MDACC Study Summary 2006-0860 (Archived)

Study Summary
No. 2006-0860:.......Liver......Chris Garrett......Gastrointestinal Medical Oncology

Study Summary Title



Study Summary Number:	2006-0860

Study Title:	A Phase II Open Label Study of Brivanib (BMS-582664), Administered Orally At A Dose of 800 Mg Daily In Subjects with Unresectable, Locally Advanced or Metastatic Hepatocellular Carcinoma Who Have Received Either No Prior Systemic Therapy or One Prior Regimen of Angiogenesis Inhibitor Therapy (CA182006)

Physician

New Patient Referral



Name:	Chris Garrett	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:	713-792-2828 Contact us about clinical trials

General Information



Disease Group:	Liver	Supported By:	N/A

Phase of Study:	Phase II	Return Visit:	Every week for the first 3 weeks. Every 3 weeks starting Week 4.

Treatment Agents:	BMS-582664	Home Care:	NA

Treatment Loc:	Independent Multicenter Arrangements

Estimated Length of Stay in Houston:	NA


Description/ Intervention:	The goal of this clinical research study is to estimate the length of disease control, in patients with advanced liver cancer that cannot be surgically removed, when treated with BMS-582664 (also called brivanib alaninate or brivanib)

Study Objectives / Outcomes

Primary Objective
To estimate the 6-month progression free survival (PFS) rate in patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) with no prior systemic therapy for HCC treated with 800 mg of brivanib (BMS-582664).

Secondary Objectives
• To estimate tumor response rate, time to response, duration of response, progression free survival, overall survival, and disease control rate for patients with no prior systemic therapy and for subjects with one prior regimen of angiogenesis inhibitor therapy.
• To assess the safety and tolerability of brivanib for subjects with no prior systemic therapy, for subjects with one prior regimen of angiogenesis inhibitor therapy, and for all patients on the study.
• To obtain samples for population pharmacokinetics of BMS-540215 (the chemical parent and active moiety) in patients with hepatocellular carcinoma treated with BMS-582664.
• To assess the effects of brivanib on pharmacodynamic markers in patients with hepatocellular carcinoma.
• To obtain blood, paraffin embedded biopsy (if available) and (optional) fresh tumor samples to identify potential predictive markers of biological response utilizing enzyme-linked immunosorbent assays (ELISA), ribonucleic acid (RNA) profiling, protein profiling, single nucleotide polymorphism (SNP) analysis, and other techniques.
• To estimate differences in and to assess the impact of brivanib on patient symptoms using FHSI-8 (Functional Assessment of Cancer Therapy, Hepatobiliary, Symptom Index) for subjects with no prior systemic therapy, for subjects with one prior regimen of angiogenesis inhibitor therapy, and for all patients on the study.

Study Status Information



Study Activation / Registration Date:	05/16/2007

IRB Review and Approval Date:	03/02/2007

Study Type:	Phase Ii Or Phase I/Ii

Recruitment Status:	Terminated

Projected Accrual:	125

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) Voluntary signed and dated institutional review board (IRB)/independent ethics committee (IEC) approved informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before performing protocol-related procedures that are not part of standard patient care.

2) Subject with diagnosis of hepatocellular carcinoma meeting the criteria below: a) Biopsy-proven HCC (Histology or cytology) OR; b) Radiological evidence of HCC by contrast-enhanced CT scan or contrast enhanced MRI (Triple-phase computed tomography of the abdomen, or gadolinium-enhanced MRI that shows lesion arterial hypervascularity and venous phase washout.) AND; i) Serology positive for Hepatitis B or C AND; ii) Alpha fetoprotein >/= 400 ug/L (must have been documented at least once at the time of diagnosis of HCC or sometime after diagnosis of HCC).

3) Not appropriate for curative surgical resection.

4) Subjects who have received local therapy such as surgery, chemoembolization, radiation therapy, hepatic arterial embolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible, provided that they either have an index lesion which has not been subjected to local therapy and/or the index lesion(s) within the field of the local therapy has shown an increase of >/= 25% in size. Local therapy must be completed at least 4 weeks prior to the baseline scan.

5) The following specific angiogenesis inhibitors will be permitted provided that there has been clear progressive disease subsequent to their administration, that there was only 1 prior regimen of therapy with 1 of these agents, & that the timeframes since their administration have elapsed as indicated: a) Sunitinib (Sutent), sorafenib (Nexavar) or thalidomide – off therapy for 2 weeks & recovered from all toxicities, with new documentation of progressive disease b) bevacizumab (Avastin) – off therapy for 6 weeks & recovered from all toxicities, with new documentation of progressive disease

6) Measurable disease - All patients must have at least 1 previously un-irradiated, bi-dimensionally measurable lesion by CT or MRI scan of >/= 20 mm. Index lesions that are previously un-irradiated & are bidimensionally measurable by spiral CT scan to be >/= 10 mm will be permitted if either of the following are true: prior histological diagnosis of HCC or prior diagnosis has been obtained using the 3 combined non-histological criteria, Target Population, criteria 2. In this latter case, original index lesion at the time of first diagnosis must have been bidimensionally measured to be >/= 20 mm.

7) (Continuation of # 6) Triphasic spiral CT or MRI scans are preferred when such equipment is available. All CT scans should employ a "hepatoma protocol" image capture technique. The following are not considered measurable lesions: a) Ascites b) Bone metastases

8) More than 4 weeks since surgery (with the exception of venous port access). More than two weeks should have elapsed for a percutaneous liver biopsy.

9) "Cancer for the Liver Italian Program" Score (CLIP) </= 3; a) No evidence of encephalopathy

10) ECOG performance status of 0, 1, 2

11) Adequate bone marrow function: a) Absolute neutrophil count >/= 1500/mm^3; b) Platelet count >/= 65,000/mm^3; c) Hemoglobin >/= 9 g/dL

12) Adequate hepatic function: a) Total bilirubin </= 2.5 mg/dL; b) AST/ALT </= 5 times the upper limit of normal (ULN); c) Serum albumin > 2.8 g/dL; d) PT or INR </= 1.8, unless patient is on therapeutic anticoagulation for a thromboembolic event that occurred greater than 6 months prior.

13) Adequate renal function: a) Creatinine </= 2.0 mg/dL, OR; b) Creatinine clearance >/= 45 mL/min based on Cockcroft formula

14) Screening blood pressure of < 140/90 mmHg

15) Left ventricular ejection fraction (LVEF) >/= 50%

16) Men and women, ages 18 and older.

17) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the study in such a manner that the risk of pregnancy is minimized. WOCBP must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication.

Exclusion Criteria:

1) WOCBP who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for the entire study period and for up to 12 weeks after the study.

2) WOCBP not using an acceptable method of contraception sufficient to prevent pregnancy according to the instructions of the Principal Investigator.

3) Women who are pregnant or breastfeeding.

4) Women with a positive blood serum pregnancy test on enrollment or prior to study drug administration.

5) Exclude patients with CLIP score >3.

6) Active bacterial infections, HIV/AIDS or other severe disease that would preclude study participation.

7) Gastrointestinal tract disease or prior surgery, resulting in an inability to take or absorb oral medication.

8) Other primary malignancy, within the last five years, except carcinoma in situ of the cervix or in situ urinary bladder or non-melanoma skin cancer.

9) Mental incapacitation (e.g. severe dementia) or psychiatric illness that would preclude study participation.

10) History of active cardiac disease: i). Uncontrolled hypertension which is defined as systolic blood pressure greater than 140 mmHg or diastolic pressure greater than 90 mmHg despite optimal medical management. Subjects with a history of persistent hypertension who are receiving treatment with calcium channel blockers that are CYP3A4 substrates should be changed to an alternative antihypertensive medication before study entry. ii). Congestive heart failure NYHA (New York Heart Association) class 3 and 4.

11) (Continuation of # 10) 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 (asymptomatic; moderate regurgitation or stenosis by imaging).

12) Clinically significant ascites refractory to diuretic therapy.

13) Presence of portal-systemic encephalopathy (evidenced by confusion, asterixis, significant sleep disturbance, or hypothermia less than 36� Celsius).

14) Evidence of portal hypertension with bleeding esophageal or gastric varices within the past 2 months: a) Prior variceal bleed permitted if patient has undergone banding and there has been no evidence of bleeding for 2 months.

15) Hyponatremia with sodium < 125 mEq/L.

16) History of allergy to BMS-582664 or related compounds.

17) Prior systemic therapy for HCC, including systemic chemotherapy (including investigational), biological therapy, or hormone therapy (except for subjects previously treated with doxorubicin on an earlier version on this protocol or subjects that have had received one prior regimen of anti-angiogenesis inhibitor therapy limited to sunitinib, sorafenib, bevacizumab, or thalidomide).

18) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

19) Subjects with a history of bleeding/coagulation disorders (with the exception of variceal bleeds as in exclusion criteria 13a) such as: a) Any history of thrombosis within the last six months b) Subjects with main portal vein thrombosis c) Subjects with coagulopathy d) Subjects who are on chronic anti-platelet therapy (aspirin 300 mg/day, clopidogrel) Subjects entering the trial on warfarin should have frequent monitoring of INR for at least the first month on study and may require longer monitoring to insure that degree of anticoagulation does not go outside the therapeutic range.

20) (Continuation of # 19) Main portal vein is defined as the part of the portal vein between the inferior vena cava and the first bifurcation into the left and right vein. It is usually located in the porta hepatis.

21) Subjects with fibrolamellar disease.

22) Subjects with portal-caval shunts.

23) Subjects who are on a liver transplant list.

24) Subjects who have any known history of known brain metastases. Should patient have any signs and symptoms of possible brain metastases, a CT/MRI of the brain should be conducted prior to enrollment as clinically indicated.

25) Subjects with centrally located cavitating lung lesions.

26) Subjects with baseline serum potassium < 3.5 mmol/L. (Potassium supplementation may be given to restore the serum potassium above this level prior to study entry)

27) Subjects with QTc (Fridericia) > 450 msec on two consecutive ECGs. (Baseline ECG should be repeated if QTc is found to be > 450 msec on screening)

28) Subjects with serious non-healing wounds, ulcers or bone fractures

Links

Registration Number: NCT00355238
Study Information on Clinical Trials Registry (clinicaltrials.gov)