Bevacizumab and Sorafenib as First-Line Therapy in Treating Patients With Locally Advanced or Metastatic Liver Cancer

Liver Cancer Clinical Trial

Official title:

Phase I/II Randomized Trial of Sorafenib and Bevacizumab as First-Line Therapy in Patients With Locally Advanced or Metastatic Hepatocellular Carcinoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00867321
• Other study ID #: NCCTG-N0745
• Secondary ID: NCI-2009-01178CD
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 2009
• Est. completion date: May 2013

Study information

• Verified date: March 2022
• Source: Alliance for Clinical Trials in Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and sorafenib may also stop the growth of liver cancer by blocking blood flow to the tumor.

PURPOSE: This randomized phase I/II trial is studying the best dose of bevacizumab when given together with sorafenib as first-line therapy in treating patients with locally advanced or metastatic liver cancer.(Phase I closed to accrual as of 11/03/2010)

Description:

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of bevacizumab in combination with sorafenib tosylate in patients with locally advanced or metastatic hepatocellular carcinoma. (Phase I closed to accrual as of 11/03/2010)

• Determine time to progression in these patients. (Phase II)

Secondary

• Determine the safety of this regimen in these patients. (Phase I closed to accrual as of 11/03/2010)

• Assess tolerability of this regimen in these patients. (Phase I closed to accrual as of 11/03/2010)

• Determine overall survival of these patients. (Phase II)

• Determine tumor response (at 6 months) in patients treated with this regimen. (Phase II)

• Determine progression-free survival of these patients. (Phase II)

• Determine response rate in patients treated with this regimen. (Phase II)

• Assess the occurrence of adverse events in these patients. (Phase II)

Tertiary

• Determine the relationship between tumor biomarkers and circulating biomarkers of vascular response and clinical outcome in patients treated with this regimen.

OUTLINE: This is a phase I, dose escalation study followed by a randomized phase II study.

• Phase I (closed to accrual as of 11/03/2010): Patients receive oral sorafenib tosylate twice daily on days 1-28 and bevacizumab IV on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

• Phase II: Patients are stratified according to gender (female vs male), ECOG performance status (0 vs 1), and Child-Pugh class (A vs B7). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral sorafenib tosylate on days 1-28 twice daily and bevacizumab IV on days 1 and 15.

• Arm II: Patients receive oral sorafenib tosylate twice daily on days 1-28. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood samples are collected periodically for analysis of circulating endothelial cells and circulating endothelial progenitor cells and angiogenic proteins in plasma by ELISA.

After completion of study treatment, patients are followed for 3 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: May 2013
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed hepatocellular carcinoma

• Locally advanced or metastatic disease that is not amenable to treatment with surgery or to orthotopic liver transplant

• Child Pugh class A or B7 disease

• Measurable disease

• No mixed cholangiocarcinoma/hepatocellular carcinoma

• No current or previously resected brain metastases

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1

• Life expectancy = 3 months

• ANC = 1,200/mm³

• Platelet count = 75,000/mm³

• Hemoglobin = 9.0 g/dL

• Total bilirubin = 1.5 times upper limit of normal (ULN)

• AST = 5 times ULN

• Alkaline phosphatase = 5 times ULN

• Urine protein = 1+ by urine protein:creatinine ratio OR 24-hour urine protein < 1 g

• QTc interval = 500 msec on baseline EKG

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for = 2 weeks after sorafenib tosylate and 6 months after bevacizumab

• None of the following risk factors for decreased LVEF:

• Prior treatment with anthracyclines

• History of myocardial infarction within the past 12 months

• No uncontrolled hypertension (defined as systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 100 mm Hg) despite optimal medical management

• No New York Heart Association class III-IV congestive heart failure

• No cardiac ventricular arrhythmias requiring antiarrhythmic therapy

• No history of hypertensive crisis or hypertensive encephalopathy

• No cardiac ventricular arrhythmia requiring anti-arrhythmic therapy within the past 6 months

• None of the following within the past 6 months:

• Transient ischemic attack

• Cerebrovascular accident

• Unstable angina or angina

• Clinically significant peripheral artery disease (i.e., claudication in less than one block) or any other arterial thrombotic event

• Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess

• Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis

• No active or recent history of hemoptysis (= ½ teaspoon of bright red blood per episode) within the past 30 days

• No evidence of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation)

• No significant traumatic injury within the past 4 weeks

• No serious or non-healing wound, ulcer, or bone fracture

• No uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements

• No other active malignancy within the past 3 years, except nonmelanotic skin cancer or carcinoma in situ of the cervix

• No comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab or sorafenib tosylate

PRIOR CONCURRENT THERAPY:

• No prior systemic chemotherapy regimens for hepatocellular carcinoma

• No prior external beam radiation to the primary site

• No prior central thoracic radiation therapy (RT), including RT to the heart

• No prior radiation (if given for another malignancy) to = 25% of the bone marrow

• At least 6 weeks since prior chemoembolization, radioembolization, radiofrequency ablation, or other local ablative therapies

• More than 4 weeks since prior biologic, hormonal, or immune therapy

• More than 4 weeks since prior and no concurrent major surgical procedure or open biopsy

• More than 7 days since prior core biopsy or other minor surgical procedure (placement of a vascular access device allowed)

• No concurrent investigational agent which would be considered as a treatment for the primary neoplasm

• No concurrent anticoagulants, except low-dose warfarin or heparin for deep venous thrombosis prophylaxis

• No other concurrent treatment for prior malignancy (other than hormonal therapy)

Related Conditions & MeSH terms

• Liver Cancer
• Liver Neoplasms

Intervention

Biological:
• bevacizumab
Given IV

Drug:
• sorafenib tosylate
Given orally

Locations

Country	Name	City	State
United States	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan
United States	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan
United States	Aurora Presbyterian Hospital	Aurora	Colorado
United States	Battle Creek Health System Cancer Care Center	Battle Creek	Michigan
United States	MeritCare Bemidji	Bemidji	Minnesota
United States	Mecosta County Medical Center	Big Rapids	Michigan
United States	Billings Clinic - Downtown	Billings	Montana
United States	CCOP - Montana Cancer Consortium	Billings	Montana
United States	Hematology-Oncology Centers of the Northern Rockies - Billings	Billings	Montana
United States	St. Vincent Healthcare Cancer Care Services	Billings	Montana
United States	Bismarck Cancer Center	Bismarck	North Dakota
United States	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota
United States	Mid Dakota Clinic, PC	Bismarck	North Dakota
United States	St. Alexius Medical Center Cancer Center	Bismarck	North Dakota
United States	Illinois CancerCare - Bloomington	Bloomington	Illinois
United States	St. Joseph Medical Center	Bloomington	Illinois
United States	Boulder Community Hospital	Boulder	Colorado
United States	Bozeman Deaconess Cancer Center	Bozeman	Montana
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	St. James Healthcare Cancer Care	Butte	Montana
United States	Graham Hospital	Canton	Illinois
United States	Illinois CancerCare - Canton	Canton	Illinois
United States	Illinois CancerCare - Carthage	Carthage	Illinois
United States	Memorial Hospital	Carthage	Illinois
United States	Rocky Mountain Oncology	Casper	Wyoming
United States	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas
United States	Medical Oncology and Hematology Associates - West Des Moines	Clive	Iowa
United States	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado
United States	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota
United States	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania
United States	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan
United States	CCOP - Colorado Cancer Research Program	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - St. Luke's Medical Center	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	St. Anthony Central Hospital	Denver	Colorado
United States	St. Joseph Hospital	Denver	Colorado
United States	CCOP - Iowa Oncology Research Association	Des Moines	Iowa
United States	John Stoddard Cancer Center at Iowa Lutheran Hospital	Des Moines	Iowa
United States	John Stoddard Cancer Center at Iowa Methodist Medical Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates at John Stoddard Cancer Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates at Mercy Cancer Center	Des Moines	Iowa
United States	Mercy Cancer Center at Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas
United States	CCOP - Duluth	Duluth	Minnesota
United States	Duluth Clinic Cancer Center - Duluth	Duluth	Minnesota
United States	Miller - Dwan Medical Center	Duluth	Minnesota
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas
United States	Swedish Medical Center	Englewood	Colorado
United States	Green Bay Oncology, Limited - Escanaba	Escanaba	Michigan
United States	Eureka Community Hospital	Eureka	Illinois
United States	Illinois CancerCare - Eureka	Eureka	Illinois
United States	CCOP - MeritCare Hospital	Fargo	North Dakota
United States	MeritCare Broadway	Fargo	North Dakota
United States	Fergus Falls Medical Group, PA	Fergus Falls	Minnesota
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas
United States	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota
United States	Galesburg Clinic, PC	Galesburg	Illinois
United States	Illinois CancerCare - Galesburg	Galesburg	Illinois
United States	St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center	Grand Junction	Colorado
United States	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan
United States	CCOP - Grand Rapids	Grand Rapids	Michigan
United States	Lacks Cancer Center at Saint Mary's Health Care	Grand Rapids	Michigan
United States	Great Falls Clinic - Main Facility	Great Falls	Montana
United States	Sletten Cancer Institute at Benefis Healthcare	Great Falls	Montana
United States	North Colorado Medical Center	Greeley	Colorado
United States	Green Bay Oncology, Limited at St. Mary's Hospital	Green Bay	Wisconsin
United States	Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	St. Mary's Hospital Medical Center - Green Bay	Green Bay	Wisconsin
United States	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center	Hartford	Connecticut
United States	Illinois CancerCare - Havana	Havana	Illinois
United States	Mason District Hospital	Havana	Illinois
United States	Northern Montana Hospital	Havre	Montana
United States	Geisinger Hazleton Cancer Center	Hazleton	Pennsylvania
United States	St. Peter's Hospital	Helena	Montana
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Cancer Center of Kansas-Independence	Independence	Kansas
United States	Dickinson County Healthcare System	Iron Mountain	Michigan
United States	Foote Memorial Hospital	Jackson	Michigan
United States	Goldschmidt Cancer Center	Jefferson City	Missouri
United States	Glacier Oncology, PLLC	Kalispell	Montana
United States	Kalispell Medical Oncology at KRMC	Kalispell	Montana
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Illinois CancerCare - Kewanee Clinic	Kewanee	Illinois
United States	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas
United States	Sparrow Regional Cancer Center	Lansing	Michigan
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Cancer Center of Kansas, PA - Liberal	Liberal	Kansas
United States	St. Mary Mercy Hospital	Livonia	Michigan
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado
United States	McKee Medical Center	Loveland	Colorado
United States	Illinois CancerCare - Macomb	Macomb	Illinois
United States	McDonough District Hospital	Macomb	Illinois
United States	Holy Family Memorial Medical Center Cancer Care Center	Manitowoc	Wisconsin
United States	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota
United States	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota
United States	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin
United States	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota
United States	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota
United States	Montana Cancer Center at St. Patrick Hospital and Health Sciences Center	Missoula	Montana
United States	Montana Cancer Specialists at Montana Cancer Center	Missoula	Montana
United States	Trinity Cancer Center at Trinity Medical Center - 7th Street Campus	Moline	Illinois
United States	Illinois CancerCare - Monmouth	Monmouth	Illinois
United States	OSF Holy Family Medical Center	Monmouth	Illinois
United States	Mercy General Health Partners	Muskegon	Michigan
United States	Cancer Center of Kansas, PA - Newton	Newton	Kansas
United States	BroMenn Regional Medical Center	Normal	Illinois
United States	Community Cancer Center	Normal	Illinois
United States	Illinois CancerCare - Community Cancer Center	Normal	Illinois
United States	Green Bay Oncology, Limited - Oconto Falls	Oconto Falls	Wisconsin
United States	Community Hospital of Ottawa	Ottawa	Illinois
United States	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois
United States	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas
United States	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois
United States	Illinois CancerCare - Pekin	Pekin	Illinois
United States	CCOP - Illinois Oncology Research Association	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois
United States	OSF St. Francis Medical Center	Peoria	Illinois
United States	Proctor Hospital	Peoria	Illinois
United States	Illinois CancerCare - Peru	Peru	Illinois
United States	Illinois Valley Community Hospital	Peru	Illinois
United States	St. Joseph Mercy Oakland	Pontiac	Michigan
United States	Mercy Regional Cancer Center at Mercy Hospital	Port Huron	Michigan
United States	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas
United States	Illinois CancerCare - Princeton	Princeton	Illinois
United States	Perry Memorial Hospital	Princeton	Illinois
United States	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Seton Cancer Institute at Saint Mary's - Saginaw	Saginaw	Michigan
United States	Comprehensive Cancer Care, PC	Saint Louis	Missouri
United States	Missouri Baptist Cancer Center	Saint Louis	Missouri
United States	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota
United States	Park Nicollet Cancer Center	Saint Louis Park	Minnesota
United States	Regions Hospital Cancer Care Center	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Cancer Center of Kansas, PA - Salina	Salina	Kansas
United States	Mayo Clinic Scottsdale	Scottsdale	Arizona
United States	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota
United States	St. Nicholas Hospital	Sheboygan	Wisconsin
United States	Welch Cancer Center at Sheridan Memorial Hospital	Sheridan	Wyoming
United States	Mercy Medical Center - Sioux City	Sioux City	Iowa
United States	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa
United States	St. Luke's Regional Medical Center	Sioux City	Iowa
United States	Medical X-Ray Center, PC	Sioux Falls	South Dakota
United States	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota
United States	Illinois CancerCare - Spring Valley	Spring Valley	Illinois
United States	Geisinger Medical Group - Scenery Park	State College	Pennsylvania
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Green Bay Oncology, Limited - Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	North Suburban Medical Center	Thornton	Colorado
United States	Munson Medical Center	Traverse City	Michigan
United States	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	St. John Macomb Hospital	Warren	Michigan
United States	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas
United States	Exempla Lutheran Medical Center	Wheat Ridge	Colorado
United States	Associates in Womens Health, PA - North Review	Wichita	Kansas
United States	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas
United States	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas
United States	CCOP - Wichita	Wichita	Kansas
United States	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas
United States	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania
United States	Willmar Cancer Center at Rice Memorial Hospital	Willmar	Minnesota
United States	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas
United States	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota
United States	Metro Health Hospital	Wyoming	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (Phase I)	MTD is defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients). If dose level (-1) is not tolerable, but dose (-3) or (-2) is below or at MTD, testing of alternate dose levels (-2a, -3a, -3b) will occur as outlined in the table. The number of dose limiting toxicities will be reported here.	From baseline up to 3 years post treatment
Primary	Time to Progression (TTP) (Phase II)	Time to progression is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Kaplan-Meier survival curves will be used to estimate the distribution of TTP.	From baseline up to 3 years post treatment
Secondary	Overall Survival	Overall survival (OS) is defined as the length of time from date of registration to a) date of death due to any cause or b) last follow-up. Kaplan-Meier survival curves will be used to estimate the distribution of OS.	Up to 3 years post treatment
Secondary	Tumor Response at 6 Months	Tumor response (at 6 months) is defined as the number of responses (complete or partial response per Section 11) over the number of eligible patients observed for at least 6 months. Tumor response will be evaluated using simple estimates of proportions.	6 months