MDACC Study Summary 2009-0419

Study Summary
No. 2009-0419:.......Liver......Ahmed Kaseb......Gastrointestinal Medical Oncology

Study Summary Title



Study Summary Number:	2009-0419

Study Title:	A Randomized, Double-blind, Multicenter Phase III Study of Brivanib versus Placebo as Adjuvant Therapy to Trans-Arterial Chemo-Embolization (TACE) in Patients with Unresectable Hepatocellular Carcinoma: The BRISK TA Study (CA182037)

Physician

New Patient Referral



Name:	Ahmed Kaseb	Patients Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Dept:	Gastrointestinal Medical Oncology	Referring MD Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Phone:	713-745-5517 Contact us about clinical trials

General Information



Disease Group:	Liver	Supported By:	BMS

Phase of Study:	Phase III	Return Visit:	Every week for the first month. Once a month thereafter.

Treatment Agents:	Brivanib TACE	Home Care:	NA

Treatment Loc:	Both at MDACC & outside MDACC at one or more Collaborating Sites or Institutions

Estimated Length of Stay in Houston:	NA


Description/ Intervention:	The goal of this clinical research study is to learn if adding brivanib to the TACE procedure can affect survival in patients with liver cancer. The safety of brivanib will also be studied.

Study Objectives / Outcomes

Primary Objective
To compare the Overall Survival (OS) of Hepatocellular Carcinoma (HCC) patients who receive brivanib as adjuvant treatments to Trans-Arterial Chemo-Embolization (TACE) therapy, with the OS of HCC patients who receive matched placebo with TACE therapy.

Secondary Objectives
1) To compare the Time-To-Disease Progression (TTDP) of patients receiving brivanib with TACE therapy to that of patients receiving placebo with TACE therapy.

2) To compare the time to extrahepatic spread or vascular invasion in the brivanib and placebo arms.

3) To determine the total number of TACE sessions in the brivanib and placebo arms and to compare the rate of TACE sessions in the brivanib and placebo arms.

4) To evaluate the safety of brivanib in combination with TACE.

Exploratory Objectives
1) To compare the investigator assessed Objective Response Rate (ORR) using modified
RECIST criteria for HCC.

2) To compare the Time-to-Radiographic-Tumor-Progression after the first TACE
session in the brivanib and placebo arms.

3) To explore population PK and exposure-response analyses.

4) To assess pharmacodynamic effect on biomarkers [e.g., collagen IV and vascular endothelial growth factor receptor (sVEGFR-2)].

5) To explore association of biomarkers [e.g., collagen IV, sVEGFR-2, and fibroblast growth factor (b-FGF)] with clinical outcomes.

6) To explore hospitalization rates and length of stay for clinical and adverse events.

Study Status Information



Study Activation / Registration Date:

IRB Review and Approval Date:	11/15/2010

Study Type:	Phase Iii

Recruitment Status:	Closed

Projected Accrual:	870

Enrollment Eligibility

If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:

1) Signed Written Informed Consent: a) Voluntary signed and dated written informed consent form in accordance with regulatory and institutional guidelines obtained before the performance of any protocol-related procedures not part of normal patient care.

2) Target Population: a) Patients with diagnosis of hepatocellular carcinoma (HCC) meeting the criteria below: i) Biopsy-proven HCC (histology or cytology), OR ii) IF Alpha fetoprotein > 400 �g/L at the time of diagnosis, require: 1. Radiological evidence of HCC showing lesion arterial hypervascularity and venous phase washout by either dynamic (triplephase), contrast-enhanced computed tomography of the abdomen or dynamic (triple-phase) contrast (gadolinium)-enhanced MRI, AND 2. Serology positive for hepatitis B or C, or cirrhosis,

3) (Continuation of crit # 2) OR iii) IF Alpha fetoprotein =/< 400 ug/L at the time of diagnosis, require: 1. Dynamic (triple-phase), contrast-enhanced computed tomography of the abdomen, AND 2. Dynamic (triple-phase) contrast (gadolinium)-enhanced MRI. BOTH CT and MRI should show radiological evidence of HCC lesion arterial hypervascularity and venous phase washout.

4) (Continuation of crit # 3) b) For HCC with less than four lesions, at least one must have a diameter =/> 5 cm OR if four or more lesions, at least one must have a diameter =/> 2 cm; c) Cirrhotic status of Child-Pugh Class A or B with a score of 7; d) ECOG performance status of 0 or 1; e) Life expectancy of at least 12 weeks; f) Ability to comply with visits/procedures required by protocol.

5) Physical and Laboratory Test Findings: a) Adequate hematologic function with absolute neutrophil counts >/= 1,500/mm^3, platelet count >/= 60 x 10^9/L, and hemoglobin >/= 8.5 g/dL; b) Adequate hepatic function with serum total bilirubin </= 3 mg/dL, serum albumin >/= 2.8 g/dL, and ALT and AST </= 5 times the institutional upper limits of normal (ULN); c) Amylase and lipase < 1.5 times the institutional upper limit of normal; d) Adequate renal function with serum creatinine </= 2.0 mg/dL

6) (Continuation of crit # 5) e) International normalized ratio (INR) < 1.7 or prothrombin time (PT) < 4 seconds above control; f) Left ventricular ejection fraction (LVEF) >/= 50% as measured by 2-D echocardiogram; g) All laboratory test finding should be stable within the range listed in a) - f) without continuous supportive treatment, such as blood transfusion, coagulation factors and/or platelet infusion, red/white blood cell growth factor administration, or albumin infusion, etc.

7) Age and Sex: a) Men and women, ages 18 or older. b) Women of childbearing potential (WOCBP), WOCBP whose male partners receive study drug, and male patients must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal.

8) (Continuation of crit # 6) Post menopause is defined as: Amenorrhea >/= 12 consecutive months without another cause or For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL.

9) (Cont of # 7) Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.

10) (Cont of # 8) In the case of urine pregnancy testing, a serum sample for pregnancy testing must also be obtained within 72 hours prior to start of investigational product to confirm the urine results. Investigational product may be initiated prior to the confirmatory serum pregnancy test results being available.

Exclusion Criteria:

1) Sex and Reproductive Status: a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the last dose of investigational product; b) Women who are pregnant or breastfeeding; c) Women with a positive pregnancy test on enrollment or prior to investigational product administration; d) Sexually active fertile men not using effective birth control up to 12 weeks after their last dose of study drug if their partners are WOCBP.

2) Target Disease Exceptions a) Diffuse pattern of disease on CT/MRI; b) Presence of extra-hepatic lesions; c) Any macroscopic vascular invasion of the portal system/vena cava or any evidence of vascular invasion on imaging; d) Surgically created shunts (e.g., portal-caval shunt); e) Any previous TACE or TAE (transarterial embolization without instillation of chemotherapy agent) procedure for HCC; f) Prior use of systemic treatment for HCC;

3) (Cont of # 2) except if the patient has had one previous TACE procedure which fulfills all of the following criteria: i) Occurred > 12 months ago, ii) Radiographic evidence of complete necrosis after the procedure and no evidence of recurrence since then, iii) Screening radiological imaging confirms that current lesion is in a location distinct from previously treated lesion and there is no recurrence of original lesion.

4) (Cont of # 3) g) Prior history of or current encephalopathy; h) Any ascites that is considered clinically significant, defined as: i) Current ascites requiring medical treatment; ii) Prior history of ascites requiring treatment, even if the ascites have since resolved.

5) Medical History and Concurrent Diseases: a) Previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated > 5 years prior to entry is permitted; b) History of cardiac disease: i) Uncontrolled hypertension which defined as systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 90 mmHg despite optimal medical management.

6) (Cont of # 4) ii) Congestive heart failure NYHA (New York Heart Association) class III and IV; iii) Active coronary artery disease, unstable or newly diagnosed angina or myocardial infarction less than 12 months prior to study entry; iv) Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin; v) Valvular heart disease >/= CTCAE Grade 2. c) QTc (Fridericia) > 450 msec on two consecutive ECGs (baseline ECG should be repeated if QTc is found to be > 450 msec).

7) (Cont of # 5) d) Thrombotic or embolic events within the past 6 months, such as a cerebrovascular accident (including transient ischemic attacks), pulmonary embolism. e) Hemorrhage/bleeding event >/= CTCAE Grade 3 within 4 weeks prior to study entry. f) Prior history of lower gastrointestinal bleeding within the past 6 months. g) History of unstable and/or active gastro-duodenal ulcers OR upper gastrointestinal bleeding within the past 6 months. However, if a patient has had a more recent gastroscopy showing complete healing of the ulcers, then this patient is eligible for the study.

8) (Cont of # 6) h) Any variceal bleed in the past 6 months; i) History of non-healing wounds or ulcers, or bone fractures within 3 months of fracture; j) Major surgical procedure, open biopsy, or significant traumatic injury less than 3 weeks prior to the start of investigational product administration or those who receive minor surgical procedures (e.g., core biopsy or fine needle aspiration) within 1 week prior to start of investigational product administration; k) History of organ allograft or on an allograft waiting list; l) Inability to swallow tablets or untreated malabsorption syndrome;

9) (Cont of # 7) m) Pre-existing thyroid abnormality of thyroid function that cannot be maintained in the normal range with medication; n) History of human immunodeficiency virus (HIV) infection; o) Active infection, less than 7 days after completing systemic antibiotic therapy; p) Active and untreated hepatitis B; q) Substance abuse, medical, psychological or social conditions that may interfere with the patient's compliance with study requirements and participation in the study or evaluation of the study results.

10) (Cont of # 8) r) Any medical condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study.

11) Physical and Laboratory Test Findings: a) Positive pregnancy test; b) Hyponatremia with sodium < 130 mmol/L; c) Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to restore the serum potassium above this level prior to study entry).

12) Allergies and Adverse Drug Reactions: a) Known or suspected history of allergy to brivanib or any agents given in association with this trial.

13) Prohibited Treatments and/or Therapies: a) Prior use of any systemic anti-cancer chemotherapy, immunotherapy, investigational or molecular targeted agents for HCC; b) Concomitant treatment with rifampin (and its analogues), or St John's Wort; c) Patients requiring anticoagulation therapy with an agent such as warfarin or heparin; d) Patients requiring chronic anti-platelet therapy (aspirin at dose =/> 300 mg/day, clopidogrel at dose =/> 75 mg/day); e) Radiotherapy within 4 weeks prior to start of study drug

14) Other Exclusion Criteria: a) Prisoners or patients who are involuntarily incarcerated; b) Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

Links

Registration Number: NCT00908752
Study Information on Clinical Trials Registry (clinicaltrials.gov)