Modified Megestrol The Clinical Trials by : Carolina R. Akib

Our product It is ”Modified Megestrol”, estrogen agonist, for treat HCC. After aprroval IND from Thai FDA we will start our CLINICAL TRIALS.

Objectives RATIONALE: Estrogen can stimulate the growth of cancer cells. Hormone therapy using modified megestrol may fight liver cancer by blocking the uptake of estrogen. It is not yet known if modified megestrol is an effective treatment for liver cancer. PURPOSE : Trial to determine the effectiveness of modified megestrol in treating patients who have liver cancer that cannot be removed by surgery.

Trial Protocol -Protocol is written document by the sponsor of the study and explains : What the trial will do, How it will be conduct, Where it will be conduct, Who may participate, How and when the participate will be evaluated.

Participant / Patients Informed written consent & explanation about process, risk & benefits, insurance ELIGIBILITY (INCLUSION & EXCLUSION CRITERIA) Disease Characterize : Diagnosis of HCC: Measurable, Estrogen receptor (+), Not amenable to surgery, No metastases, No previous or simultaneous secondary malignant disease

Participant / Patients, cont…. Patient Characteristic Age : Over 18 Gender : Both Performance status : Karnofsky scale ≥ 70 Life expectancy : At least 12 weeks Function of organs : Hepatic : SGOT, bilirubin, albumin Renal : Creatinin Other : Not pregnant or nursing Fertile patients No physical illness No other malignancy

Participant / Patients, cont…. Prior Concurrent Therapy : Biologic therapy : Not specified Chemotherapy : No chemoembolization, chemotherapy, antihormonal therapy Endocrine therapy : Not specified Radiotherapy : Not specified Surgery : No prior surgery for HCC Other : No prior percutaneous injection-HCC

Trial Sites Multicenter – University hospitals in Bangkok Mahidol University Hospital King Chulalongkorn University Hospital Thammasat University Hospital National Cancer Center Hospital

Phase I Objectives:  To define tolerable dose (MTD) of Modified Megestrol.  Describe common side effects  Describe pharmacologics in humans Number of participant (Study size) : patients (3-6 cohort w/ 3-6 patients each cohort) Medications & Dosages: Starting dose: 0.1 x LD 10 from preclinical trial, increase (dose escalation)  MTD. Length of the study: 3-6 months Evaluation time : baseline & every 2 months. Variable : General Scale of Grading Toxicity from WHO.

Phase II Objectives :  Response rate (the ability of the Modified Megestrol to produce tumor shrinkage), survival, quality of life.  Possibly pharmacodynamics relationship Number of participant (Study size) : < 100 patients Medications & Dosages: Starting dose range MTD  fixed dose Length of the study: 3-6 months Evaluation time : baseline & every 2 month Variable : Tumor response & Survival.

Phase III A randomized, double-blind, multicenter study. Patients are randomized to 1 of 2 treatment arms. Objectives:  Compare the overall survival of patients with inoperable HCC treated with Modified Megestrol vs Original Megestrol.  Compare the quality of life of patients treated with these drug.

Phase III, cont … Number of participant (Study size) : 100-thousands patients Arm I: Patients receive fixed dose of Modified Megestrol for 1 year. Arm II: Patients receive oral Original Megestrol for 1 year. Quality of life is assessed at baseline and then monthly for 1 year.

Schematic of the Phase III Source population of patients with HCC Randomized CT study sample Modified M (n=200)Original M (n=100) Recruit & Register Randomize Patients Treat, monitor, evaluate, and compare outcomes

Phase IV Start after FDA approves NDA of Modified Megestrol. Objectives: late / uncommon effects of Modified Megestrol Medications & Dosages: Fixed dose of Modified Megestrol Sample size : Length of the study : 10 years

Data Processing Data Handling All calculations will perform with recent statistical package. Variable :Tumour response: histologic, size, function of organs, Quality of life : changes in appetite, BW, feeling of well-being, survival. Record Keeping, Independent data Monitoring Committee

Summary Phase IPhase IIPhase IIIPhase IV Monitor variable Function of organs Tumor resp, Quality of L Other side effects Size Dosage0.1LD 10  MTD 80% MTD  fixed dose I: Fixed dose of MM II: OM Fixed dose Length3-6 month 1 year10 years End- points MTD (Rx threshold) efficacy & fixed dose (safety & efficacy) comparing treatment (randomized CT) late/ uncommon effects