AZD6244 and Sorafenib in Advanced Hepatocellular Carcinoma

Study Overview
=================
Brief Summary
-----------------
This will be a phase I/II clinical trial testing the combination of sorafenib and AZD6244 in advanced hepatocellular carcinoma with Childs A liver cirrhosis. The aim of the phase I portion is to determine appropriate dose of this drug combination. The phase 2 study will look at effectiveness and safety of this drug combination

Detailed Description
-----------------
Patients with unresectable BCLC Stage B/C hepatocellular carcinoma that is biopsy-proven ( histology or cytology from prior tumor biopsy specimen is acceptable Patients without prior systemic treatment ( chemotherapy or molecular targeted therapy) except prior adjuvant therapy, if given more than 6 months ago Child-Pugh class A only ECOG performance status 0 or 1

Official Title
-----------------
A Phase 1/2 Study of AZD6244 in Combination With Sorafenib in Advanced Hepatocellular Carcinoma

Conditions
-----------------
Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Drug: AZD6244 and sorafenib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with unresectable BCLC Stage B/C hepatocellular carcinoma that is biopsy-proven ( histology or cytology from prior tumor biopsy specimen is acceptable) Patients without prior systemic treatment ( chemotherapy or molecular targeted therapy) except prior adjuvant therapy, if given more than 6 months ago Patients who had prior local therapy ( TACE; PEI; RFA) more than 4 weeks prior to study entry No radiotherapy within 4 weeks before entry Child-Pugh class A only ( Appendix A) Age 21 years and older ECOG performance status 0 or 1 ( Appendix A) Life expectancy > 3 months. Patients must have normal organ and marrow function as defined below: Absolute neutrophil count > 1.5 x 109/L;Platelets> 75 x 109/L; Haemoglobin > 9.0g/dl;Total bilirubin < 51umol/L ( 3 mg /dL); AST(SGOT)/ALT(SGPT) < 5 X institutional ULN; Creatinine 1.5 ULN; INR <1.7 or prothrombin time ( PT) <4 seconds above ULN; Left ventricular ejection fraction (LVEF) >50% Measurable disease according to RECIST. A lesion which has previously been locally treated (including TACE or RFA) is eligible as long as there is evidence of disease progression Suitable for oral administration of drug Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Prior systemic therapy including sorafenib or a MEK inhibitor or sunitinib or other investigational drugs Any prior local therapy ( surgery, radiation therapy, hepatic arterial embolization, or cryoablation) within 4 weeks of study entry. Prior liver transplant NCI CTCAE grade > 3 hemorrhage within 4 weeks of starting study treatment, or documented variceal hemorrhage of any grade within 12 months of study entry (as documented on endoscopy) Presence of esophageal varices (> Grade 2) at risk of bleeding and/or serious or non-healing wound/ulcer ( as documented by endoscopy) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of study entry Patients with underlying inflammatory bowel disease, partial or complete bowel obstruction or chronic diarrhea Any of the following within the 12 months prior to study drug administration: severe/unstable angina, myocardial infarction, coronary artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, including transient ischemic attack, or pulmonary embolism. History of cardiac disease: active congestive heart failure cardiac arrythmias of NCI CTCAE grade >2 or requiring pacemaker uncontrolled hypertension cardiomyopathy atrial fibrillation rate >100bpm Patients with factors that increase the risk of QT prolongation or arrhythmic events ( hypokalemia, family history of long QT interval syndrome) or QTc interval of > 450ms for males or > 470ms for females on screening

Ages Eligible for Study
-----------------
Minimum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD6244 and sorafenib<br>AZD6244+ sorafenib | Drug: AZD6244 and sorafenib<br>* dose escalation of AZD6244; sorafenib 400mg bd<br>* Other names: nexavar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the combination of AZD6244 and sorafenib in patients with advanced hepatocellular cancer. |  | 12-15months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate if the combination sorafenib and AZD6244 increases Time To Progression (TTP) over sorafenib alone in patients with advanced hepatocellular carcinoma patients. |  | 2-3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HCC, hepatocellular carcinoma, liver cancer