GW786034 In Subjects With Locally Recurrent Or Metastatic Clear Cell Renal Cell Carcinoma

Study Description

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Brief Summary:

Phase II, multi-center, two-stage study utilising a randomised discontinuation design to evaluate the safety and efficacy of GW786034 (pazopanib) in adult subjects with locally recurrent or metastatic clear-cell Renal Cell Carcinoma (RCC). After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Renal Cell	Drug: GW786034; Drug: Placebo	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	225 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase II Study of GW786034 Using a Randomised Discontinuation Design in Subjects With Locally Recurrent or Metastatic Clear-Cell Renal Cell Carcinoma
Study Start Date :	October 2005
Actual Primary Completion Date :	March 2008
Actual Study Completion Date :	September 2013

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Pazopanib; All patients receive GW786034. At week 12, some subjects will be randomized based on response (SD) and the others will remain on drug. After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib.	Drug: GW786034; All patients receive GW786034. At week 12, some subjects will be randomized based on response (SD) and the others will remain on drug. After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib.
Placebo Comparator: Placebo; All patients receive GW786034. At week 12, some subjects will be randomized based on response (SD) and the others will remain on drug. After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib.	Drug: Placebo; All patients receive GW786034. At week 12, some subjects will be randomized based on response (SD) and the others will remain on drug. After the interim analysis, the design was changed to an open label, single arm study with all subjects receiving pazopanib.

Outcome Measures

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Primary Outcome Measures :

1. Overall Response by RECIST Criteria [ Time Frame: Baseline to Response (up to 2.40 years). Assessments occurred at Week 12 and every 8 weeks thereafter. ]
   The overall response is the number of participants who experience a confirmed complete (CR) or partial response (PR) of the total analysis population. Per the Response Evaluation Criteria In Solid Tumors (RECIST): CR = all detectable tumor has disappeared, PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum, Progressive disease (PD) = a >=20% increase in target lesions, Stable Disease = small changes that do not meet previously given criteria.
2. Stable Disease at 12 Weeks - Interim Analysis of First 60 Participants [ Time Frame: Week 12 ]
   The protocol called for an interim analysis of the first 60 participants to determine their status at Week 12, and to determine the number of participants with stable disease, although all categories were reported. Stable disease is defined as a disease that has not grown enough to be called progressive disease and has not shrunk enough to be called partial/complete response.

Secondary Outcome Measures :

1. Duration of Response [ Time Frame: First response until progression of disease (up to 2.40 years). Assessments occurred at Week 12 and every 8 weeks thereafter. ]
   Using RECIST criteria: date of first confirmed tumor response (CR or PR) to date of tumor progression or to death. Participants who did not progress or die were censored at their last radiologic assessment. Only participants who had a response were analyzed.
2. Progression-free Survival [ Time Frame: From the first day of treatment to the earliest date of disease progression or death due to any cause (up to 2.40 years) ]
   Progression-free Survival is defined as the interval between the first day of treatment and the earliest date of disease progression or death due to any cause, whichever occurred first. Progressive disease is defined as a >=20% increase in target lesions.

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:

• Histologically or cytologically confirmed diagnosis of Renal Cell Carcinoma of predominantly clear-cell histology (excluding chromophobe, papillary, collecting duct, and undifferentiated tumors) which is metastatic or locally recurrent
• Either no prior systemic therapy or failed only 1 prior cytokine-based or bevacizumab-based therapy
• Evidence of documented measurable disease by RECIST criteria
• Male or female at least 21 years of age

A woman is eligible to enter and participate in the study if she is of:

1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who:

   • Has had a hysterectomy,
   • Has had a bilateral oophorectomy (ovariectomy),
   • Has had a bilateral tubal ligation,
   • Is post-menopausal (total cessation of menses for >= 1 year).

2. Childbearing potential, has a negative serum pregnancy test at Screening Period and serum or urine pregnancy test at Day1, and agrees to use adequate contraception. GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:

   • An intrauterine device (IUD) with a documented failure rate of less than 1% per year.
   • Vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female.
   • Complete abstinence from sexual intercourse for 14 days before exposure to investigation product, through the clinical trial, and for at least 21 days after the last dose of investigational product.
   • Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

A man with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception (e.g. condom) or abstinence during the study and for 28 days following the last dose of investigational drug.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
• Adequate bone marrow function.
• Adequate hepatic function.
• Adequate renal function.
• Adequate PT/PTT or INR/aPTT.
• Able to swallow and retain oral medications.
• Written informed consent.

Exclusion criteria:

• Received prior non-cytokine or non-bevacizumab therapies .
• Received chemotherapy for renal cell carcinoma.
• Have had any major surgery, radiotherapy, or immunotherapy within the last 28 days and/or not recovered from prior therapy.
• History of hypercalcemia within two months of start of therapy.
• Patients who are pregnant or lactating.
• Poorly controlled hypertension.
• QTc prolongation defined as a QTc interval ≥ 480 msecs or other significant ECG abnormalities.
• Has Class II, III or IV heart failure as defined by the New York Heart Association functional classification system. A subject who has a history of Class II heart failure and is asymptomatic on treatment may be considered eligible.
• Any history of cerebrovascular accident [CVA].
• History of myocardial infarction, admission for unstable angina, cardiac angioplasty or stenting within the last 12 weeks.
• History of venous thrombosis in last 12 weeks.
• Current use of therapeutic warfarin.
• Use of antiplatelet agents other than aspirin (≤ 325 mg/day).
• Leptomeningeal or brain metastases.
• Prior history of malignancies other than renal cell carcinoma (except for basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or the subject has been free of any other malignancies for > 5 years).
• Any serious and/or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with subject safety or obtaining informed consent.
• History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism or excretion of study drugs. Has any unresolved bowel obstruction or diarrhea.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
• Is on any specifically prohibited medication or requires any of these medications during treatment with GW786034.

Contacts and Locations

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Locations

United States, California
GSK Investigational Site
Duarte, California, United States, 91010-3000
GSK Investigational Site
Los Angeles, California, United States, 90095
GSK Investigational Site
Orange, California, United States, 92868
GSK Investigational Site
San Francisco, California, United States, 94115
United States, Colorado
GSK Investigational Site
Aurora, Colorado, United States, 80010
United States, Georgia
GSK Investigational Site
Tucker, Georgia, United States, 30084
United States, Indiana
GSK Investigational Site
Indianapolis, Indiana, United States, 46202
United States, New York
GSK Investigational Site
New York, New York, United States, 10032-3713
United States, Ohio
GSK Investigational Site
Cleveland, Ohio, United States, 44106
GSK Investigational Site
Cleveland, Ohio, United States, 44195
United States, Tennessee
GSK Investigational Site
Nashville, Tennessee, United States, 37203
United States, Texas
GSK Investigational Site
Dallas, Texas, United States, 75246
Australia, New South Wales
GSK Investigational Site
Camperdown, New South Wales, Australia, 2050
GSK Investigational Site
Kogarah, New South Wales, Australia, 2217
GSK Investigational Site
Randwick, New South Wales, Australia, 2031
Australia, Victoria
GSK Investigational Site
East Melbourne, Victoria, Australia, 3002
GSK Investigational Site
Footscay, Victoria, Australia, 3011
GSK Investigational Site
Heidelberg, Victoria, Australia, 3084
GSK Investigational Site
Parkville, Victoria, Australia, 3050
Belgium
GSK Investigational Site
Bruxelles, Belgium, 1070
GSK Investigational Site
Bruxelles, Belgium, 1200
GSK Investigational Site
Gent, Belgium, 9000
GSK Investigational Site
Jette, Belgium, 1090
GSK Investigational Site
Liège, Belgium, 4000
GSK Investigational Site
Roeselare, Belgium, 8800
GSK Investigational Site
Wilrijk, Belgium, 2610
China, Guangdong
GSK Investigational Site
Guangzhou, Guangdong, China, 510060
China, Jiangsu
GSK Investigational Site
Nanjing, Jiangsu, China, 210029
China, Shandong
GSK Investigational Site
Jinan, Shandong, China, 250012
China, Zhejiang
GSK Investigational Site
Hangzhou, Zhejiang, China, 310003
China
GSK Investigational Site
Beijing, China, 100034
GSK Investigational Site
Beijing, China, 100853
GSK Investigational Site
Shanghai, China, 200040
Czech Republic
GSK Investigational Site
Brno, Czech Republic, 656 53
GSK Investigational Site
Hradec Kralove, Czech Republic, 500 05
GSK Investigational Site
Praha 2, Czech Republic, 12808
Hong Kong
GSK Investigational Site
Hong Kong, Hong Kong
GSK Investigational Site
Kowloon, Hong Kong
GSK Investigational Site
Tuen Mun, Hong Kong
Israel
GSK Investigational Site
Haifa, Israel, 31096
GSK Investigational Site
Petach Tikva, Israel, 49100
GSK Investigational Site
Tel Aviv, Israel, 64239
GSK Investigational Site
Zrifin, Israel, 70300
Taiwan
GSK Investigational Site
Taipei, Taiwan, 100
GSK Investigational Site
Taipei, Taiwan

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director:	GSK Clinical Trials	GlaxoSmithKline

More Information

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

Publications:

Bonate PL, Suttle AB. Modeling tumor growth kinetics after treatment with pazopanib or placebo in patients with renal cell carcinoma. Cancer Chemother Pharmacol. 2013 Jul;72(1):231-40. doi: 10.1007/s00280-013-2191-0. Epub 2013 May 29.

Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. doi: 10.1200/JCO.2008.21.6994. Epub 2009 Dec 14.

Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, Figlin RA, Hutson TE, Sternberg CN, Amado RG, Pandite LN, Heymach JV. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012 Aug;13(8):827-37. doi: 10.1016/S1470-2045(12)70241-3. Epub 2012 Jul 2.

White AJ, LaGerche A, Toner GC, Whitbourn RJ. Apical ballooning syndrome during treatment with a vascular endothelial growth factor receptor antagonist. Int J Cardiol. 2009 Jan 24;131(3):e92-4. Epub 2007 Oct 24.

Xu CF, Reck BH, Goodman VL, Xue Z, Huang L, Barnes MR, Koshy B, Spraggs CF, Mooser VE, Cardon LR, Pandite LN. Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma. J Hepatol. 2011 Jun;54(6):1237-43. doi: 10.1016/j.jhep.2010.09.028. Epub 2011 Feb 12.

Xu CF, Reck BH, Xue Z, Huang L, Baker KL, Chen M, Chen EP, Ellens HE, Mooser VE, Cardon LR, Spraggs CF, Pandite L. Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism. Br J Cancer. 2010 Apr 27;102(9):1371-7. doi: 10.1038/sj.bjc.6605653. Epub 2010 Apr 13.

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

Goldstein D, Rosenberg JE, Figlin RA, Townsend RR, McCann L, Carpenter C, Pandite L. Is change in blood pressure a biomarker of pazopanib and sunitinib efficacy in advanced/metastatic renal cell carcinoma? Eur J Cancer. 2016 Jan;53:96-104. doi: 10.1016/j.ejca.2015.10.006. Epub 2015 Dec 15.

Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT00244764 History of Changes
Other Study ID Numbers:	VEG102616
First Posted:	October 27, 2005
Results First Posted:	January 25, 2011
Last Update Posted:	March 27, 2017
Last Verified:	September 2015

Keywords provided by GlaxoSmithKline:

Angiogenesis; Renal Cell Carcinoma; Solid tumors; Pazopanib(GW786034)

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma	Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases