The purpose of this study is to compare treatment with RAD001 plus best supportive care (BSC) to placebo plus BSC in patients with advanced HCC whose disease progressed while on or after sorafenib treatment or who are intolerant to sorafenib.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
546
Everolimus (labeled as RAD001) was formulated as tablets of 2.5 mg strength and blisterpacked in units of 10 tablets.
Everolimus Placebo matched to the everolimus 2.5 mg tablet strength was blister-packed in units of 10 tablets. Matching placebo tablets were formulated to be indistinguishable from the everolimus tablets. Everolimus placebo was taken as a daily oral dose of 7.5 mg and was defined as the control drug.
BSC was defined as drug or non-drug therapies, nutritional support, physical therapy or anything that the Investigator believed to be in the patient's best interest, but excluding other antineoplastic treatments. BSC administered to the patient throughout the study was to be reported on the Concomitant Medication/Significant Non-Drug Therapy electronic case report from (eCRF). Permitted BSC treatments during the study included, but were not limited to, the following: Pain medication to allow the patient to be as comfortable as possible, Bisphosphonates for bone metastases, Localized radiotherapy, for the treatment of pre-existing, painful bone metastases, Nutritional support or appetite stimulants (i.e. megestrol) as recommended by the Investigator, Oxygen therapy and blood products or transfusions
Overall Survival (OS)
OS was defined as the time from the date of randomization to the date of death from any cause. The comparison of OS between the 2 arms was done using a stratified log-rank test at one-sided 2.5% level of significance.
Time frame: When 454 OS events were observed
Time to Tumor Progression (TTP)
TTP was defined as the time from the date of randomization to the date of the first documented radiologic confirmation of disease progression. Since the study did not meet the primary objective, TTP was not formally tested.
Time frame: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient
Percentage of Participants With Disease Control Rate (DCR)
DCR is defined as the proportion of participants with a best objective response (BOR) of complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST. The BOR was the best response recorded from the start of the treatment until disease progression. CR is disappearance of all target lesions; PR is at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; SD is neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. PD is at least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
Time frame: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient
Time to Definitive Deterioration of ECOG Performance Score (PS) Score
Change in Eastern Cooperative Oncology Group (ECOG) were assessed by time to definitive performance status deterioration by at least one category on the ECOG scale. Deterioration was considered definitive if no improvement in the ECOG PS was observed at a subsequent measurement. ECOG PS: 0=Fully active, able to carry on all pre-disease performance without restriction, 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2=Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; 5=Dead
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Highlands Oncology Group Dept of Highlands Oncology Grp
Fayetteville, Arkansas, United States
Compassionate Cancer Care Medical Group CCCMG
Fountain Valley, California, United States
University of California San Diego - Moores Cancer Center SC - 3
La Jolla, California, United States
California Pacific Medical Center California Pacific Med
San Francisco, California, United States
Rocky Mountain Cancer Centers RMCC - Denver-Midtown (4)
Greenwood Village, Colorado, United States
Queen's Medical Center Queens Cancer Center
Honolulu, Hawaii, United States
The Sidney Kimmel Cancer Center at Johns Hopkins Hospital Dept. of SKCC @ JHU
Baltimore, Maryland, United States
Massachusetts General Hospital Dept. of Mass General Hospital
Boston, Massachusetts, United States
Midwest Cancer Care Physicians Research Medical Center
Kansas City, Missouri, United States
VA Sierra Nevada Health Care System Dept. of VA Sierra Nevada HCS
Reno, Nevada, United States
...and 121 more locations
Time frame: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.
Time to Definitive Deterioration of EORTC QLQ-C30 Scores
The primary quality of life endpoint was the time to definitive 5% deterioration from baseline in the global health status/quality of life scale of the EORTC QLQ-C30 questionnaire. Definitive deterioration by at least 5% is defined as a decrease in score by at least 5% compared to baseline, with no later observed increase above this threshold. The EORTC quality of life questionnaire (QLQ) is an integrated system for assessing the healthrelated quality of life (QoL) of cancer patients participating in international clinical trials. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Time frame: Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.
Pharmacokinetics Assessments - Cmin
Cmin is the pre-dose blood concentration at steady-state (ng/mL). Pre-dose (Cmin) blood samples were collected from all patients in both arms at Visit 3. Steady-state for the Cmin sample was defined as continuous administration of the same dose in the last 4 days prior to the collection of the Cmin sample. Steady-state for the 5 mg every other day regimen was defined as the state when the 5 mg dose was taken 2 days and 4 days before sampling. PK samples were only drawn at visit 3, and only analyzed for patients receiving everolimus at steady state (if patients had received the dose the previous 4 days). In addition summary statistics were only done for each everolimus dose when 3 samples were available. Only valid pre-dose (Cmin) everolimus samples were included in the analysis.
Time frame: Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.
Pharmacokinetics Assessments - Cmax
Cmax is the maximum (peak) blood drug concentration after dose administration (ng/mL) calculated as the maximum of C1h and C2h. C1h was 1 hour post-dose blood concentration (ng/mL) and C2h was 2 hour post-dose blood concentration (ng/mL). C1h and C2h post-dose samples were collected from all patients in both arms at Visit 3. Steady-state for the C1h and C2h samples was defined as continuous administration of the same dose in the previous 4 days and the day on which the C1h and C2h samples were collected. Steady-state for the 5 mg every other day regimen was defined as the state when the 5 mg dose was taken 2 days and 4 days before sampling. PK samples were only drawn at visit 3, and only analyzed for patients receiving everolimus at steady state (if patients had received the dose the previous 4 days). In addition summary statistics were only done for each everolimus dose when 3 samples were available. Only valid C1h and C2h everolimus samples were included in the analysis.
Time frame: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.