Randomized Phase I/II of RAD001 in Advanced Hepatocellular Carcinoma (HCC)

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-Pugh's class A or B
• Phase II: To assess the disease control rate of advanced Child-Pugh's class A or B HCC patients receiving the determined MTD of once daily and weekly oral RAD001 in phase I

1. 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 2.5, 5.0, 7.5 to 10 mg/day without splitting, with or without food. The RAD001 dose level of weekly schedule will be escalated from 20, 30, 50 to 70 mg/week 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 2.5 gm/day in daily schedule arm and at 20 mg/week 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, Simon's 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.
3. Safety Assessment: Toxicity assessment:

• Evaluation of toxicity will be performed on patient-base.
• Clinical and laboratory toxicity/symptomatology will be graded according to NCI common toxicity criteria (CTC) version 3.0.
• Abnormal liver functional tests are common in patients with HCC, only abnormal elevation of ALT will be considered as indicator of hepatotoxicity.

1. 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. t1/2: 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, AEs/concomitant 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.
• Investigators/research 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 (e.g., 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 3.0.
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.