Clinical trial NCT01638533: Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glioma
Hematopoietic and Lymphoid Cell Neoplasm
Lymphoma
Metastatic Malignant Solid Neoplasm
Neuroendocrine Neoplasm
Recurrent Adult Soft Tissue Sarcoma
Recurrent Bladder Carcinoma
Recurrent Breast Carcinoma
Recurrent Chronic Lymphocytic Leukemia
Recurrent Colorectal Carcinoma
Recurrent Head and Neck Carcinoma
Recurrent Lung Carcinoma
Recurrent Malignant Solid Neoplasm
Recurrent Melanoma
Recurrent Pancreatic Carcinoma
Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
Recurrent Prostate Carcinoma
Recurrent Renal Cell Carcinoma
Recurrent Thyroid Gland Carcinoma
Refractory Chronic Lymphocytic Leukemia
Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
Stage III Breast Cancer AJCC v7
Stage III Colorectal Cancer AJCC v7
Stage III Cutaneous Melanoma AJCC v7
Stage III Lung Cancer AJCC v7
Stage III Pancreatic Cancer AJCC v6 and v7
Stage III Prostate Cancer AJCC v7
Stage III Renal Cell Cancer AJCC v7
Stage III Soft Tissue Sarcoma AJCC v7
Stage IIIA Breast Cancer AJCC v7
Stage IIIA Colorectal Cancer AJCC v7
Stage IIIA Cutaneous Melanoma AJCC v7
Stage IIIB Breast Cancer AJCC v7
Stage IIIB Colorectal Cancer AJCC v7
Stage IIIB Cutaneous Melanoma AJCC v7
Stage IIIC Breast Cancer AJCC v7
Stage IIIC Colorectal Cancer AJCC v7
Stage IIIC Cutaneous Melanoma AJCC v7
Stage IV Breast Cancer AJCC v6 and v7
Stage IV Colorectal Cancer AJCC v7
Stage IV Cutaneous Melanoma AJCC v6 and v7
Stage IV Lung Cancer AJCC v7
Stage IV Pancreatic Cancer AJCC v6 and v7
Stage IV Prostate Cancer AJCC v7
Stage IV Renal Cell Cancer AJCC v7
Stage IV Soft Tissue Sarcoma AJCC v7
Stage IVA Colorectal Cancer AJCC v7
Stage IVB Colorectal Cancer AJCC v7
Unresectable Solid Neoplasm
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Celgene Corporation
First posted: 2012-07-11
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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 x 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 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 and biologic/antibody therapies (including immunotherapies) are 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
* 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 if a patient must take ondansetron, they may NOT take any other concomitant agents which might impact their QTc
* 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

Primary outcomes:
measure: Maximum tolerated dose 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 5.0
timeFrame: 28 days
measure: 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 5.0
timeFrame: 28 days
measure: Pharmacokinetic (PK) profile of romidepsin in patients with varying degrees of hepatic dysfunction using liquid chromatography-electrospray ionization tandem mass spectrometric method
timeFrame: 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
Secondary outcomes:
measure: Child-Pugh classification of hepatic dysfunction
timeFrame: Baseline
measure: Antitumor activity assessed using Response Evaluation Criteria in Solid Tumors and the International Workshop Lymphoma Response Criteria
timeFrame: Up to 30 days
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Bethesda
country: United States
facility: National Cancer Institute Developmental Therapeutics Clinic
state: Maryland
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Toronto
country: Canada
facility: University Health Network-Princess Margaret Hospital
state: Ontario
Study officials:
affiliation: JHU Sidney Kimmel Comprehensive Cancer Center LAO
name: Roisin M Connolly
role: PRINCIPAL_INVESTIGATOR
References: