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 March 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01638533
First received: July 9, 2012
Last updated: July 16, 2014
Last verified: March 2014

July 9, 2012
July 16, 2014
June 2012
September 2015   (final data collection date for primary outcome measure)
  • 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 ] [ Designated as safety issue: Yes ]
    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).
  • 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 ] [ Designated as safety issue: Yes ]
    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.
  • 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 ] [ Designated as safety issue: No ]
    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.
  • 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 ] [ Designated as safety issue: Yes ]
    Analyses will be descriptive in nature in this phase I study. We will characterize observed toxicities by dose level within each category of liver dysfunction (mild, moderate, severe, and liver transplant). We will summarize these results in relation to what is known about romidepsin in a population without liver dysfunction (as defined in this protocol).
  • Dose-limiting toxicity (DLT) 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 ] [ Designated as safety issue: Yes ]
    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.
  • 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 ] [ Designated as safety issue: No ]
    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 (Cmax) and area under the curve (AUC) for each group.
Complete list of historical versions of study NCT01638533 on ClinicalTrials.gov Archive Site
  • Child-Pugh classification of hepatic dysfunction [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Correlations of the Child-Pugh classification of hepatic dysfunction with the observed toxicities and plasma PK of romidepsin administration will be explored.
  • Antitumor activity assessed using Response Evaluation Criteria in Solid Tumors and the International Workshop Lymphoma Response Criteria [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    Association of antitumor activity and romidepsin treatment will be documented.
  • Correlation of the Child-Pugh classification of hepatic dysfunction with the observed toxicities and plasma PK of romidepsin administration [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Antitumor activity associated with romidepsin treatment using Response Evaluation Criteria in Solid Tumors and the International Workshop Lymphoma Response Criteria [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction
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

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.

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Hepatic Complications
  • Hepatosplenic T-cell Lymphoma
  • Intraocular Lymphoma
  • Male Breast Cancer
  • Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma
  • Nodal Marginal Zone B-cell Lymphoma
  • Noncutaneous Extranodal Lymphoma
  • Peripheral T-cell Lymphoma
  • Recurrent Adenoid Cystic Carcinoma of the Oral Cavity
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Basal Cell Carcinoma of the Lip
  • Recurrent Bladder Cancer
  • Recurrent Breast Cancer
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity
  • Recurrent Lymphoepithelioma of the Nasopharynx
  • Recurrent Lymphoepithelioma of the Oropharynx
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Melanoma
  • Recurrent Metastatic Squamous Neck Cancer With Occult Primary
  • Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity
  • Recurrent Mucoepidermoid Carcinoma of the Oral Cavity
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Recurrent Pancreatic Cancer
  • Recurrent Salivary Gland Cancer
  • Recurrent Small Lymphocytic Lymphoma
  • Recurrent Squamous Cell Carcinoma of the Hypopharynx
  • Recurrent Squamous Cell Carcinoma of the Larynx
  • Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Recurrent Squamous Cell Carcinoma of the Nasopharynx
  • Recurrent Squamous Cell Carcinoma of the Oropharynx
  • Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Recurrent Verrucous Carcinoma of the Larynx
  • Recurrent Verrucous Carcinoma of the Oral Cavity
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Hairy Cell Leukemia
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Stage III Adenoid Cystic Carcinoma of the Oral Cavity
  • Stage III Basal Cell Carcinoma of the Lip
  • Stage III Bladder Cancer
  • Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity
  • Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity
  • Stage III Lymphoepithelioma of the Nasopharynx
  • Stage III Lymphoepithelioma of the Oropharynx
  • Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity
  • Stage III Mucoepidermoid Carcinoma of the Oral Cavity
  • Stage III Pancreatic Cancer
  • Stage III Salivary Gland Cancer
  • Stage III Squamous Cell Carcinoma of the Hypopharynx
  • Stage III Squamous Cell Carcinoma of the Larynx
  • Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage III Squamous Cell Carcinoma of the Nasopharynx
  • Stage III Squamous Cell Carcinoma of the Oropharynx
  • Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Stage III Verrucous Carcinoma of the Larynx
  • Stage III Verrucous Carcinoma of the Oral Cavity
  • Stage IIIA Breast Cancer
  • Stage IIIA Melanoma
  • Stage IIIB Breast Cancer
  • Stage IIIB Melanoma
  • Stage IIIC Breast Cancer
  • Stage IIIC Melanoma
  • Stage IV Bladder Cancer
  • Stage IV Breast Cancer
  • Stage IV Lymphoepithelioma of the Nasopharynx
  • Stage IV Melanoma
  • Stage IV Pancreatic Cancer
  • Stage IV Squamous Cell Carcinoma of the Hypopharynx
  • Stage IV Squamous Cell Carcinoma of the Nasopharynx
  • Stage IVA Adenoid Cystic Carcinoma of the Oral Cavity
  • Stage IVA Basal Cell Carcinoma of the Lip
  • Stage IVA Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity
  • Stage IVA Inverted Papilloma of the Paranasal Sinus and Nasal Cavity
  • Stage IVA Lymphoepithelioma of the Oropharynx
  • Stage IVA Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity
  • Stage IVA Mucoepidermoid Carcinoma of the Oral Cavity
  • Stage IVA Salivary Gland Cancer
  • Stage IVA Squamous Cell Carcinoma of the Larynx
  • Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage IVA Squamous Cell Carcinoma of the Oropharynx
  • Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Stage IVA Verrucous Carcinoma of the Larynx
  • Stage IVA Verrucous Carcinoma of the Oral Cavity
  • Stage IVB Adenoid Cystic Carcinoma of the Oral Cavity
  • Stage IVB Basal Cell Carcinoma of the Lip
  • Stage IVB Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity
  • Stage IVB Inverted Papilloma of the Paranasal Sinus and Nasal Cavity
  • Stage IVB Lymphoepithelioma of the Oropharynx
  • Stage IVB Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity
  • Stage IVB Mucoepidermoid Carcinoma of the Oral Cavity
  • Stage IVB Salivary Gland Cancer
  • Stage IVB Squamous Cell Carcinoma of the Larynx
  • Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage IVB Squamous Cell Carcinoma of the Oropharynx
  • Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Stage IVB Verrucous Carcinoma of the Larynx
  • Stage IVB Verrucous Carcinoma of the Oral Cavity
  • Stage IVC Adenoid Cystic Carcinoma of the Oral Cavity
  • Stage IVC Basal Cell Carcinoma of the Lip
  • Stage IVC Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity
  • Stage IVC Inverted Papilloma of the Paranasal Sinus and Nasal Cavity
  • Stage IVC Lymphoepithelioma of the Oropharynx
  • Stage IVC Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity
  • Stage IVC Mucoepidermoid Carcinoma of the Oral Cavity
  • Stage IVC Salivary Gland Cancer
  • Stage IVC Squamous Cell Carcinoma of the Larynx
  • Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage IVC Squamous Cell Carcinoma of the Oropharynx
  • Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Stage IVC Verrucous Carcinoma of the Larynx
  • Stage IVC Verrucous Carcinoma of the Oral Cavity
  • T-cell Large Granular Lymphocyte Leukemia
  • Testicular Lymphoma
  • Tongue Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Waldenström Macroglobulinemia
  • Drug: romidepsin
    Given IV
    Other Names:
    • FK228
    • FR901228
    • Istodax
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
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.
Interventions:
  • Drug: romidepsin
  • Other: pharmacological study
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
132
Not Provided
September 2015   (final data collection date for primary outcome measure)

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
    • Excluding prostate cancer, renal cell cancer, neuroendocrine tumors, lung cancer, colorectal cancers, soft tissue sarcomas, glioma and thyroid cancer 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: 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
  • 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 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 as reported but lacking substantial evidence for causing QTc prolongation and Torsades de Pointes will be allowed, although if an alternative medication can be substituted, that would be preferable
  • 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
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with this drug
  • Warfarin is not permitted
Both
18 Years and older
No
United States,   Canada
 
NCT01638533
NCI-2012-01040, NCI-2012-01040, CDR0000737061, J11105, 9008, UM1CA186690, U01CA070095, UM1CA186686, UM1CA186691, U01CA062505, U01CA069912, P30CA006973, UM1CA186644, U01CA132123, UM1CA186717
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Roisin Connolly Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
National Cancer Institute (NCI)
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP