Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Measuring Effects of Pazopanib Hydrochloride in Patients With Metastatic Kidney Cancer

• Sponsor: University of Chicago (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01599832
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 20
• Locations: 4
• Arm: 1
• Duration (Months): 42
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to find out what effects pazopanib (pazopanib hydrochloride) (also called Votrient®) may have on MRI (magnetic resonance imaging) scans, blood pressure, and various proteins in the blood. Pazopanib is Food and Drug Administration (FDA) approved for treating renal cell cancer. It is an agent that prevents angiogenesis, which is new blood vessel formation. The use of pazopanib described in this study is a standard of care, but the additional MRI and blood tests that will be performed are experimental

Condition or Disease	Intervention/Treatment	Phase
Clear Cell Renal Cell Carcinoma; Recurrent Renal Cell Cancer; Stage IV Renal Cell Cancer	Drug: pazopanib hydrochloride; Other: laboratory biomarker analysis; Procedure: dynamic contrast-enhanced magnetic resonance imaging; Other: pharmacogenomic studies	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. To determine whether a K^trans rise from nadir is predictive of subsequent tumor growth.

SECONDARY OBJECTIVES:

1. To determine the association between changes in mean ambulatory blood pressure measurements, K^trans, and tumor size changes with pazopanib therapy.

2. To determine the association between changes in soluble vascular endothelial growth factor receptor 2 (sVEGFR2) measurements, K^trans, and tumor size changes with pazopanib therapy.

TERTIARY OBJECTIVES:

1. To explore previously described single nucleotide polymorphisms (SNP's) as pharmacogenomic biomarkers.

2. To model tumor growth kinetics using radiologic tumor size measurements. III. To explore other serum and plasma based putative biomarkers of vascular endothelial growth factor (VEGF) pathway inhibition.

OUTLINE:

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: DCE-MRI as Pazopanib Biomarker in Metastatic Renal Cancer
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (pazopanib hydrochloride, DCE-MRI) Patients receive pazopanib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7.	Drug: pazopanib hydrochloride; Given PO; Other Names: GW786034B Votrient ; Other: laboratory biomarker analysis; Correlative studies; Procedure: dynamic contrast-enhanced magnetic resonance imaging; Undergo dynamic contrast-enhanced magnetic resonance imaging; Other Names: DCE-MRI ; Other: pharmacogenomic studies; Correlative studies; Other Names: Pharmacogenomic Study

Outcome Measures

Primary Outcome Measures

1. Disease Progression [2 years]

   Specifically, whether the change in K^trans (the rise from nadir) as a time-dependent covariate, as assessed by the method described in Donner, is associated with disease progression.Progression was assessed using Response Evaluation Criteria in Solid Tumors (Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum recorded since the treatment started OR the appearance of one or more new lesions OR unequivocal progression of existing non-target lesions)

Secondary Outcome Measures

1. Change in K^Trans From Baseline [Baseline and 1, 8, 16, and 24 weeks post-treatment]

   K^trans is a derived measure from dynamic contrast-enhanced magnetic resonance imaging that reflects perfusion rate and capillary permeability. The change is reported as the log-transformed ratio of K^trans value at follow-up/baseline.

2. Changes in Blood Pressure From Baseline to Post-treatment [Baseline and 1 week post-treatment]

3. Changes in sVEGFR2 From Baseline to Post-treatment [Baseline and 1 week post-treatment]

Other Outcome Measures

1. Progression-free Survival [2 years]

   Specifically, whether baseline K^trans is associated with progression-free survival. Progression was assessed using Response Evaluation Criteria in Solid Tumors (Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum recorded since the treatment started OR the appearance of one or more new lesions OR unequivocal progression of existing non-target lesions)

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 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; procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol

• Histologically confirmed diagnosis of clear cell renal cancer

• Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less

• Measurable disease at least 2 cm in the shortest dimension in the abdomen or pelvis

• No clinical contra-indication to contrast enhanced MRI

• No prior pazopanib therapy

• Archived tumor tissue must be provided for all subjects

• Absolute neutrophil count (ANC) >= 1.5 X 10^9/L

• Hemoglobin >= 9 g/dL (5.6 mmol/L); subjects may not have had a transfusion within 7 days of screening assessment

• Platelets >= 100 X 10^9/L

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

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 X ULN; concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN are not permitted

• Estimated glomerular filtration rate (GFR) (modification of renal disease [MDRD] equation) > 30 ml/min

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

• 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 < 40 pg/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; acceptable contraceptive methods include:

• 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

• Oral contraceptive, either combined or progestogen alone

• Injectable progestogen

• Implants of levonorgestrel

• Estrogenic vaginal ring

• Percutaneous contraceptive patches

• Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year

• Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject

• Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

• Not lactating; female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

Exclusion Criteria:

• Prior malignancy; Note: Subjects who have had another malignancy and have been disease-free for 3 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible

• History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 months prior to first dose of study drug; screening with CNS imaging studies (computed tomography [CT] or MRI) is required only if clinically indicated or if the subject has a history of CNS metastases

• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:

• Active peptic ulcer disease

• Known intraluminal metastatic lesion/s with risk of 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

• Presence of uncontrolled infection

• Corrected QT interval (QTc) > 480 msecs using Bazett's formula

• 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)

• Poorly controlled hypertension (defined as systolic blood pressure (SBP) of >= 140 mmHg or diastolic blood pressure [DBP] of >= 90 mmHg); Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry; blood pressure (BP) must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP/DBP values from each BP assessment must be < 140/90 mmHg in order for a subject to be eligible for the study

• History of cerebrovascular accident including transient ischemic attack (TIA), 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)

• Evidence of active bleeding or bleeding diathesis

• Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels

• Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 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

• Treatment with any of the following therapies:

• Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib OR

• Anti-cancer chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib

• Any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment

• Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is progressing in severity, except alopecia

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470
2	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
3	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
4	Illinois Cancer Care (Peoria)	Peoria	Illinois	United States	61615

Sponsors and Collaborators

• University of Chicago
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Walter Stadler, University of Chicago Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Chicago
• ClinicalTrials.gov Identifier: NCT01599832
• Other Study ID Numbers: 12-0121; NCI-2012-00676
• First Posted: May 16, 2012
• Last Update Posted: Jun 8, 2017
• Last Verified: May 1, 2017

• Additional relevant MeSH terms: Carcinoma, Renal Cell

Study Results

Participant Flow

Arm/Group Title	Treatment (Pazopanib Hydrochloride, DCE-MRI)
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7. pazopanib hydrochloride: Given PO laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Undergo dynamic contrast-enhanced magnetic resonance imaging pharmacogenomic studies: Correlative studies
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Pazopanib Hydrochloride, DCE-MRI)
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7. pazopanib hydrochloride: Given PO laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Undergo dynamic contrast-enhanced magnetic resonance imaging pharmacogenomic studies: Correlative studies
Overall Participants	20
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63
Sex: Female, Male (Count of Participants)
Female	14 70%
Male	6 30%
Race/Ethnicity, Customized (Count of Participants)
White	13 65%
African American	2 10%
Hispanic	2 10%
Not reported	3 15%
Region of Enrollment (Count of Participants)
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Disease Progression
Description	Specifically, whether the change in K^trans (the rise from nadir) as a time-dependent covariate, as assessed by the method described in Donner, is associated with disease progression.Progression was assessed using Response Evaluation Criteria in Solid Tumors (Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum recorded since the treatment started OR the appearance of one or more new lesions OR unequivocal progression of existing non-target lesions)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The accrued sample size of n=20 did not permit further assessment (as described in the Outcome Measure Description) of the primary endpoint, so simply reporting the median progression-free survival here

Arm/Group Title	Treatment (Pazopanib Hydrochloride, DCE-MRI)
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7. pazopanib hydrochloride: Given PO laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Undergo dynamic contrast-enhanced magnetic resonance imaging pharmacogenomic studies: Correlative studies
Measure Participants	20
Median (Full Range) [weeks]	32.1

2. Secondary Outcome

Title	Change in K^Trans From Baseline
Description	K^trans is a derived measure from dynamic contrast-enhanced magnetic resonance imaging that reflects perfusion rate and capillary permeability. The change is reported as the log-transformed ratio of K^trans value at follow-up/baseline.
Time Frame	Baseline and 1, 8, 16, and 24 weeks post-treatment

Outcome Measure Data

Analysis Population Description

Included those with a baseline K^Trans value and at least 1 K^trans value at follow-up

Arm/Group Title	Treatment (Pazopanib Hydrochloride, DCE-MRI)
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7. pazopanib hydrochloride: Given PO laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Undergo dynamic contrast-enhanced magnetic resonance imaging pharmacogenomic studies: Correlative studies
Measure Participants	17
week 1	-0.680 (0.729)
week 8	-1.049 (0.634)
week 16	-0.998 (0.757)
week 24	-0.755 (0.952)

3. Secondary Outcome

Title	Changes in Blood Pressure From Baseline to Post-treatment
Time Frame	Baseline and 1 week post-treatment

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Treatment (Pazopanib Hydrochloride, DCE-MRI)
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7. pazopanib hydrochloride: Given PO laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Undergo dynamic contrast-enhanced magnetic resonance imaging pharmacogenomic studies: Correlative studies
Measure Participants	0

4. Secondary Outcome

Title	Changes in sVEGFR2 From Baseline to Post-treatment
Time Frame	Baseline and 1 week post-treatment

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Treatment (Pazopanib Hydrochloride, DCE-MRI)
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7. pazopanib hydrochloride: Given PO laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Undergo dynamic contrast-enhanced magnetic resonance imaging pharmacogenomic studies: Correlative studies
Measure Participants	0

5. Other Pre-specified Outcome

Title	Progression-free Survival
Description	Specifically, whether baseline K^trans is associated with progression-free survival. Progression was assessed using Response Evaluation Criteria in Solid Tumors (Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum recorded since the treatment started OR the appearance of one or more new lesions OR unequivocal progression of existing non-target lesions)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Included those with a baseline K^trans value

Arm/Group Title	Treatment (Pazopanib Hydrochloride, DCE-MRI)
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7. pazopanib hydrochloride: Given PO laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Undergo dynamic contrast-enhanced magnetic resonance imaging pharmacogenomic studies: Correlative studies
Measure Participants	18
Median (Full Range) [weeks]	32.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment (Pazopanib Hydrochloride, DCE-MRI)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.083
	Comments	P-value was from test of significance of log-transformed baseline K^trans.
	Method	Regression, Cox
	Comments	Multivariate model with adjustment for prior treatment, and clinical prognostic index (good/intermediate/poor) (n=16 had complete data)

Adverse Events

Adverse Event Reporting Description	All serious adverse events are reported. For other adverse events, those that occurred in >5% of patients are reported.
Arm/Group Title	Treatment (Pazopanib Hydrochloride, DCE-MRI)
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo dynamic contrast-enhanced MRI at baseline, day 8, and prior to courses 3, 5, and 7. pazopanib hydrochloride: Given PO laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Undergo dynamic contrast-enhanced magnetic resonance imaging pharmacogenomic studies: Correlative studies
All Cause Mortality
	Treatment (Pazopanib Hydrochloride, DCE-MRI)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Pazopanib Hydrochloride, DCE-MRI)
	Affected / at Risk (%)	# Events
Total	8/20 (40%)
Gastrointestinal disorders
Diarrhea	1/20 (5%)
General disorders
Pain	1/20 (5%)
Investigations
Alanine aminotransferase increased	1/20 (5%)
Musculoskeletal and connective tissue disorders
Muscle Weakness lower limb	2/20 (10%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant, and unspecified	2/20 (10%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/20 (5%)
Vascular disorders
Hypertension	1/20 (5%)
Other (Not Including Serious) Adverse Events
	Treatment (Pazopanib Hydrochloride, DCE-MRI)
	Affected / at Risk (%)	# Events
Total	16/20 (80%)
Blood and lymphatic system disorders
Anemia	6/20 (30%)
Gastrointestinal disorders
Constipation	7/20 (35%)
Diarrhea	13/20 (65%)
Mucositis oral	3/20 (15%)
Nausea	11/20 (55%)
Vomiting	7/20 (35%)
Abdominal pain	2/20 (10%)
General disorders
Fatigue	13/20 (65%)
Non-cardiac chest pain	2/20 (10%)
Pain	3/20 (15%)
Investigations
Alanine aminotransferase increased	4/20 (20%)
Alkaline phosphatase increased	4/20 (20%)
Aspartate aminotransferase increased	3/20 (15%)
Blood bilirubin increased	5/20 (25%)
Weight loss	2/20 (10%)
Creatinine increased	2/20 (10%)
Platelet count decreased	3/20 (15%)
White blood cell decreased	2/20 (10%)
Metabolism and nutrition disorders
Anorexia	11/20 (55%)
Hypoalbuminemia	6/20 (30%)
Hyponatremia	3/20 (15%)
Hypophosphatemia	3/20 (15%)
Hypercalcemia	2/20 (10%)
Hypoglycemia	2/20 (10%)
Musculoskeletal and connective tissue disorders
Back pain	2/20 (10%)
Nervous system disorders
Dysgeusia	3/20 (15%)
Headache	2/20 (10%)
Dizziness	2/20 (10%)
Renal and urinary disorders
Proteinuria	3/20 (15%)
chronic kidney disease	2/20 (10%)
Hematuria	2/20 (10%)
Skin and subcutaneous tissue disorders
Hair color change	2/20 (10%)
Vascular disorders
Hypertension	6/20 (30%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.