Pazopanib Hydrochloride After Leuprolide Acetate or Goserelin Acetate in Treating Patients With Relapsed Prostate Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00454571
• Collaborator: (none)
• Enrollment: 37
• Locations: 2
• Arms: 2
• Duration (Months): 54
• Patients Per Site: 18.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This randomized phase II trial is studying how well pazopanib hydrochloride works after leuprolide or goserelin in treating patients with relapsed prostate cancer. Pazopanib hydrochloride 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. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as leuprolide acetate or goserelin acetate, may lessen the amount of androgens made by the body. Giving pazopanib after leuprolide or goserelin may be an effective treatment for prostate cancer

Condition or Disease	Intervention/Treatment	Phase
Recurrent Prostate Cancer	Drug: pazopanib hydrochloride; Drug: leuprolide acetate; Drug: goserelin acetate	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine if pazopanib hydrochloride is able to increase time to progression, as measured by prostate-specific antigen (PSA), after 6 months of limited gonadotropin-releasing hormone (GnRH) agonist therapy comprising leuprolide acetate or goserelin in patients with androgen-sensitive relapsed stage D0 prostate cancer.

SECONDARY OBJECTIVES:

1. Determine the adverse events in patients treated with this regimen. II. To monitor for changes in testosterone in relationship to pazopanib therapy versus observation.

OUTLINE:

Patients receive androgen blockade comprising GnRH agonist therapy (e.g., leuprolide acetate or goserelin acetate) for 6 months. Patients who develop metastases or have PSA progression while on GnRH agonist therapy are removed from the study and placed on total androgen blockade. The remaining patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo observation.

After completion of study treatment, patients are followed up periodically for up to 12 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Phase II Study of GW786034 (Pazopanib) in Stage D0 Relapsed Androgen Sensitive Prostate Cancer Following Limited GnRH Agonist Therapy
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pazopanib Patients receive pazopanib hydrochloride PO QD on days 1-28 after treatment with leuprolide acetate and goserelin acetate. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: pazopanib hydrochloride; Given PO; Other Names: GW786034B Votrient ; Drug: leuprolide acetate; Other Names: Enantone LEUP Lupron Lupron Depot ; Drug: goserelin acetate; Other Names: ICI-118630 ZDX Zoladex
Active Comparator: Observation Patients undergo observation after treatment with leuprolide acetate and goserelin acetate.	Drug: leuprolide acetate; Other Names: Enantone LEUP Lupron Lupron Depot ; Drug: goserelin acetate; Other Names: ICI-118630 ZDX Zoladex

Outcome Measures

Primary Outcome Measures

1. Median Time to PSA Progression [Baseline, every 4 weeks during treatment, and up to 12 months after completion of study treatment]

   The median time to disease progression for the therapy and observation groups will be estimated using the Kaplan-Meier estimate and compared using the log-rank test.

Secondary Outcome Measures

1. Median PSA Progression-free Survival [Time from randomization to PSA progression or death from any cause]

   Kaplan-Meier estimates for PSA progression-free survival will be computed for the pazopanib and active surveillance groups and compared using the log rank test. The outcome measure is median PSA progression-free survival time.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed prostate cancer

• Stage D0

• Must have undergone some definitive local therapy for prostate cancer

• Must be free of macrometastatic disease, as evidenced by computed tomography (CT) scan and bone scan, if serum PSA ≥ 10 ng/mL prior to GnRH agonist therapy

• Progressive disease meeting the following criteria: NOTE: Patients who have undergone a prostatectomy and have two detectable, rising serum PSA levels are eligible

• Two consecutive rises in PSA above nadir recorded after definite local therapy

• Serum PSA concentrations must have absolute value of > 0.5 ng/mL (separated by ≥ 2 weeks) prior to beginning GnRH agonist therapy

• PSA < 0.5 ng/mL

• Testosterone < 30 ng/mL

• No measurable disease

• No brain metastases requiring steroid or anticonvulsant therapy

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 OR Karnofsky PS 60- 100%

• Prothrombin time (PT)/international normalization ratio (INR)/partial thromboplastin time (PTT) ≤ 1.2 times upper limit of normal (ULN)

• Bilirubin normal

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN

• Creatinine ≤ 1.5 times ULN OR creatinine clearance > 50 mL/min

• Proteinuria ≤ 1+ on 2 consecutive dipsticks > 1 week apart

• Urine protein: creatinine ratio < 1 OR urine protein < 1.0 g/24 hours

• Fertile patients must use effective double-barrier contraception during study therapy OR completely abstain from sexual intercourse 14 days prior to, during, and for ≥ 21 days after completion of study therapy

• No history of allergic reactions attributed to compounds of similar chemical or biological composition to pazopanib hydrochloride or to other agents used in the study

• No concurrent uncontrolled illness including, but not limited to, any of the following:

• Ongoing or active infection

• Psychiatric illness or social situations that would preclude compliance with study requirements

• No human immunodeficiency virus (HIV) positivity

• No condition that impairs the ability to swallow and retain pazopanib hydrochloride tablets, including any of the following:

• Gastrointestinal tract disease resulting in an inability to take oral medication

• Requirement for intravenous (IV) alimentation

• Prior surgical procedures affecting absorption

• Active peptic ulcer disease

• No other conditions, including any of the following:

• Serious or nonhealing wound, ulcer, or bone fracture

• Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days

• Cerebrovascular accident within the past 6 months

• Myocardial infarction, admission for unstable angina, cardiac angioplasty, or stenting within the past 6 months

• Venous thrombosis within the past 12 weeks

• New York Heart Association (NYHA) class III or IV heart failure

• History of currently treated asymptomatic NYHA class II heart failure allowed

• Systolic blood pressure (BP) ≤ 140 mm Hg and diastolic BP ≤ 90 mm Hg

• Prior initiation or adjustment of BP medication allowed provided that the average of 3 BP readings at a visit prior to enrollment is < 140/90 mm Hg

• More than 3 months since prior antiandrogen

• More than 4 months since prior orchiectomy or implantable luteinizing LHRH agonist

• No prior GnRH agonists except for neoadjuvant or adjuvant therapy associated with local therapy

• Patients who have started a GnRH agonist for micrometastatic disease after local therapy allowed provided the following criteria are met:

• Progressive disease

• Willing to discontinue therapy before 6 months have elapsed

• Have signed consent prior to completing 6 months of the initial hormone therapy

• Are within 4 months of initiating GnRH agonist therapy

• No prior or concurrent GnRH antagonist therapy

• No concurrent ketoconazole

• No concurrent cytochrome P450 2C9 (CYP2C9) substrates, including any of the following:

• Anticoagulants (e.g., warfarin [therapeutic doses only])

• Low molecular weight heparin or prophylactic low-dose warfarin allowed

• Oral hypoglycemics (e.g., glipizide, glyburide, tolbutamide, glimepiride, or nateglinide)

• Ergot derivatives (e.g., dihydroergotamine, ergonovine, ergotamine, or methylergonovine)

• Neuroleptics (e.g., pimozide)

• Erectile dysfunction agents (e.g., sildenafil, tadalafil, or vardenafil)

• Antiarrhythmics (e.g., bepridil, flecainide, lidocaine, mexiletin, amiodarone, quinidine, or propafenone)

• Immune modulators (e.g., cyclosporine, tacrolimus, or sirolimus)

• Miscellaneous medications (e.g., theophylline, quetiapine, risperidone, tacrine, clozapine, or atomoxetine)

• No concurrent medications associated with the risk of QTc prolongation and/or Torsades de Pointes

• Replacement of drugs that do not carry these risks allowed

• No other concurrent non-Food and Drug Administration (FDA)-approved agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470
2	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Edwin Posadas, University of Chicago Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00454571
• Other Study ID Numbers: NCI-2009-00202; N01CM62201; CDR0000538086; 14954A
• First Posted: Mar 30, 2007
• Last Update Posted: Feb 10, 2016
• Last Verified: Sep 1, 2012

• Additional relevant MeSH terms: Prostatic Neoplasms; Leuprolide; Goserelin

Study Results

Participant Flow

Arm/Group Title	Pazopanib, Leuprolide Acetate, and Goserelin Acetate	Leuprolide Acetate and Goserelin Acetate Only
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD on days 1-28 after treatment with leuprolide acetate and goserelin acetate. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. pazopanib hydrochloride: Given PO leuprolide acetate goserelin acetate	Patients undergo observation after treatment with leuprolide acetate and goserelin acetate. leuprolide acetate goserelin acetate
Period Title: Overall Study
STARTED	18	19
COMPLETED	5	13
NOT COMPLETED	13	6

Baseline Characteristics

Arm/Group Title	Pazopanib, Leuprolide Acetate, and Goserelin Acetate	Leuprolide Acetate and Goserelin Acetate Only	Total
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD on days 1-28 after treatment with leuprolide acetate and goserelin acetate. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. pazopanib hydrochloride: Given PO leuprolide acetate goserelin acetate	Patients undergo observation after treatment with leuprolide acetate and goserelin acetate. leuprolide acetate goserelin acetate	Total of all reporting groups
Overall Participants	18	19	37
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	74	71	72
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	18 100%	19 100%	37 100%

Outcome Measures

1. Primary Outcome

Title	Median Time to PSA Progression
Description	The median time to disease progression for the therapy and observation groups will be estimated using the Kaplan-Meier estimate and compared using the log-rank test.
Time Frame	Baseline, every 4 weeks during treatment, and up to 12 months after completion of study treatment

Outcome Measure Data

Analysis Population Description

Patients were taken off study early, so many survival times were censored. At no point during the study did the proportion of subjects who progressed drop to 50%. Thus, it was not possible to calculate median time to disease progression.

Arm/Group Title	Pazopanib, Leuprolide Acetate, and Goserelin Acetate	Leuprolide Acetate and Goserelin Acetate Only
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD on days 1-28 after treatment with leuprolide acetate and goserelin acetate. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. pazopanib hydrochloride: Given PO leuprolide acetate goserelin acetate	Patients undergo observation after treatment with leuprolide acetate and goserelin acetate. leuprolide acetate goserelin acetate
Measure Participants	0	0

2. Secondary Outcome

Title	Median PSA Progression-free Survival
Description	Kaplan-Meier estimates for PSA progression-free survival will be computed for the pazopanib and active surveillance groups and compared using the log rank test. The outcome measure is median PSA progression-free survival time.
Time Frame	Time from randomization to PSA progression or death from any cause

Outcome Measure Data

Analysis Population Description

Patients were taken off study early, so many survival times were censored. At no point during the study did the proportion of subjects who progressed drop to 50%. Thus, it was not possible to calculate median time to PSA progression.

Arm/Group Title	Pazopanib, Leuprolide Acetate, and Goserelin Acetate	Leuprolide Acetate and Goserelin Acetate Only
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD on days 1-28 after treatment with leuprolide acetate and goserelin acetate. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. pazopanib hydrochloride: Given PO leuprolide acetate goserelin acetate	Patients undergo observation after treatment with leuprolide acetate and goserelin acetate. leuprolide acetate goserelin acetate
Measure Participants	0	0

Adverse Events

Time Frame	1 year
Arm/Group Title	Pazopanib, Leuprolide Acetate, and Goserelin Acetate		Leuprolide Acetate and Goserelin Acetate Only
Arm/Group Description	Patients receive pazopanib hydrochloride PO QD on days 1-28 after treatment with leuprolide acetate and goserelin acetate. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. pazopanib hydrochloride: Given PO leuprolide acetate goserelin acetate		Patients undergo observation after treatment with leuprolide acetate and goserelin acetate. leuprolide acetate goserelin acetate
All Cause Mortality
	Pazopanib, Leuprolide Acetate, and Goserelin Acetate		Leuprolide Acetate and Goserelin Acetate Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pazopanib, Leuprolide Acetate, and Goserelin Acetate		Leuprolide Acetate and Goserelin Acetate Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/18 (27.8%)		0/19 (0%)
Cardiac disorders
Chest pain - cardiac	1/18 (5.6%)		0/19 (0%)
Investigations
Alanine aminotransferase increased	1/18 (5.6%)		0/19 (0%)
Nervous system disorders
Dizziness	1/18 (5.6%)		0/19 (0%)
Vascular disorders
Hypertension	1/18 (5.6%)		0/19 (0%)
Thromboembolic event	1/18 (5.6%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Pazopanib, Leuprolide Acetate, and Goserelin Acetate		Leuprolide Acetate and Goserelin Acetate Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/18 (88.9%)		2/19 (10.5%)
Blood and lymphatic system disorders
Anemia	4/18 (22.2%)		0/19 (0%)
Ear and labyrinth disorders
Tinnitus	1/18 (5.6%)		0/19 (0%)
Eye disorders
Blurred vision	1/18 (5.6%)		0/19 (0%)
Eye disorders - Other	1/18 (5.6%)		0/19 (0%)
Gastrointestinal disorders
Abdominal pain	2/18 (11.1%)		0/19 (0%)
Constipation	2/18 (11.1%)		1/19 (5.3%)
Diarrhea	12/18 (66.7%)		0/19 (0%)
Dyspepsia	3/18 (16.7%)		0/19 (0%)
Esophagitis	1/18 (5.6%)		0/19 (0%)
Flatulence	2/18 (11.1%)		0/19 (0%)
Gastrointestinal disorders - Other	1/18 (5.6%)		0/19 (0%)
Hemorrhoids	1/18 (5.6%)		0/19 (0%)
Mucositis oral	1/18 (5.6%)		0/19 (0%)
Nausea	3/18 (16.7%)		0/19 (0%)
Oral pain	1/18 (5.6%)		0/19 (0%)
Stomach pain	1/18 (5.6%)		0/19 (0%)
Vomiting	1/18 (5.6%)		0/19 (0%)
General disorders
Edema face	1/18 (5.6%)		0/19 (0%)
Fatigue	9/18 (50%)		0/19 (0%)
Pain	3/18 (16.7%)		1/19 (5.3%)
Investigations
Alanine aminotransferase increased	7/18 (38.9%)		0/19 (0%)
Alkaline phosphatase increased	1/18 (5.6%)		0/19 (0%)
Aspartate aminotransferase increased	8/18 (44.4%)		0/19 (0%)
Blood bilirubin increased	1/18 (5.6%)		0/19 (0%)
Creatinine increased	1/18 (5.6%)		0/19 (0%)
Lymphocyte count decreased	2/18 (11.1%)		0/19 (0%)
Platelet count decreased	3/18 (16.7%)		0/19 (0%)
Weight gain	0/18 (0%)		1/19 (5.3%)
Weight loss	3/18 (16.7%)		0/19 (0%)
White blood cell decreased	2/18 (11.1%)		0/19 (0%)
Metabolism and nutrition disorders
Anorexia	4/18 (22.2%)		0/19 (0%)
Hyperglycemia	4/18 (22.2%)		0/19 (0%)
Hyperkalemia	1/18 (5.6%)		0/19 (0%)
Hypoalbuminemia	3/18 (16.7%)		0/19 (0%)
Hypoglycemia	1/18 (5.6%)		0/19 (0%)
Hypomagnesemia	1/18 (5.6%)		0/19 (0%)
Hyponatremia	2/18 (11.1%)		0/19 (0%)
Hypophosphatemia	2/18 (11.1%)		0/19 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/18 (5.6%)		0/19 (0%)
Back pain	1/18 (5.6%)		0/19 (0%)
Chest wall pain	1/18 (5.6%)		0/19 (0%)
Musculoskeletal and connective tissue disorder - Other, specify	0/18 (0%)		1/19 (5.3%)
Nervous system disorders
Dizziness	1/18 (5.6%)		0/19 (0%)
Dysgeusia	3/18 (16.7%)		0/19 (0%)
Headache	4/18 (22.2%)		0/19 (0%)
Memory impairment	1/18 (5.6%)		0/19 (0%)
Nervous system disorders - Other	1/18 (5.6%)		0/19 (0%)
Peripheral sensory neuropathy	1/18 (5.6%)		0/19 (0%)
Psychiatric disorders
Anxiety	1/18 (5.6%)		0/19 (0%)
Libido decreased	0/18 (0%)		1/19 (5.3%)
Renal and urinary disorders
Proteinuria	1/18 (5.6%)		0/19 (0%)
Renal and urinary disorders - Other	1/18 (5.6%)		0/19 (0%)
Urinary frequency	2/18 (11.1%)		0/19 (0%)
Urinary incontinence	2/18 (11.1%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/18 (5.6%)		0/19 (0%)
Cough	1/18 (5.6%)		0/19 (0%)
Dyspnea	4/18 (22.2%)		0/19 (0%)
Skin and subcutaneous tissue disorders
Alopecia	3/18 (16.7%)		0/19 (0%)
Photosensitivity	1/18 (5.6%)		0/19 (0%)
Pruritus	1/18 (5.6%)		0/19 (0%)
Skin and subcutaneous tissue disorders - Other	3/18 (16.7%)		0/19 (0%)
Skin ulceration	1/18 (5.6%)		0/19 (0%)
Vascular disorders
Hot flashes	3/18 (16.7%)		1/19 (5.3%)
Hypertension	9/18 (50%)		0/19 (0%)
Hypotension	1/18 (5.6%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.