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Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2016 by National Cancer Institute (NCI)
Celgene Corporation
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: July 9, 2012
Last updated: February 1, 2017
Last verified: November 2016
This phase I trial studies the side effects and best dose of romidepsin in treating patients with lymphoma, chronic lymphocytic leukemia, or solid tumors with liver dysfunction. Romidepsin may stop the growth of cancer cells by entering the cancer cells and by blocking the activity of proteins that are important for the cancer's growth and survival.

Condition Intervention Phase
Metastatic Solid Neoplasm
Neuroendocrine Neoplasm
Recurrent Adult Soft Tissue Sarcoma
Recurrent Bladder Carcinoma
Recurrent Breast Carcinoma
Recurrent Chronic Lymphocytic Leukemia
Recurrent Colorectal Carcinoma
Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma
Recurrent Head and Neck Carcinoma
Recurrent Lung Carcinoma
Recurrent Melanoma
Recurrent Pancreatic Carcinoma
Recurrent Prostate Carcinoma
Recurrent Renal Cell Carcinoma
Recurrent Solid Neoplasm
Recurrent Thyroid Gland Carcinoma
Refractory Chronic Lymphocytic Leukemia
Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma
Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Stage III Lung Cancer
Stage III Pancreatic Cancer
Stage III Prostate Cancer
Stage III Renal Cell Cancer
Stage III Soft Tissue Sarcoma
Stage IIIA Breast Cancer
Stage IIIA Colorectal Cancer
Stage IIIA Skin Melanoma
Stage IIIB Breast Cancer
Stage IIIB Colorectal Cancer
Stage IIIB Skin Melanoma
Stage IIIC Breast Cancer
Stage IIIC Colorectal Cancer
Stage IIIC Skin Melanoma
Stage IV Breast Cancer
Stage IV Lung Cancer
Stage IV Pancreatic Cancer
Stage IV Prostate Cancer
Stage IV Renal Cell Cancer
Stage IV Skin Melanoma
Stage IV Soft Tissue Sarcoma
Stage IVA Colorectal Cancer
Stage IVB Colorectal Cancer
Unresectable Solid Neoplasm
Other: Pharmacological Study
Drug: Romidepsin
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase 1 and Pharmacokinetic Single Agent Study of Romidepsin in Patients With, Lymphomas, Chronic Lymphocytic Leukemia and Select Solid Tumors and Varying Degrees of Liver Dysfunction

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Dose-limiting toxicity of romidepsin in groups of patients with varying degree of hepatic dysfunction according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 [ Time Frame: 28 days ]
    In order to define levels of hepatic impairment at which dose modifications of romidepsin are required, data will be combined across hepatic dysfunction groups to evaluate the association between toxicity, dose, and liver assay level(s). The outcome variable, drug tolerance and dose-limiting toxicities will be modeled as function of dose and liver assay using multivariate linear regression. Higher order terms of the predictor variables and interactions will be included if there is evidence of non-linear and/or non-additive associations.

  • MTD of romidepsin in groups of patients with varying degree of hepatic dysfunction according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 [ Time Frame: 28 days ]
    Analyses will be descriptive in nature. The observed toxicities will be characterized by dose level within each category of liver dysfunction (mild, moderate, severe, and liver transplant). These results will be summarized in relation to what is known about romidepsin in a population without liver dysfunction (as defined in this protocol).

  • PK profile of romidepsin in patients with varying degrees of hepatic dysfunction using liquid chromatography-electrospray ionization tandem mass spectrometric method [ Time Frame: 0, 1, 2, 3, 4, 4.25, 4.5, 5, 6, 8, 10, 24, and 48 hours after initiation of the infusion on day 1 ]
    PK variables will be tabulated and descriptive statistics calculated for each function group. Geometric means and coefficients of variation will be presented for maximum concentration and area under the curve for each group.

Secondary Outcome Measures:
  • Antitumor activity assessed using Response Evaluation Criteria in Solid Tumors and the International Workshop Lymphoma Response Criteria [ Time Frame: Up to 30 days ]
    Association of antitumor activity and romidepsin treatment will be documented.

  • Child-Pugh classification of hepatic dysfunction [ Time Frame: Baseline ]
    Correlations of the Child-Pugh classification of hepatic dysfunction with the observed toxicities and plasma PK of romidepsin administration will be explored.

Estimated Enrollment: 132
Study Start Date: June 2012
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (romidepsin)
Patients receive romidepsin IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Pharmacological Study
Correlative studies
Drug: Romidepsin
Given IV
Other Names:
  • Antibiotic FR 901228
  • Depsipeptide
  • FK228
  • FR901228
  • Istodax
  • N-[(3S,4E)-3-Hydroxy-7-mercapto-1-oxo-4-heptenyl]-D-valyl-D-cysteinyl-(2Z)-2-amino-2-butenoyl-L-valine, (4->1) Lactone, Cyclic

Detailed Description:


I. To establish the safety and tolerability of romidepsin given on days 1, 8, and 15 of a 28 day cycle to patients with varying degrees of liver dysfunction (mild, moderate and severe).

II. To establish the maximum tolerated dose (MTD) and appropriate dosing recommendations for romidepsin in such patients.

III. To characterize the pharmacokinetics (PK) of romidepsin in patients with varying degrees of liver dysfunction.


I. To explore correlations of the Child-Pugh classification of liver dysfunction with the observed toxicities and plasma PK of romidepsin administration.

II. To document any preliminary evidence of antitumor activity at tolerable doses of romidepsin in patients with varying degrees of liver dysfunction.

OUTLINE: This is a dose-escalation study.

Patients receive romidepsin intravenously (IV) over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed (at original diagnosis or subsequent recurrence or progression) lymphoma, chronic lymphocytic lymphoma (CLL) or solid tumor; patients with lymphoma or CLL must have radiologically or clinically evaluable disease, and be refractory to standard therapy as defined by relapse within 6 months of last treatment (see note below); patients with solid tumors must have radiologically or clinically evaluable disease that is metastatic, unresectable, progressive, or recurrent, and for which standard curative measures do not exist or are no longer effective

    • Patients with a liver mass, raised alpha-fetoprotein level (>= 500 ng/mL) and positive serology for hepatitis, consistent with a diagnosis of hepatocellular carcinoma will be eligible without the need for pathologic confirmation of the diagnosis
    • Patients with prostate cancer, renal cell cancer, neuroendocrine tumors, lung cancer, colorectal cancers, soft tissue sarcomas, glioma and thyroid cancer are excluded in the normal and mild cohorts due to a lack of efficacy in these tumor types in phase 2 studies; patients with breast, pancreatic, bladder, head and neck cancers, as well as melanoma and other malignancies are eligible
    • Note: patients with prostate cancer, renal cell cancer, lung cancer, colorectal cancers, soft tissue sarcomas, glioma and thyroid cancer are allowed to enroll in the moderate and severe cohorts provided the patients:

      • Sign a separate consent form which outlines the lack of efficacy observed in prior studies
      • Are consented to the study by a protocol-specified designee who is not their longitudinal oncologist; patients with neuroendocrine tumors are still excluded from the moderate and severe cohorts
    • Note: as romidepsin is approved for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) or cutaneous T cell lymphoma (CTCL), these patients would be eligible WITHOUT the requirement of having 'relapsed within 6 months of last treatment'
  • Life expectancy of > 3 months
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Hemoglobin >= 9 g/dL (transfusions and/or erythropoietin are permitted)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L (or platelet count >= 30 × 10^9 cells/L in patients with lymphoma or CLL if bone marrow disease involvement is documented)
  • Creatinine =< twice upper limit institutional normal
  • Patients with abnormal liver function will be eligible and will be grouped according to the criteria below

    • Group A (normal hepatic function)

      • Bilirubin =< upper limit of normal (ULN) and aspartate aminotransferase (AST) =< ULN
    • Group B (mild hepatic dysfunction)

      • B1: bilirubin =< ULN and AST > ULN
      • B2: bilirubin > ULN but =< 1.5 x ULN and any AST
    • Group C (moderate hepatic dysfunction)

      • Bilirubin > 1.5 x ULN to =< 3 x ULN and any AST
    • Group D (severe hepatic dysfunction)

      • Bilirubin > 3 x ULN and up to investigators discretion and any AST
    • Patients with active hemolysis should be excluded; no distinction will be made between liver dysfunction due to metastases and liver dysfunction due to other causes; registration laboratory investigations will be used to assign a patient to a hepatic function group; liver function tests should be repeated within 24 hours prior to starting initial therapy and may result in the patients' group assignment being altered if different to registration test results
  • Patients with brain metastases who require corticosteroids or non-enzyme inducing anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to enrollment; patients with known brain metastases should have completed brain irradiation (whole brain or gamma knife) more than 4 weeks before starting the protocol; patients on enzyme inducing anticonvulsants are not eligible; note that patients should have had their steroids tapered to low dose (i.e. < 1.5 mg of dexamethasone/day) due to the potential for higher dexamethasone doses to induce cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
  • Patients with biliary obstruction for which a stent has been placed are eligible, provided the shunt has been in place for at least 10 days prior to the first dose of romidepsin and the liver function has stabilized; two measurements at least 2 days apart that put the patient in the same hepatic dysfunction stratum will be accepted as evidence of stable hepatic function; there should be no evidence of biliary sepsis
  • Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or PK of romidepsin will be determined following review of their case by the site principal investigator

    • Patients treated with any of the medications prohibited must discontinue their use at least 7 days prior to the first dose of romidepsin; certain other agents that interact with the CYP3A4 system may be used with caution
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; note: since romidepsin binds to the estrogen receptor, the effectiveness of estrogen containing contraceptives may be reduced
  • Human immunodeficiency virus (HIV)-positive patients who are not receiving: agents with the potential for PK interactions with romidepsin or hepatotoxic antiretrovirals (nucleoside reverse-transcriptase inhibitors [NRTIs]: abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine), dual protease inhibitor (PI)-based regimens except low-dose boosting with ritonavir, atazanavir, indinavir, maraviroc, and nevirapine may be eligible; additionally, the HIV-positive patients should have a cluster of differentiation (CD)4 count > 250/mm^3; if the specific cause of hepatic dysfunction is unknown, the patient should be worked up for other viral causes of hepatitis and their eligibility determined after consultation with the principal investigator
  • Patients who have received prior romidepsin use are eligible
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had (prior to entering the study): major surgery is not permitted within 4 weeks of romidepsin administration; anti-cancer therapy including chemotherapy, radiotherapy, hormonal (with the exception of hormones for thyroid conditions), and other investigational agents will not be allowed within 14 days or five (5) half-lives (whichever is longer) prior to the first dose of romidepsin (6 weeks for nitrosoureas or mitomycin C); additionally, participants must have recovered to less than grade 2 clinically significant adverse effect(s)/toxicity(ies) of the previous therapy, with the exception of alopecia, unless approved by the principal investigator; biologics or immunotherapy will not be allowed within 28 days prior to, or during, romidepsin administration
  • Patients with prostate cancer, renal cell cancer, neuroendocrine tumors, lung cancer, colorectal cancers, soft tissue sarcomas, glioma, and thyroid cancer are excluded in the normal and mild cohorts due to a lack of efficacy in these tumor types in phase 2 studies; patients with prostate cancer, renal cell cancer, lung cancer, colorectal cancers, soft tissue sarcomas, glioma and thyroid cancer are allowed to enroll in the moderate and severe cohorts only; patients with neuroendocrine tumors are still excluded from the moderate and severe cohorts
  • Patients may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to romidepsin, including cyclic tetrapeptide compounds
  • Concurrent medications associated with a known risk of corrected QT interval (QTc) prolongation and/or Torsades de Pointes are not allowed within 2 weeks of initiation of study treatment; those medications listed as a possible risk for causing QTc prolongation and Torsades de Pointes will be allowed, although if an alternative medication can be substituted, that would be preferable; granisetron is an acceptable antiemetic on this study, but ondansetron is not
  • Thiazolidinedione agents such as rosiglitazone and pioglitazone are not permitted
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
  • Patients with current evidence of significant cardiovascular disease (New York Heart Association class III or IV cardiac disease), symptomatic congestive heart failure, dilated/hypertrophic or restrictive cardiomyopathy, myocardial infarction (within the past 6 months), unstable angina, unstable arrhythmia or a need for anti-arrhythmic therapy (use of medications for rate control for atrial fibrillation is allowed such as calcium channel blockers and beta-blockers, if stable medication for at least last month prior to initiation of romidepsin treatment and medication not listed as causing Torsades de Pointes), or evidence of acute ischemia on electrocardiogram (ECG); marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval > 450 msec*; long QT syndrome; the required use of concomitant medication that may cause Torsades de Pointes or may cause a significant prolongation of the QTc

    • Note: due to difficulties assessing QTc in patients with heart block, they may be eligible if deemed safe by a cardiologist; if a patient must take ondansetron as their antiemetic, their QTc may NOT be over 450 (no exception for patients with heart block)
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with this drug
  • Warfarin is not permitted
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01638533

United States, California
City of Hope Comprehensive Cancer Center Suspended
Duarte, California, United States, 91010
University of California Davis Comprehensive Cancer Center Active, not recruiting
Sacramento, California, United States, 95817
City of Hope South Pasadena Recruiting
South Pasadena, California, United States, 91030
Contact: Stephen C. Koehler    626-396-2900   
Principal Investigator: Stephen C. Koehler         
United States, Georgia
Emory University/Winship Cancer Institute Suspended
Atlanta, Georgia, United States, 30322
United States, Illinois
University of Chicago Comprehensive Cancer Center Suspended
Chicago, Illinois, United States, 60637
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Roisin M. Connolly    410-955-8804   
Principal Investigator: Roisin M. Connolly         
National Cancer Institute Developmental Therapeutics Clinic Active, not recruiting
Bethesda, Maryland, United States, 20892
National Institutes of Health Clinical Center Active, not recruiting
Bethesda, Maryland, United States, 20892
United States, Michigan
Wayne State University/Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Ulka N. Vaishampayan    313-576-9363      
Principal Investigator: Ulka N. Vaishampayan         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Paul Haluska    507-284-2511   
Principal Investigator: Paul Haluska         
United States, Ohio
Case Western Reserve University Withdrawn
Cleveland, Ohio, United States, 44106
United States, Pennsylvania
Penn State Milton S Hershey Medical Center Suspended
Hershey, Pennsylvania, United States, 17033-0850
Thomas Jefferson University Hospital Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Ashwin R. Sama    215-955-6084      
Principal Investigator: Ashwin R. Sama         
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact: Roisin M. Connolly    410-614-9217   
Principal Investigator: Roisin M. Connolly         
Canada, Ontario
University Health Network-Princess Margaret Hospital Suspended
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
National Cancer Institute (NCI)
Celgene Corporation
Principal Investigator: Roisin Connolly JHU Sidney Kimmel Comprehensive Cancer Center LAO
  More Information

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01638533     History of Changes
Other Study ID Numbers: NCI-2012-01040  NCI-2012-01040  NA_00052587  NCI-2013-01545  CDR0000737061  J11105  9008  9008  P30CA006973  U01CA132123  U01CA062505  U01CA069912  U01CA070095  UM1CA186644  UM1CA186686  UM1CA186689  UM1CA186690  UM1CA186691  UM1CA186716  UM1CA186717 
Study First Received: July 9, 2012
Last Updated: February 1, 2017

Additional relevant MeSH terms:
Breast Neoplasms
Lung Neoplasms
Prostatic Neoplasms
Colorectal Neoplasms
Pancreatic Neoplasms
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Carcinoma, Renal Cell
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Liver Diseases
Urinary Bladder Neoplasms
Lymphoma, T-Cell, Peripheral
Thyroid Neoplasms
Neuroendocrine Tumors
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms by Site
Breast Diseases
Skin Diseases processed this record on February 24, 2017