AZD6244 and Sorafenib in Advanced Hepatocellular Carcinoma

Study Description

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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

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma	Drug: AZD6244 and sorafenib	Phase 1; Phase 2

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

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	30 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1/2 Study of AZD6244 in Combination With Sorafenib in Advanced Hepatocellular Carcinoma
Study Start Date :	November 2009
Actual Primary Completion Date :	February 2014
Actual Study Completion Date :	January 2015

Arms and Interventions

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Arm	Intervention/treatment
Experimental: AZD6244 and sorafenib; AZD6244+ sorafenib	Drug: AZD6244 and sorafenib; dose escalation of AZD6244; sorafenib 400mg bd; Other Names: AZD6244,; MEK inhibitor,; sorafenib,; Raf kinase inhibitor; nexavar

Outcome Measures

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Primary Outcome Measures :

1. 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. [ Time Frame: 12-15months ]

Secondary Outcome Measures :

1. To investigate if the combination sorafenib and AZD6244 increases Time To Progression (TTP) over sorafenib alone in patients with advanced hepatocellular carcinoma patients. [ Time Frame: 2-3 years ]

Eligibility Criteria

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Ages Eligible for Study:	21 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Locations

Singapore
National University Hospital Singapore
Singapore, Singapore, 119074
National Cancer Centre Singapore
Singapore, Singapore, 169610

Sponsors and Collaborators

National Cancer Centre, Singapore

Investigators

Principal Investigator:	Su Pin Choo	National Cancer Centre, Singapore

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Toh HC, Thng CH, Chow P, Ong HS, Chung A, Goh BC, Smith PD, Soo KC. AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J Hepatol. 2010 Jan;52(1):79-87. doi: 10.1016/j.jhep.2009.10.008. Epub 2009 Oct 28.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tai WM, Yong WP, Lim C, Low LS, Tham CK, Koh TS, Ng QS, Wang WW, Wang LZ, Hartano S, Thng CH, Huynh H, Lim KT, Toh HC, Goh BC, Choo SP. A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC). Ann Oncol. 2016 Dec;27(12):2210-2215. doi: 10.1093/annonc/mdw415. Epub 2016 Sep 28.

Responsible Party:	Choo Su Pin, Senior Consultant, National Cancer Centre, Singapore
ClinicalTrials.gov Identifier:	NCT01029418 History of Changes
Other Study ID Numbers:	09-20-HEP
First Posted:	December 10, 2009
Last Update Posted:	April 16, 2015
Last Verified:	April 2015

Keywords provided by Choo Su Pin, National Cancer Centre, Singapore:

HCC; hepatocellular carcinoma; liver cancer

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Hepatocellular; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases	Sorafenib; Niacinamide; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Vitamin B Complex; Vitamins; Micronutrients; Growth Substances; Physiological Effects of Drugs