Carboplatin and Paclitaxel With or Without Sorafenib Tosylate in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery

Recurrent Melanoma Clinical Trial

Official title:

A Double-Blind, Randomized, Placebo-Controlled Phase III Trial of Carboplatin, Paclitaxel and Sorafenib Versus Carboplatin, Paclitaxel and Placebo in Patients With Unresectable Locally Advanced or Stage IV Melanoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00110019
• Other study ID #: NCI-2012-02978
• Secondary ID: NCI-2012-02978E2
• Status: Completed
• Phase: Phase 3
• First received: May 3, 2005
• Last updated: September 28, 2015
• Start date: June 2005
• Est. completion date: August 2012

Study information

• Verified date: July 2015
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial studies carboplatin, paclitaxel, and sorafenib tosylate to see how well they work compared to carboplatin and paclitaxel in treating patients with stage III or stage IV melanoma that cannot be removed by surgery. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether giving carboplatin and paclitaxel together with sorafenib tosylate is more effective than carboplatin and paclitaxel in treating melanoma.

Description:

PRIMARY OBJECTIVES:

I. To compare the overall survival of patients with unresectable stage III or stage IV melanoma treated with carboplatin, paclitaxel and placebo versus carboplatin, paclitaxel and sorafenib (sorafenib tosylate).

II. To compare progression-free survival, response rate, and safety of patients with unresectable stage III or stage IV melanoma treated with carboplatin, paclitaxel and placebo versus carboplatin, paclitaxel and sorafenib.

III. To analyze the pharmacokinetic and pharmacogenetic properties of sorafenib including angiogenesis, monooxygenases polymorphisms and multidrug resistance (MDR).

IV. To assess the association of expression markers in the patient tumor with clinical outcome.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30 minutes on day 1. Patients also receive sorafenib tosylate orally (PO) twice daily (BID) (approximately every 12 hours) on days 2-19.

Arm II: Patients receive paclitaxel and carboplatin as in Arm I. Patients also receive placebo PO BID (approximately every 12 hours) on days 2-19.

In both arms, treatment repeats every 21 days for 10 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease or who achieve a partial response or complete response may continue to receive sorafenib tosylate or placebo alone BID (approximately every 12 hours) on days 1-21. Courses with sorafenib tosylate or placebo repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 823
• Est. completion date: August 2012
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histological or cytological confirmed melanoma that is metastatic or unresectable; patients must have a history of cutaneous, mucosal or unknown primary site

• Patients who have received prior systemic cytotoxic chemotherapy for treatment of melanoma are ineligible; the following groups are eligible with regard to prior systemic therapy either in the adjuvant or metastatic disease setting:

• No prior therapy

• Immunotherapy consisting of interferon, interleukin-2, granulocyte macrophage colony-stimulating factor (GM-CSF) or vaccine

• One prior investigational therapy (cannot be chemotherapy or an inhibitor of rat sarcoma [Ras], serine/threonine kinase [Raf], or mitogen-activated protein kinase kinase [MEK])

• NOTE: Chemotherapy given via isolated limb perfusion is allowed

• Prior radiation therapy is allowed; however, if radiation has been administered to a lesion, there must be radiographic evidence of progression of that lesion in order for that lesion to constitute measurable disease or to be included in the measured target lesions

• All sites of disease must be evaluated within 4 weeks of registration; patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• White blood count >= 3,000/mm^3

• Absolute granulocyte count >= 1,500/mm^3

• Platelet count >= 100,000/mm^3

• Serum creatinine =< 2.0 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40 ml/min (neither drug is cleared by the kidney)

• Total bilirubin =< 1.5 x ULN (< 3.0 x ULN in the presence of Gilbert's disease)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5.0 ULN in the presence of liver metastases)

• International normalized ratio (INR) =< 1.5 and a partial thromboplastin time (PTT) within normal limits (patients who are on therapeutic anticoagulation with warfarin should have documentation of a normal prothrombin time [PT]/PTT prior to initiating that therapy)

• Patients must not have ocular melanoma

• Patients must have discontinued immunotherapy or radiation therapy at least 4 weeks prior to initiation of treatment and recovered from adverse events due to those agents

• Patients must not receive any other investigational agents during the period on study or the four weeks prior to initiation of treatment

• Patients must not have a history or clinical evidence of brain metastasis; patients must be evaluated with a head magnetic resonance imaging (MRI) within 4 weeks prior to enrollment

• Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for >= 5 years prior to the time of randomization

• Patients must not have any evidence of bleeding diathesis

• Patients must not have a serious intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, clinically significant cardiovascular disease (e.g. uncontrolled hypertension, myocardial infarction, unstable angina), New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or grade II or greater peripheral vascular disease within 1 year prior to study entry, or psychiatric illness/social situations that would limit compliance with study requirements

• Patients must not be taking cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or phenobarbital), rifampin or St. John's Wort

• Women must not be pregnant or breast-feeding

• All females of childbearing potential must have a blood test or urine study within 4 weeks prior to registration to rule out pregnancy

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant while participating in this study, she should inform her treating physician immediately; if a man impregnates a woman while participating in this study, he should inform his treating physician immediately as well

• Human immunodeficiency virus (HIV)-positive patients are excluded from the study

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma
• Mucosal Melanoma
• Recurrent Melanoma
• Stage IIIA Skin Melanoma
• Stage IIIB Skin Melanoma
• Stage IIIC Skin Melanoma
• Stage IV Skin Melanoma

Intervention

Drug:
• Carboplatin
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Paclitaxel
Given IV

Other:
• Pharmacological Study
Correlative studies
• Placebo
Given PO

Drug:
• Sorafenib Tosylate
Given PO

Locations

Country	Name	City	State
Australia	Sydney West Area Health Service-Westmead Hospital	Westmead	New South Wales
United States	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio
United States	Phoebe Putney Memorial Hospital	Albany	Georgia
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Fox Valley Hematology and Oncology	Appleton	Wisconsin
United States	Atlanta Regional CCOP	Atlanta	Georgia
United States	Piedmont Hospital	Atlanta	Georgia
United States	The Medical Center of Aurora	Aurora	Colorado
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Frontier Cancer Center and Blood Institute-Billings	Billings	Montana
United States	Montana Cancer Consortium NCORP	Billings	Montana
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Mid Dakota Clinic	Bismarck	North Dakota
United States	IU Health Bloomington	Bloomington	Indiana
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Boulder Community Hospital	Boulder	Colorado
United States	Montefiore Medical Center-Wakefield Campus	Bronx	New York
United States	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California
United States	University of Vermont College of Medicine	Burlington	Vermont
United States	Aultman Health Foundation	Canton	Ohio
United States	Mercy Medical Center	Canton	Ohio
United States	Cedar Rapids Oncology Association	Cedar Rapids	Iowa
United States	Physicians' Clinic of Iowa PC	Cedar Rapids	Iowa
United States	Cancer Center of Kansas - Chanute	Chanute	Kansas
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston	Charleston	West Virginia
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Martha Jefferson Hospital	Charlottesville	Virginia
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Erlanger Medical Center	Chattanooga	Tennessee
United States	Swedish Covenant Hospital	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	The Christ Hospital	Cincinnati	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Columbus CCOP	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Heartland Oncology and Hematology LLP	Council Bluffs	Iowa
United States	Danville Regional Medical Center	Danville	Virginia
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Genesis Medical Center - East Campus	Davenport	Iowa
United States	Oakwood Hospital and Medical Center	Dearborn	Michigan
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Dekalb Medical Center	Decatur	Georgia
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Exempla Saint Joseph Hospital	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Delaware County Memorial Hospital	Drexel Hill	Pennsylvania
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Oncology Hematology Associates of Northern Pennsylvania	Dubois	Pennsylvania
United States	Duke University Medical Center	Durham	North Carolina
United States	Veterans Adminstration New Jersey Health Care System	East Orange	New Jersey
United States	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York
United States	Advocate Sherman Hospital	Elgin	Illinois
United States	Aurora Cancer Care-Southern Lakes	Elkhorn	Wisconsin
United States	Swedish Medical Center	Englewood	Colorado
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Sanford Medical Center-Fargo	Fargo	North Dakota
United States	Hurley Medical Center	Flint	Michigan
United States	McLeod Regional Medical Center	Florence	South Carolina
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Holy Cross Hospital	Fort Lauderdale	Florida
United States	Southwest Florida Regional Medical Center	Fort Meyers	Florida
United States	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana
United States	Frederick Memorial Hospital	Frederick	Maryland
United States	Unity Hospital	Fridley	Minnesota
United States	Mercy Hospital Fort Smith	Ft. Smith	Arkansas
United States	Northeast Georgia Medical Center	Gainesville	Georgia
United States	University of Florida	Gainesville	Florida
United States	Glens Falls Hospital	Glens Falls	New York
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Altru Cancer Center	Grand Forks	North Dakota
United States	Grand Rapids Clinical Oncology Program	Grand Rapids	Michigan
United States	Marin Cancer Care Inc	Greenbrae	California
United States	East Carolina University	Greenville	North Carolina
United States	Hackensack University Medical CCOP	Hackensack	New Jersey
United States	Virginia Oncology Associates-Hampton	Hampton	Virginia
United States	PinnacleHealth Cancer Center-Community Campus	Harrisburg	Pennsylvania
United States	Hartford Hospital	Hartford	Connecticut
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Hinsdale Hematology Oncology Associates Incorporated	Hinsdale	Illinois
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Edwards Comprehensive Cancer Center	Huntington	West Virginia
United States	Saint Mary's Medical Center	Huntington	West Virginia
United States	Cleveland Clinic Cancer Center Independence	Independence	Ohio
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Baptist Cancer Institute	Jacksonville	Florida
United States	Freeman Health System	Joplin	Missouri
United States	Jupiter Medical Center	Jupiter	Florida
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	East Tennessee Baptist Hospital-Mercy Health Partners	Knoxville	Tennessee
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Lakeland Regional Cancer Center	Lakeland	Florida
United States	Saint Mary Medical and Regional Cancer Center	Langhorne	Pennsylvania
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Beebe Medical Center	Lewes	Delaware
United States	Central Maine Medical Center	Lewiston	Maine
United States	Saint Rita's Medical Center	Lima	Ohio
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Longmont United Hospital	Longmont	Colorado
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Medical Center of Central Georgia	Macon	Georgia
United States	Dean Hematology and Oncology Clinic	Madison	Wisconsin
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Holy Family Memorial Hospital	Manitowoc	Wisconsin
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana
United States	Trinity Medical Center	Moline	Illinois
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	Laura and Issac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Licking Memorial Hospital	Newark	Ohio
United States	Bay Area Tumor Institute	Oakland	California
United States	Cancer Care Associates	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Saint Joseph Hospital - Orange	Orange	California
United States	Florida Hospital Orlando	Orlando	Florida
United States	Stanford Cancer Institute	Palo Alto	California
United States	Singing River Hospital	Pascagoula	Mississippi
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	Kaiser Permanente	Portland	Oregon
United States	Western Oncology Research Consortium	Portland	Oregon
United States	Pottstown Memorial Medical Center	Pottstown	Pennsylvania
United States	MidHudson Regional Hospital of Westchester Medical Center	Poughkeepsie	New York
United States	Kansas City CCOP	Prairie Village	Kansas
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Kaiser Permanente-Redwood City	Redwood City	California
United States	Kaiser Permanente-Richmond	Richmond	California
United States	Southern Regional Medical Center	Riverdale	Georgia
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Interlakes Foundation Inc-Rochester	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	Kaiser Permanente-Roseville	Roseville	California
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Kaiser Permanente - Sacramento	Sacramento	California
United States	Oncology Care Associates PLLC	Saint Joseph	Michigan
United States	Center for Cancer Care and Research	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Saint Louis-Cape Girardeau CCOP	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Salina Regional Health Center	Salina	Kansas
United States	Kaiser Permanente-San Diego Mission	San Diego	California
United States	Veterans Administration-San Diego Medical Center	San Diego	California
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	Kaiser Permanente-San Francisco	San Francisco	California
United States	Kaiser Permanente-Santa Teresa-San Jose	San Jose	California
United States	Santa Rosa Memorial Hospital	Sana Rosa	California
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Kaiser Permanente-Santa Rosa	Santa Rosa	California
United States	Hematology and Oncology Associates of North East Pennsylvania	Scranton	Pennsylvania
United States	Scranton Hematology Oncology	Scranton	Pennsylvania
United States	Group Health Cooperative-Seattle	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Sanford Cancer Center-Oncology Clinic	Sioux Falls	South Dakota
United States	Memorial Hospital of South Bend	South Bend	Indiana
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Geisinger Medical Group	State College	Pennsylvania
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Moffitt Cancer Center	Tampa	Florida
United States	North Suburban Medical Center	Thornton	Colorado
United States	Munson Medical Center	Traverse City	Michigan
United States	Carle Cancer Center	Urbana	Illinois
United States	Carle Clinic-Urbana Main	Urbana	Illinois
United States	South Georgia Medical Center	Valdosta	Georgia
United States	Kaiser Permanente-Vallejo	Vallejo	California
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Kent County Hospital	Warwick	Rhode Island
United States	Cedar Valley Medical Specialists	Waterloo	Iowa
United States	Cancer Center of Kansas - Wellington	Wellington	Kansas
United States	Chester County Hospital	West Chester	Pennsylvania
United States	Jennersville Regional Hospital	West Grove	Pennsylvania
United States	Cancer Center of Kansas - Main Office	Wichita	Kansas
United States	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas
United States	Minnesota Oncology and Hematology PA-Woodbury	Woodbury	Minnesota
United States	Cleveland Clinic Wooster Specialty Center	Wooster	Ohio
United States	Commonwealth Hematology Oncology PC-Worcester	Worcester	Massachusetts
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	WellSpan Health-York Hospital	York	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Overall survival is defined as time from study entry to death from any cause. The comparison of overall survival was conducted in intention-to-treat population.	Survival was assessed every 3 months if patient is < 2 years from study entry. Every 6 months is patient is 2-5 years from study entry.	No
Secondary	Progression-free Survival	Progression-free survival was defined as time from study entry to disease progression or death from any cause, whichever occurred first. Patients without disease progression were censored at last date of assessment. Disease progression was assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0.	Tumor response was assessed after every 2 cycles during cycle 1 through 10, and every 3 cycles after cycle 10. Survival was assessed every 3 months if patient is < 2 years from study entry, and every 6 months if 2-5 years from study entry.	No
Secondary	Objective Response (Complete and Partial Response) Rate	Tumor response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. Objective response =complete response (CR) + partial response (PR). Complete response is defined as disappearance of all target lesions. Partial response is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum of longest diameters.	Tumor response was assessed after every 2 cycles during cycle 1 through 10. After cycle 10, tumor response was assessed after every 3 cycles.	No