Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Romidepsin and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients with Stage IB-IVB Relapsed or Refractory T-cell Lymphomas

Protocol: OSU-14287

Full Title

A Multicenter Phase I dose-finding and preliminary efficacy study of the histone deacetylase inhibitor romidepsin (Istodax®) in combination with doxorubicin HCl liposomal (or Doxil®) for the treatment of adults with relapsed or refractory T-cell lymphomas

Purpose

This phase I clinical trial studies the side effects and best dose of romidepsin when given with pegylated liposomal doxorubicin hydrochloride in treating patients with stage IB-IVB T-cell lymphoma that has returned after a period of improvement or does not respond to treatment. Romidepsin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pegylated liposomal doxorubicin hydrochloride, 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. Giving romidepsin with pegylated liposomal doxorubicin hydrochloride may be a better treatment for T-cell lymphoma.

Study Objective

PRIMARY OBJECTIVES:

I. To determine the maximal tolerable dose (MTD) and recommended Phase II dose of romidepsin in combination with doxorubicin hydrochloride (HCl) liposomal (pegylated liposomal doxorubicin hydrochloride).

SECONDARY OBJECTIVES:

I. To determine complete response (CR) rate and overall response rate (CR+partial response [PR] rates).

II. To determine time to response (TTR), duration of response (DOR), and time to progression (TTP).

TERTIARY OBJECTIVES:

I. To assess potential biomarkers of response and synergy.

OUTLINE: This is a dose-escalation study of romidepsin.

Patients receive romidepsin intravenously (IV) over 4 hours on days 1, 8, and 15 and pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then every 3 months for 1 year.

Are you eligible?

Inclusion Criteria:

Able to understand and voluntarily sign an informed consent form

Able to adhere to the study visit schedule and other protocol requirements

Biopsy-proven, measurable, stage IB-IVB relapsed or refractory cutaneous T-cell lymphoma after 2 lines of skin-directed therapy or one prior line of systemic therapy (Note: extracorporeal photopheresis will be considered a systemic therapy for this study)

Patients with large cell transformation of cutaneous T cell lymphoma are eligible

Patients with systemic T cell lymphoma of any stage and any subtypes; patient must have had at least one standard chemotherapy and measurable disease at the time of enrollment

Patients with systemic T cell lymphomas who relapsed after autologous transplant are eligible

Patients with prior treatment of histone deacetylase (HDAC) inhibitors or doxorubicin liposome or doxil are eligible

All cancer therapy, including radiation, topical steroid, and chemotherapy, must have been discontinued at least 1 week or 3 half-lives whichever is the longest prior to treatment in this study; the only exceptions are participants who are symptomatic from their skin lesions and have been on corticosteroids for prolonged periods of time (> 60 days) without change may continue use of either systemic steroid (equivalent to =< 10 mg per day of prednisone) or topical steroids are eligible for this study if the frequency and dosage steroids has not changed for 60 days prior to the study; these participants should continue on the same dose of systemic/topical steroid throughout the study period unless they achieve a complete response at which time steroids can be discontinued

Patients are allowed to continue any medications with known activity in T cell lymphomas at the pre-enrollment doses for conditions other than T cell lymphomas (i.e., steroids for sarcoidosis), as long as there is evidence of T cell lymphoma progression while patients were on these agents

Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry

Absolute neutrophil count >= 750/mm^3

Platelet count >= 75,000/mm^3

Total bilirubin =< 2 x upper limit of normal (ULN)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN

Calculated creatinine clearance >= 30 ml/min (by the Cockcroft-Gault equation)

Disease free of prior malignancies for >= 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast; patients with early stage of prostate cancer under clinical surveillance without therapy are eligible

Negative serum pregnancy test at the time of enrollment for females of childbearing potential

For males and females of child-producing potential, use of effective contraceptive methods during the study to include 2 methods of contraception, one being a condom

Life expectancy >= 90 days

Exclusion Criteria:

Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form

Pregnant or breast feeding females

Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study

Prior allogeneic hematopoietic cell transplant

Prior solid organ transplant

Cumulative anthracycline exposure greater than 450 mg/m^2 doxorubicin equivalents prior to enrollment

Known active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); patients who are seropositive because of prior hepatitis B virus vaccination are eligible

Any active central nervous system or meningeal involvement

Congenital long QT syndrome

Baseline corrected QT (QTc) interval >= 480 milliseconds

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 magnetic resonance imaging (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)

Any cardiac finding that is deemed ineligible at the discretion of the investigator

Patients taking drugs leading to significant QT prolongation and unable to stop drugs prior to treatment

Concomitant use of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors or inducers unless able to stop medication(s) prior to starting study therapies

Non-Hodgkin’s Lymphoma (B- & T-Cell) Multiple Myeloma Hodgkin’s Lymphoma Chronic Lymphocytic Leukemia Lymphoma Leukemia