Pazopanib Hydrochloride Before Surgery in Treating Patients With Kidney Cancer

• Sponsor: Case Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01158521
• Collaborator: (none)
• Enrollment: 25
• Locations: 2
• Arm: 1
• Duration (Months): 67
• Patients Per Site: 12.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pazopanib hydrochloride before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This phase II trial is studying how well pazopanib hydrochloride works when given before surgery in treating patients with kidney cancer.

Condition or Disease	Intervention/Treatment	Phase
Clear Cell Renal Cell Carcinoma; Stage I Renal Cell Cancer; Stage II Renal Cell Cancer; Stage III Renal Cell Cancer	Drug: pazopanib hydrochloride; Procedure: therapeutic conventional surgery	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the rate of partial nephrectomy in patients with primary renal tumors otherwise requiring radical nephrectomy after neoadjuvant pazopanib treatment.

SECONDARY OBJECTIVES:

1. To determine the safety, tumor diameter/volume change, conversion of hilar to non-hilar tumors and surgical morbidity of neoadjuvant pazopanib for renal cell carcinoma (RCC).

OUTLINE:

Patients receive oral pazopanib hydrochloride once daily for up to 18 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.

After completion of study treatment, patients are followed up for 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Pazopanib to Enable Partial Nephrectomy
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive oral pazopanib hydrochloride once daily for up to 18 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.	Drug: pazopanib hydrochloride; Oral pazopanib hydrochloride once daily for up to 18 weeks in the absence of disease progression or unacceptable toxicity.; Other Names: GW786034 Votrient ; Procedure: therapeutic conventional surgery; Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Could Undergo Partial Nephrectomy After Pazopanib Therapy [Partial nephrectomy performed after 8 to 16-weeks of pazopanib prescription. The median interval from treatment start to surgery was 10.6 weeks.]

   The primary end point was the percentage of patients who could undergo partial nephrectomy after pazopanib therapy. A reduction in tumor size, with pazopanib treatment, may permit the use of a partial nephrectomy, as opposed to a radical nephrectomy. This would help preserve additional vascularized parenchyma.

Secondary Outcome Measures

1. Residual Vascularized Parenchyma After Pazopanib Therapy and Subsequent Surgery Relative to Pre-therapy Assessment. [After 8 to 16-weeks of pazopanib therapy and 7 day washout prior to surgery.]

   Measurement of total parenchymal tissue that could be saved with pazopanib therapy and subsequent surgery, which was performed via a volumetric analysis of CT images.

2. Change in Tumor Diameter [At the conclusion of 8 to 16-week treatment with pazopanib therapy.]

   Median (cm) tumor size reduction after pazopanib treatment, relative to baseline (i.e., before treatment).

3. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for Target Lesions: Complete Response, Partial Response, Overall Response (OR)=CR+PR [At the end of 8 to 16-weeks of treatment]

   Efficacy of pazopanib was evaluated via the Response Evaluation Criteria in Solid Tumors, version 1.1. Assessed by MRI. Definitions of response include Complete Response (CR), Disappearance of target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR)=CR+PR

4. Surgical Morbidity [post-surgery]

   Conversion of tumor post therapy so that there is < 10% risk that a partial nephrectomy would be associated with a high risk of significant postoperative morbidity (e.g. conversion of tumor post therapy to ≥ 3 mm away from renal hilum (main renal artery, renal vein, or primary branches)

5. Reduction in Tumor Volume After Treatment [After 8 to 16-weeks of pazopanib treatment]

   Median (cm^3) tumor size reduction after pazopanib treatment, relative to baseline (i.e., before treatment).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion

• Histologically or cytologically proven renal carcinoma with a clear cell component

• Need for optimized partial nephrectomy based on one or more of the following criteria (all applicable criteria should be recorded and one criterion designated as the primary reason):

• Functional or anatomic solitary kidney, bilateral tumors, or pre-existing chronic kidney disease (CKD; estimated glomerular filtration rate (GFR) by Cockcroft-Gault formula < 60 mL/min) and tumor amenable to partial nephrectomy, but partial nephrectomy would result in estimated GFR < 30 mL/min; this estimation will be based on current estimated GFR, nuclear renal scan to estimate relative renal function (if 2 kidneys), tumor location(s), and amount of normal renal parenchyma that would need to be removed with nephrectomy

• Radical nephrectomy is required for tumor excision; however, it would result in estimated GFR < 30 mL/min; this estimation will be based on current estimated GFR, nuclear renal scan to estimate relative renal function (if 2 kidneys), tumor location(s), and amount of normal renal parenchyma that would need to be removed with radical nephrectomy

• Greater than 30% likelihood that a partial nephrectomy would be associated with a high risk of significant morbidity (e.g. hemorrhage) due to proximity to the renal hilum (within 3 mm of main renal artery, renal vein or their primary branches) and/or other anatomic factors as determined by the operating surgeon

• Renal nephrometry score of 10-12

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

• Karnofsky >= 70%

• Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x laboratory upper limit of normal (ULN)

• Serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x laboratory upper limit of normal (ULN)

• Total serum bilirubin =< 1.5 x ULN

• Absolute neutrophil count (ANC) >= 1500/uL

• Platelets >= 100,000/uL

• Hemoglobin >= 9.0 g/dL (no transfusion permitted within 1 week)

• Serum creatinine =< 2.5 mg/dL

• Urine to protein to creatinine (UPC) ratio < 1; if UPC > 1, then a 24-hour urine protein must be assessed; subjects must have a 24-hour urine protein value < 1g to be eligible

• Prothrombin time (PT) or international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.2 X upper limit of normal (ULN)

• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures; subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow up

• A female is eligible to enter and participate in this study if she is of:

• Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had: a hysterectomy; a bilateral oophorectomy (ovariectomy); a bilateral tubal ligation; is post-menopausal

• Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for >= 1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40pg/mL (< 140 pmol/L)

• Subjects using HRT must have experienced total cessation of menses for >= 1 year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT

• Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception; GlaxoSmithKlein (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 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 investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product; or double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide)

Exclusion

• Prior systemic treatment for RCC

• Evidence of any distant metastatic disease

• Evidence of bleeding diathesis or coagulopathy; patients with hematuria from the primary renal tumor are eligible provided all other eligibility criteria are met

• History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting; myocardial infarction; unstable angina; coronary artery bypass graft surgery; symptomatic peripheral vascular disease

• Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)

• Prolongation of corrected QT interval (QTc) > 480 msecs

• Hypertension that cannot be controlled by medications to < 160/90 mmHg

• History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months (Note: subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible)

• Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major)

• Hemoptysis within 6 weeks of first dose of study drug

• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures

• Unable or unwilling to discontinue use of prohibited medications for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study

• Clinically significant gastrointestinal abnormalities that may increase the risk for GI bleeding including, but not limited to: active peptic ulcer disease; known intraluminal metastatic lesion/s with suspected bleeding; inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment

• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: malabsorption syndrome; major resection of the stomach or small bowel

• Prior major surgery or trauma (NOT including biopsy of renal mass; also procedures such as catheter placement not considered to be major) within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer

• Presence of uncontrolled infection

• Other severe acute or chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44195
2	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111

Sponsors and Collaborators

• Case Comprehensive Cancer Center

Investigators

• Principal Investigator: Brian Rini, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01158521
• Other Study ID Numbers: CASE4809; NCI-2010-01392
• First Posted: Jul 8, 2010
• Last Update Posted: Sep 12, 2018
• Last Verified: Aug 1, 2018

• Additional relevant MeSH terms: Carcinoma, Renal Cell

Study Results

Participant Flow

Arm/Group Title	Treatment Group
Arm/Group Description	Patients receive oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride. pazopanib hydrochloride: Oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. therapeutic conventional surgery: Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.
Period Title: Overall Study
STARTED	25
COMPLETED	25
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment Group
Arm/Group Description	Patients receive oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride. pazopanib hydrochloride: Oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. therapeutic conventional surgery: Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.
Overall Participants	25
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	4 16%
Male	21 84%
Region of Enrollment (participants) [Number]
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Could Undergo Partial Nephrectomy After Pazopanib Therapy
Description	The primary end point was the percentage of patients who could undergo partial nephrectomy after pazopanib therapy. A reduction in tumor size, with pazopanib treatment, may permit the use of a partial nephrectomy, as opposed to a radical nephrectomy. This would help preserve additional vascularized parenchyma.
Time Frame	Partial nephrectomy performed after 8 to 16-weeks of pazopanib prescription. The median interval from treatment start to surgery was 10.6 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	Patients receive oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride. pazopanib hydrochloride: Oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. therapeutic conventional surgery: Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.
Measure Participants	25
Count of Participants [Participants]	6 24%

2. Secondary Outcome

Title	Residual Vascularized Parenchyma After Pazopanib Therapy and Subsequent Surgery Relative to Pre-therapy Assessment.
Description	Measurement of total parenchymal tissue that could be saved with pazopanib therapy and subsequent surgery, which was performed via a volumetric analysis of CT images.
Time Frame	After 8 to 16-weeks of pazopanib therapy and 7 day washout prior to surgery.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Group
Arm/Group Description	Patients receive oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride. pazopanib hydrochloride: Oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. therapeutic conventional surgery: Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.
Measure Participants	25
Mean (Inter-Quartile Range) [cm^3]	173

3. Secondary Outcome

Title	Change in Tumor Diameter
Description	Median (cm) tumor size reduction after pazopanib treatment, relative to baseline (i.e., before treatment).
Time Frame	At the conclusion of 8 to 16-week treatment with pazopanib therapy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Group
Arm/Group Description	Patients receive oral pazopanib hydrochloride once daily for up to 18 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride. pazopanib hydrochloride: Oral pazopanib hydrochloride once daily for up to 18 weeks in the absence of disease progression or unacceptable toxicity. therapeutic conventional surgery: Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.
Measure Participants	25
Median (Inter-Quartile Range) [cm]	5.5

4. Secondary Outcome

Title	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for Target Lesions: Complete Response, Partial Response, Overall Response (OR)=CR+PR
Description	Efficacy of pazopanib was evaluated via the Response Evaluation Criteria in Solid Tumors, version 1.1. Assessed by MRI. Definitions of response include Complete Response (CR), Disappearance of target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR)=CR+PR
Time Frame	At the end of 8 to 16-weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Group
Arm/Group Description	Patients receive oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride. pazopanib hydrochloride: Oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. therapeutic conventional surgery: Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.
Measure Participants	25
Count of Participants [Participants]	10 40%

5. Secondary Outcome

Title	Surgical Morbidity
Description	Conversion of tumor post therapy so that there is < 10% risk that a partial nephrectomy would be associated with a high risk of significant postoperative morbidity (e.g. conversion of tumor post therapy to ≥ 3 mm away from renal hilum (main renal artery, renal vein, or primary branches)
Time Frame	post-surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Group
Arm/Group Description	Patients receive oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride. pazopanib hydrochloride: Oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. therapeutic conventional surgery: Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.
Measure Participants	25
Count of Participants [Participants]	16 64%

6. Secondary Outcome

Title	Reduction in Tumor Volume After Treatment
Description	Median (cm^3) tumor size reduction after pazopanib treatment, relative to baseline (i.e., before treatment).
Time Frame	After 8 to 16-weeks of pazopanib treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Group
Arm/Group Description	Patients receive oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride. pazopanib hydrochloride: Oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. therapeutic conventional surgery: Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.
Measure Participants	25
Mean (Inter-Quartile Range) [cm^3]	92

Adverse Events

Arm/Group Title	Treatment Group
Arm/Group Description	Patients receive oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride. pazopanib hydrochloride: Oral pazopanib hydrochloride once daily for up to 16 weeks in the absence of disease progression or unacceptable toxicity. therapeutic conventional surgery: Patients undergo either partial or radical nephrectomy at least 7 days after completion of pazopanib hydrochloride.
All Cause Mortality
	Treatment Group
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Serious Adverse Events
	Treatment Group
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Group
	Affected / at Risk (%)	# Events
Total	25/25 (100%)
Blood and lymphatic system disorders
Thrombocytepenia	1/25 (4%)
Thrombocytopenia	12/25 (48%)
Gastrointestinal disorders
Diarrhea	13/25 (52%)
Nausea/vomiting	12/25 (48%)
Mucositis	11/25 (44%)
General disorders
Fatigue	2/25 (8%)
Fatigue	19/25 (76%)
Taste Change	12/25 (48%)
Hair Depigmentation	11/25 (44%)
Hepatobiliary disorders
Elevated Liver Enzymes	5/25 (20%)
Liver enzymes	12/25 (48%)
Increased Bilirubin	5/25 (20%)
Metabolism and nutrition disorders
Weight Loss	6/25 (24%)
Psychiatric disorders
Anorexia	11/25 (44%)
Renal and urinary disorders
Increased Creatinine	6/25 (24%)
Skin and subcutaneous tissue disorders
Hand-foot syndrome	9/25 (36%)
Vascular disorders
Hypertension	9/25 (36%)
Hypertension	4/25 (16%)

Limitations/Caveats

Requires further prospective study. Moreover, in this study, assessment of if partial nephrectomy is feasible prior to surgery was based on subjective measures. Outcome of subjects if they did not receive neoadjuvant therapy is unknown.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.