Belinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction
- Registration Number
- NCT01273155
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
- Belinostat is an experimental cancer treatment drug that works by helping to turn on genes that limit cell growth and survival of cancer cells. These genes are often switched off in tumors. Belinostat has been given to patients with different types of cancer to measure its safety and effectiveness, but it has not been given in a formal trial to cancer patients who have abnormal liver function. Because belinostat is processed by the liver, its safety and effectiveness needs to be established in individuals who have abnormal liver function. Researchers are interested in comparing the effects of belinostat as a cancer treatment drug in individuals with normal and abnormal liver function.
Objectives:
* To test the safety and effectiveness of belinostat in individuals who have solid tumors and lymphomas and who also have abnormal liver function.
* To compare the results of belinostat treatment in individuals with normal and abnormal liver function.
Eligibility:
* Individuals at least 18 years of age who have been diagnosed with solid tumors or lymphomas that have not responded to standard treatment.
* Individuals with normal liver function and varying degrees of abnormal liver function (mild, moderate, severe) are eligible.
Design:
* Participants will be screened with a full medical history and physical examination, as well as blood and urine tests, and tumor imaging studies. Participants will then be divided into study groups based on their liver function.
* Participants will receive belinostat in cycles of treatment. Except for cycle 1, all cycles will last 21 days. Cycle 1 will last 28 days. For cycle 1 only, participants will receive a single dose of belinostat 1 week before the regular 21-day treatment cycle starts.
* In each cycle, participants will receive belinostat once a day for 5 days, and will be asked to keep a medication diary to record any side effects.
* Participants will have regular clinic visits with blood and urine sample collection and imaging studies to evaluate the cancer's response to treatment.
* Participants may continue to take belinostat for as long as the cancer responds to the treatment.
- Detailed Description
Background:
* Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs are frequently deregulated in cancer cells, leading to an increase in deacetylation and the silencing of genes that normally control cell cycle arrest and apoptosis.
* Belinostat has growth inhibitory activity in several malignancies in vitro and in vivo, both as a single agent and in combination with chemotherapeutic agents. Several Phase I and II clinical trials have been conducted to date in patients with solid tumor and hematologic malignancies; belinostat has been generally well tolerated.
* Belinostat is metabolized in the liver and therefore, the safety and dosing of belinostat needs to be established in patients with varying degrees of hepatic dysfunction.
Objectives:
* Establish the safety and tolerability of belinostat given on days 1 through 5 of 21-day cycles to patients with varying degrees of liver dysfunction.
* Define the maximum tolerated dose (MTD) and recommended dose of belinostat given on days 1 through 5 of 21-day cycles to patients with varying degrees of liver dysfunction.
* Evaluate the pharmacokinetics (PK) of one dose of belinostat (400 mg/m(2)) in patients with varying degrees of liver dysfunction.
* Obtain preliminary evidence of anti-tumor activity at tolerable doses of belinostat in patients with varying degrees of liver dysfunction.
* Measure direct versus indirect bilirubin levels and correlate these with observed toxicities, PK.
Eligibility:
-Adults with solid tumors or lymphomas whose disease has progressed after standard therapy or who have no acceptable standard treatment options. Patients with normal and varying degrees of hepatic dysfunction (mild, moderate, and severe) are eligible.
Study Design:
-Patients will be divided into 4 dose escalation cohorts based on their level of liver dysfunction. Belinostat will be administered intravenously (IV) over 30 minutes. On day -7 (Cycle 1 only), all patients will receive a single dose of 400 mg/m(2) belinostat. On days 1 through 5 of each cycle, patients will receive belinostat at a dose dependent on the level of hepatic dysfunction and dose level. Mild, moderate, and severe liver dysfunction cohorts will begin on dose level 1; patients with normal hepatic function will not have their dose escalated (see below). The total length of Cycle 1 will be 28 days; all other cycles will be 21 days. No more than 12 evaluable patients with normal hepatic function will be accrued.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 72
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Normal Function-Belinostat 1000 mg/m(2) Belinostat Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Mild Dysfunction-Belinostat 750 mg/m(2) Belinostat Mild Liver Dysfunction was defined as bilirubin \>Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) \> ULN. Mild Dysfunction-Belinostat 1000 mg/m(2) Belinostat Mild Liver Dysfunction was defined as bilirubin \>Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) \> ULN. Moderate Dysfunction-Belinostat 500 mg/m(2) Belinostat Moderate Liver Dysfunction was defined as bilirubin \>1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Severe Dysfunction-Belinostat 250 mg/m(2) Belinostat Severe Liver Dysfunction was defined as bilirubin \>3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Moderate Dysfunction-Belinostat 750 mg/m(2) Belinostat Moderate Liver Dysfunction was defined as bilirubin \>1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Severe Dysfunction-Belinostat 350 mg/m(2) Belinostat Severe Liver Dysfunction was defined as bilirubin \>3 but ≤ 10 x ULN and any aspartate aminotransferase (AST).
- Primary Outcome Measures
Name Time Method Dose Limiting Toxicity (DLTs) First cycle of therapy, 28 days. A DLT was defined as an adverse event deemed possibly, probably, or definitely related to administration of study drugs and met the following criteria: grade≥3 non-hematological toxicity (except grade ≥3 diarrhea, nausea, vomiting responsive to supportive therapy);grade≥3 rise in creatinine (except grade 3 able to be corrected to grade 1 or baseline with intravenous fluids within 24hrs); grade≥3 electrolyte toxicities (except those able to be corrected to grade 1 or baseline within 48hrs); grade 4 thrombocytopenia; grade 4 neutropenia for \>5 days or febrile neutropenia; any neurotoxicity grade≥2 not reversible to grade 1 or baseline within 2wks; or any delay in treatment by ≥2wks due to treatment-related toxicity. Worsening liver function, as defined by a rise in serum bilirubin not related to tumor progression, was considered a DLT if a patient with mild dysfunction became severe for 1wk, or if a patient in either the moderate/severe groups had a \>1.5x increase in bilirubin for 1 wk.
Maximum Tolerated Dose (MTD) of Belinostat According to Degree of Liver Dysfunction First cycle of therapy, 28 days In order to maintain consistent dosing across the hepatic dysfunction groups, the dose recommended for cohorts with greater liver dysfunction could be no greater than the dose for cohorts of lesser dysfunction. In other words, it was assumed that a particular group would not tolerate a dose not tolerated by a group with lesser dysfunction and conversely, will tolerate a dose tolerated by a group with greater dysfunction. If a higher dose was tolerated in a group of greater dysfunction, but not in the group of lesser dysfunction, the lower dose would be recommended for both groups. The highest dose to be explored was no greater than the recommended dose for patients with normal liver function.
Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug From Cycle 1 Day -7 up to 12 (21-day) cycles The number of participants experiencing each adverse event by liver function cohort at each dose level. The grade refers to the severity of the Adverse Event. Grade 1 Mild; Grade 2 Moderate; Grade 3 Severe or medically significant but not immediately life-threatening; Grade 4 Life-threatening consequences; Grade 5 Death related to adverse event.
Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion. Maximum plasma concentrations (Cmax) for belinostat and five metabolites on Cycle 1 Day -7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after start of infusion; and 5, 10, 15, 60, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion. Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf) for belinostat and four metabolites on Cycle 1 Day -7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) of Belinostat Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion. Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) for Belinostat glucuronide, a Belinostat Metabolite on Cycle 1 Day-7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion. Half-life Period (t1/2) of belinostat and five metabolites on Cycle 1 Day -7 as a function of degree of liver function.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Clearance (CL) Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion. Clearance (CL) of Belinostat on Cycle 1 Day-7 as a function of degree of liver dysfunction
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Volume of Distribution at Steady State (Vss) Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion. Belinostat Apparent volume of distribution at steady state (Vss) on Cycle 1 Day-7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Metabolic Ratios of Maximum Plasma Concentrations (Cmax) for the Belinostat Metabolic Pathway Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion. Metabolic ratios of Maximum Plasma Concentrations (Cmax), reported as a geometric mean (geometric standard deviation), for the belinostat metabolic pathway on Cycle 1 Day-7 as a function of degree of liver dysfunction.
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Metabolic Ratios of Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf) for the Belinostat Metabolic Pathway Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion. Metabolic ratios of Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf), reported as geometric mean (geometric standard deviation), for the belinostat metabolic pathway on Cycle 1 Day-7 as a function of degree of liver dysfunction.
- Secondary Outcome Measures
Name Time Method Best Response at baseline and every two 21-day cycles of treatment, up to 12 cycles Radiologic response assessments by computed tomography (CT) scans were performed at baseline and every two cycles of treatment based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Per RECIST v1.1 Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum diameters; Stable Disease (SD), neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for Progression of Disease (PD), taking as reference the smallest sum diameters while on study; PD, \>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) and an absolute increase of at least 5mm or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). From Cycle 1 Day -7 up to 12 (21-day) cycles. Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Trial Locations
- Locations (7)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States
USC Norris Cancer Center
🇺🇸Los Angeles, California, United States
University of California, Davis
🇺🇸Davis, California, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Albert Einstein College of Medicine
🇺🇸Bronx, New York, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States