: 212-326-5720


Fred Hutch / University of Washington Cancer Consortium
Status: ACTIVE
Contact: Andrei R. Shustov
Phone: 206-606-6739


I. Determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combination of oral azacitidine (5-azacitidine) and romidepsin. (Phase I)

II. Evaluate the safety and toxicity of the combinations of oral 5-azacitidine and romidepsin. (Phase I)

III. Estimate the overall response rate (ORR) (complete + partial response) of the combination of oral 5-azacitidine and romidepsin in patients with relapsed/refractory T-cell lymphoma. (Phase II)

IV. Determine the overall response rates (complete responses + partial responses) of oral azacitidine and romidepsin in patients with germinal center (GC)-derived B-cell lymphomas. (Exploratory cohort)

V. Determine progression free survival (PFS) and time to treatment failure (TTF). (Exploratory cohort)

VI. Determine the duration of response (DOR). (Exploratory cohort)

VII. Determine the safety and tolerability of oral azacitidine and romidepsin in patients with relapsed or refractory GC-derived B-cell lymphoid malignancies. (Exploratory cohort)


I. Describe the maximum number of cycles received. (Phase I)

II. Describe the number of dose delays and dose reductions at the MTD. (Phase I)

III. Describe the anti-tumor activity of the combination. (Phase I)

IV. Evaluate the overall response rate (ORR), progression free survival (PFS), and duration of response (DOR) of the study population. (Phase I)

V. Estimate the DOR and PFS of the combination in patients with T-cell lymphoma. (Phase II)

VI. Estimate the overall survival of patients with T-Cell lymphoma on study. (Phase II)

VII. Identify potential pre-treatment biomarkers of response based on gene expression profile ([GEP] and/or methylation array) to clinical outcome. (Phase II)

VIII. Evaluate the pharmacokinetic (PK) profile of oral azacitidine and romidepsin. (Exploratory cohort)

IX. Evaluate and compare pharmacodynamic (PD) endpoints with PK endpoints. (Exploratory cohort)


I. Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and post- treatment), including gene expression profiling and genome wide methylation status. (Phase I)

II. Evaluate the pharmacokinetic profile for oral 5-azacitidine and romidepsin when given as a combination in cycle 1 at various time intervals. (Phase I)

III. Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and post- treatment) including gene expression and genome wide methylation patterns. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive azacitidine orally (PO) once daily (QD) on days 1-14 or 1-21 and romidepsin intravenously (IV) over 4 hours on days 8 and 15 or 8, 15, and 22. Courses repeat every 21 (dose levels 1-4) or 28 (dose levels 5-6) days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, and then every 3 months.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center

Principal Investigator
Owen O'Connor

  • Primary ID AAAM3752
  • Secondary IDs NCI-2014-00121
  • ID NCT01998035