Ignite Creation Date:
2024-05-05 @ 5:10 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00390195
Status:
UNKNOWN
Last Update Posted:
2009-07-02
First Post:
2006-10-17
Brief Title:
Randomized Phase III of RAD001 in Advanced Hepatocellular Carcinoma HCC
Sponsor:
National Health Research Institutes Taiwan
Organization:
National Health Research Institutes Taiwan
Study Overview
Official Title:
Randomized Phase III of Rapamycin Analog RAD001 in Advanced Hepatocellular Carcinoma - With a Pharmacokinetic Study of RAD001
Status:
UNKNOWN
Status Verified Date:
2009-06
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The mTOR has been examined in hepatocellular carcinomas as well This pathway is up-regulated in a proportion of hepatocellular carcinoma HCC and that rapamycin inhibits cell proliferation and blocks S6K phosphorylation Inhibition of mTOR had been shown to suppress substantially the liver tumor growth Nevertheless inhibition of mTOR was demonstrated to have a clinical response in some cancer types These reports imply that inhibition of mTOR could be a promising therapeutic strategy in the treatment of HCC Therefore we hypothesize that RAD001 a rapamycin analog can inhibit the mTOR and subsequently suppress the liver tumor in the treatment of HCC patients
This study is aimed to investigate the safety efficacy pharmacokinetics pharmacogenetics and feasibility of RAD001 in advanced HCC patients This study will be a randomized phase I study with dose escalation and subsequently a phase II study of intent to treat as well as pharmacokinetic pharmacogenetic and surrogate marker study of RAD001
This study is aimed to investigate the safety efficacy pharmacokinetics pharmacogenetics and feasibility of RAD001 in advanced HCC patients This study will be a randomized phase I study with dose escalation and subsequently a phase II study of intent to treat as well as pharmacokinetic pharmacogenetic and surrogate marker study of RAD001
Detailed Description:
Objectives
1 Primary Objectives
Phase I To assess the maximal tolerated dose MTD of once daily and weekly oral RAD001 in patients with advanced HCC of Child-Pughs class A or B
Phase II To assess the disease control rate of advanced Child-Pughs class A or B HCC patients receiving the determined MTD of once daily and weekly oral RAD001 in phase I
2 Secondary Objectives
Phase I To investigate the following items in the advanced HCC patients receiving RAD001
1 Dose-limiting toxicity
2 Pharmacokinetics study
3 Pharmacogenetic study
4 Surrogate marker study on the PTEN total and Phosphorylated forms of Akt of tumor tissues
5 Disease control rate
Phase II To investigate the following items in the advanced HCC patients receiving RAD001
1 Overall survival
2 Toxicity profile
3 Pharmacogenetic study
4 Surrogate marker study on the PTEN total and Phosphorylated forms of Akt of tumor tissues
Study Design This study will be a randomized phase I study with dose escalation and subsequently a phase II study of intent to treat as well as pharmacokinetic pharmacogenetic and surrogate marker study of RAD001
Sample Size Upto 134 patients Phase I in cohort of 3-6 to test each dose level and a upto 48 patients to reach the expected MTD 24 patients in each schedule of treatment arm Phase II 18 patients of each schedule at the first stage and 25 patients of each schedule at the second stage
Study Medication The RAD001 dose level of daily schedule will be escalated from 25 50 75 to 10 mgday without splitting with or without food The RAD001 dose level of weekly schedule will be escalated from 20 30 50 to 70 mgweek without splitting The dose and schedule of RAD001 in the phase II study will be dependent on the result of phase I study RAD001 will be supplied by Novartis Co
Study Conduct Patients will be enrolled onto a sequence of receiving an oral dose of RAD001 The schedule of RAD001 will be either once daily or once weekly Throughout the whole phase I and II study an eligible patient will be randomized into either arm of daily or weekly schedule In the phase I part each cohort of dose level will have 3 patients The dose of oral RAD001 will be initially fixed at 25 gmday in daily schedule arm and at 20 mgweek in weekly schedule arm One treatment course is defined as 4 weeks of RAD001 therapy When no patient experiences dose-limiting toxicity DLT at certain level subsequent patients would be randomized to the next dose level When 1 out of 3 patients developed DLT 3 additional patients would be treated with the same dose level Three patients will be further recruited to the next dose level when none of that 3 additional patients experience DLT No intra-individual dose-escalation will be performed In the phase II part Simons optimal two-stage approach will be used in both daily and weekly schedules If one responder is observed at the first stage of eighteen patients in either treatment schedule further twenty-five patients will be accrued
Therapeutic Assessment
1 Efficacy assessment
Radiological response To evaluate the disease control rate complete response partial response stable disease by computed tomography after every 8 weeks of therapy and according to RECIST guideline
Biological response
1 To evaluate the change of serum a-fetoprotein level
2 To evaluate the change of plasma angiogenic factors levels
2 Safety Assessment Toxicity assessment
Evaluation of toxicity will be performed on patient-base
Clinical and laboratory toxicitysymptomatology will be graded according to NCI common toxicity criteria CTC version 30
Abnormal liver functional tests are common in patients with HCC only abnormal elevation of ALT will be considered as indicator of hepatotoxicity
3 Pharmacokinetic Pharmacogenetic Surrogate Marker Assessments
Pharmacokinetic assessments
1 Cmax peak concentration
2 tmax time to achieve peak concentration
3 Cmin trough concentration
4 Cave average concentration
5 AUCt area under curve within a given time
6 t12 elimination half life
Pharmacogenetic assessments
1 Polymorphic CYP3A4
2 Polymorphic CYP3A5
3 Polymorphic P-glycoprotein
Surrogate marker assessments
1 PTEN
2 Total and Phosphorylated forms of Akt
Procedures
1 Screening will be done within 2 weeks before starting treatment and will include all parameters listed below except for pharmacokinetics AEsconcomitant medications and toxicity assessments as well as informed consent patient eligibility medical history a pregnancy test if indicated EKG and urinalysis
2 During treatment
Physical examination including vital sign measurements height weight AEs and toxicity evaluation at the first day of each week during the initial 4 weeks biweekly at the subsequently 8 weeks and 4-weekly thereafter
Performance status will be assessed on the first day of each treatment course
Investigatorsresearch nurses should monitor patients in each treatment course and should instruct patients regarding the signs and symptoms of RAD001 toxicity as described in the Information for Patients section of the RAD001 product labeling
The laboratory tests hemogram clinical chemistry will be conducted weekly at the first 4 weeks biweekly at the subsequent 8 weeks and 4- weekly thereafter
Imaging studies for tumor response will be performed every 2 courses
Patient clinical and biological responses will be noted at the end of the study
Statistical Analysis No formal inferential statistical analyses will be performed Data will be summarized using descriptive statistics number of patients mean median standard deviation minimum and maximum for continuous variables and using frequency and percentage for discrete variables For the safety analyses data will be presented for all patients An accounting of the study patients by disposition will be tabulated Demographic data eg age gender medical history cancer history and other baseline characteristics will be summarized
1 Safety Evaluation The general safety and tolerability of RAD001 will be assessed using the following safety endpoints AEs routine clinical laboratory evaluations hemogram serum chemistry and urinalysis physical examination concomitant medications and Eastern Cooperative Oncology Group ECOG performance status The grade of AEs at the time of rescue as determined from the NCI-CTC version 30
2 Pharmacokinetic Analysis Pharmacokinetic parameters will be determined from plasma drug and metabolite concentration curves using non- compartmental approaches Mean SD plasma drug concentration values will be summarized and plotted for each dose group All parameters described will be summarized with means and standard deviations The concentration in plasma determined at each sampling time point will be furnished on the original scale for each subject participating in the study The pharmacokinetic parameters Cmax Cmin Cave and AUC will be analyzed on the logarithmic scale of measurement The parameters of elimination half- life and tmax will be analyzed on the original scale
3 Efficacy Analysis The efficacious parameters will be determined by mean of disease control rate and median of time to tumor progression TTP and overall survival OS using Kaplan-Meier method The efficacious parameters will be added with 95 confidence interval All calculations will be based on the intent-to-treat principle
1 Primary Objectives
Phase I To assess the maximal tolerated dose MTD of once daily and weekly oral RAD001 in patients with advanced HCC of Child-Pughs class A or B
Phase II To assess the disease control rate of advanced Child-Pughs class A or B HCC patients receiving the determined MTD of once daily and weekly oral RAD001 in phase I
2 Secondary Objectives
Phase I To investigate the following items in the advanced HCC patients receiving RAD001
1 Dose-limiting toxicity
2 Pharmacokinetics study
3 Pharmacogenetic study
4 Surrogate marker study on the PTEN total and Phosphorylated forms of Akt of tumor tissues
5 Disease control rate
Phase II To investigate the following items in the advanced HCC patients receiving RAD001
1 Overall survival
2 Toxicity profile
3 Pharmacogenetic study
4 Surrogate marker study on the PTEN total and Phosphorylated forms of Akt of tumor tissues
Study Design This study will be a randomized phase I study with dose escalation and subsequently a phase II study of intent to treat as well as pharmacokinetic pharmacogenetic and surrogate marker study of RAD001
Sample Size Upto 134 patients Phase I in cohort of 3-6 to test each dose level and a upto 48 patients to reach the expected MTD 24 patients in each schedule of treatment arm Phase II 18 patients of each schedule at the first stage and 25 patients of each schedule at the second stage
Study Medication The RAD001 dose level of daily schedule will be escalated from 25 50 75 to 10 mgday without splitting with or without food The RAD001 dose level of weekly schedule will be escalated from 20 30 50 to 70 mgweek without splitting The dose and schedule of RAD001 in the phase II study will be dependent on the result of phase I study RAD001 will be supplied by Novartis Co
Study Conduct Patients will be enrolled onto a sequence of receiving an oral dose of RAD001 The schedule of RAD001 will be either once daily or once weekly Throughout the whole phase I and II study an eligible patient will be randomized into either arm of daily or weekly schedule In the phase I part each cohort of dose level will have 3 patients The dose of oral RAD001 will be initially fixed at 25 gmday in daily schedule arm and at 20 mgweek in weekly schedule arm One treatment course is defined as 4 weeks of RAD001 therapy When no patient experiences dose-limiting toxicity DLT at certain level subsequent patients would be randomized to the next dose level When 1 out of 3 patients developed DLT 3 additional patients would be treated with the same dose level Three patients will be further recruited to the next dose level when none of that 3 additional patients experience DLT No intra-individual dose-escalation will be performed In the phase II part Simons optimal two-stage approach will be used in both daily and weekly schedules If one responder is observed at the first stage of eighteen patients in either treatment schedule further twenty-five patients will be accrued
Therapeutic Assessment
1 Efficacy assessment
Radiological response To evaluate the disease control rate complete response partial response stable disease by computed tomography after every 8 weeks of therapy and according to RECIST guideline
Biological response
1 To evaluate the change of serum a-fetoprotein level
2 To evaluate the change of plasma angiogenic factors levels
2 Safety Assessment Toxicity assessment
Evaluation of toxicity will be performed on patient-base
Clinical and laboratory toxicitysymptomatology will be graded according to NCI common toxicity criteria CTC version 30
Abnormal liver functional tests are common in patients with HCC only abnormal elevation of ALT will be considered as indicator of hepatotoxicity
3 Pharmacokinetic Pharmacogenetic Surrogate Marker Assessments
Pharmacokinetic assessments
1 Cmax peak concentration
2 tmax time to achieve peak concentration
3 Cmin trough concentration
4 Cave average concentration
5 AUCt area under curve within a given time
6 t12 elimination half life
Pharmacogenetic assessments
1 Polymorphic CYP3A4
2 Polymorphic CYP3A5
3 Polymorphic P-glycoprotein
Surrogate marker assessments
1 PTEN
2 Total and Phosphorylated forms of Akt
Procedures
1 Screening will be done within 2 weeks before starting treatment and will include all parameters listed below except for pharmacokinetics AEsconcomitant medications and toxicity assessments as well as informed consent patient eligibility medical history a pregnancy test if indicated EKG and urinalysis
2 During treatment
Physical examination including vital sign measurements height weight AEs and toxicity evaluation at the first day of each week during the initial 4 weeks biweekly at the subsequently 8 weeks and 4-weekly thereafter
Performance status will be assessed on the first day of each treatment course
Investigatorsresearch nurses should monitor patients in each treatment course and should instruct patients regarding the signs and symptoms of RAD001 toxicity as described in the Information for Patients section of the RAD001 product labeling
The laboratory tests hemogram clinical chemistry will be conducted weekly at the first 4 weeks biweekly at the subsequent 8 weeks and 4- weekly thereafter
Imaging studies for tumor response will be performed every 2 courses
Patient clinical and biological responses will be noted at the end of the study
Statistical Analysis No formal inferential statistical analyses will be performed Data will be summarized using descriptive statistics number of patients mean median standard deviation minimum and maximum for continuous variables and using frequency and percentage for discrete variables For the safety analyses data will be presented for all patients An accounting of the study patients by disposition will be tabulated Demographic data eg age gender medical history cancer history and other baseline characteristics will be summarized
1 Safety Evaluation The general safety and tolerability of RAD001 will be assessed using the following safety endpoints AEs routine clinical laboratory evaluations hemogram serum chemistry and urinalysis physical examination concomitant medications and Eastern Cooperative Oncology Group ECOG performance status The grade of AEs at the time of rescue as determined from the NCI-CTC version 30
2 Pharmacokinetic Analysis Pharmacokinetic parameters will be determined from plasma drug and metabolite concentration curves using non- compartmental approaches Mean SD plasma drug concentration values will be summarized and plotted for each dose group All parameters described will be summarized with means and standard deviations The concentration in plasma determined at each sampling time point will be furnished on the original scale for each subject participating in the study The pharmacokinetic parameters Cmax Cmin Cave and AUC will be analyzed on the logarithmic scale of measurement The parameters of elimination half- life and tmax will be analyzed on the original scale
3 Efficacy Analysis The efficacious parameters will be determined by mean of disease control rate and median of time to tumor progression TTP and overall survival OS using Kaplan-Meier method The efficacious parameters will be added with 95 confidence interval All calculations will be based on the intent-to-treat principle
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None