Pazopanib in Treating Patients With Metastatic Urothelial Cancer

Phase 2

Completed

Conditions: Distal Urethral Cancer
Proximal Urethral Cancer
Recurrent Bladder Cancer
Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter
Recurrent Urethral Cancer
Stage IV Bladder Cancer
Transitional Cell Carcinoma of the Bladder
Urethral Cancer Associated With Invasive Bladder Cancer

Interventions: Drug: pazopanib hydrochloride

Registration Number: NCT00471536

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial is studying the side effects and how well pazopanib works in treating patients with metastatic urothelial cancer. Pazopanib 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.

Detailed Description: PRIMARY OBJECTIVES:

I. Assess the anti tumor activity and toxicity profile of pazopanib hydrochloride in patients with metastatic urothelial cancer.

SECONDARY OBJECTIVES:

I. Evaluate the pharmacokinetics of pazopanib hydrochloride in these patients. II. Evaluate pre- and post-treatment changes in circulating endothelial cells, monocytes and platelets, and angiogenesis-related factors in these patients.

OUTLINE: This is a multicenter study. Patients receive oral pazopanib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically for correlative studies and pharmacological studies. Samples are analyzed for vascular endothelial growth factor (VEGF) and soluble VEGF receptor II concentration via ELISA. Circulating endothelial cells are also measured.

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 19

Inclusion Criteria

Histologically or cytologically confirmed transitional cell cancer of the urothelium or bladder
- Metastatic disease
Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 2.0 cm by conventional techniques OR ≥ 1.0 cm by spiral CT scan
No known brain metastases
ECOG performance status 0-2
Life expectancy ≥ 12 weeks
Platelet count ≥ 100,000/mm^3
WBC ≥ 3,000/mm^3
Absolute neutrophil count ≥ 1,500/mm^3
Bilirubin normal
AST and ALT ≤ 2.5 times upper limit of normal (ULN)
Creatinine normal OR creatinine clearance ≥ 60 mL/min
PT/INR/PTT ≤ 1.2 times ULN
No proteinuria > 1+ on two consecutive dipsticks measured ≥ 1 week apart
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No history of allergic reactions attributed to compounds of similar chemical or biological composition to pazopanib hydrochloride or other agents used in the study
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 IV alimentation
- Prior surgical procedures affecting absorption
- Active peptic ulcer disease
No uncontrolled illness that would limit compliance with study therapy including, but not limited to, any of the following:
- Ongoing or active infection
- Psychiatric illness or social situations
No QTc prolongation (defined as a QTc interval ≥ 480 msecs) or other significant ECG abnormalities (e.g., frequent ventricular ectopy, evidence of ongoing myocardial ischemia)
No other conditions, including any of the following:
- Serious or non-healing 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, cardiac arrhythmia, or admission for unstable angina within the past 12 weeks
- Venous thrombosis within the past 12 weeks
- New York Heart Association (NYHA) class III or IV heart failure
  - Asymptomatic NYHA class II heart failure on treatment allowed
No other active second malignancy other than non-melanoma skin cancer
- Patients are not considered to have an active malignancy if they have completed anti-cancer therapy and are considered by their physician to be ≤ 30% risk of relapse
At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
At least 4 weeks since prior radiotherapy
Prior palliative radiotherapy to metastatic lesions allowed provided there is ≥ 1 measurable and/or evaluable lesion(s) that has not been irradiated
At least 4 weeks since prior surgery
One prior chemotherapy regimen for metastatic urothelial or bladder cancer
More than 12 weeks since prior cardiac angioplasty or stenting
Prior adjuvant or neoadjuvant therapy allowed
No prior experimental treatment for metastatic disease
No other prior or concurrent investigational agents
No concurrent combination antiretroviral therapy for HIV-positive patients
No concurrent CYP2C9 substrates, including any of the following:
- Anticoagulants (e.g., warfarin [therapeutic doses only])
  - Low molecular weight heparin and prophylactic low-dose warfarin (≤ 2 mg daily) allowed
- Oral hypoglycemics (e.g., glipizide, glyburide, tolbutamide, glimepiride, or nateglinide)
- Ergot derivatives (e.g., dihydroergotamine, ergonovine, ergotamine, or methylergonovine)
- Antipsychotics (e.g., pimozide or clozapine)
- Erectile dysfunction agents (e.g., sildenafil, tadalafil, or vardenafil)
- Antiarrhythmics (e.g., bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine, or propafenone)
- Immune modulators (e.g., cyclosporine, tacrolimus, or sirolimus)
- Miscellaneous drugs (e.g., theophylline, quetiapine, risperidone, tacrine, or atomoxetine)
No other concurrent anticancer agents or therapies
No concurrent medications that are associated with a risk of QTc prolongation and/or Torsades de Pointes

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (enzyme inhibitor therapy)	pazopanib hydrochloride	Patients receive 800 mg oral pazopanib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Best Tumor Response (Complete [CR] or Partial Response [PR] by Response Evaluation Criteria in Solid Tumors [RECIST])	Participants will be evaluated every 8 weeks during treatment and up to 1 year after completion of treatment.	Tumor response is defined as the total number of eligible patients whose disease has a complete or partial response to GW786034 according to the RECIST criteria. Per RECIST v1.0 criteria: A Complete Response (CR) requires the disappearance of all target lesions. A Partial Response (PR) requires \>=30% decrease in the sum of the longest diameter of target lesions from baseline measurement. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for response.

Secondary Outcome Measures

Name	Time	Method
Adverse Events Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0	Every 4 weeks during treatment (maximum duration was 44 weeks)	The maximum grade for each adverse event considered to be at least possibly related to treatment will be recorded. Frequency tables will be constructed.
Confirmed Tumor Response (CR and PR)	Documented on 2 consecutive evaluations 8 weeks apart from the start of the treatment until disease progression/recurrence, assessed up to 1 year	Tumor response is defined as the total number of eligible patients whose disease has a complete or partial response to GW786034 according to the RECIST criteria. A confirmed response is defined as a CR or PR and is documented on 2 consecutive evaluations.
Time to Disease Progression	Every 3 months from registration until progressive disease (PD), assessed up to 2 years after registration	The distribution of progression-free survival times will be estimated using the Kaplan-Meier method.
Duration of Response	From the time an objective response is first noted to be either a CR or PR to the date progression is documented, assessed up to 1 year	The distribution of response durations will be estimated using the Kaplan-Meier method.
Survival Time	Time from registration until death due to any cause, assessed every 6 months after PD for up to 2 years after registration	The distribution of survival times will be estimated using the Kaplan-Meier method.

Trial Locations

Locations (9): Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
Chinese University of Hong Kong-Prince of Wales Hospital
🇨🇳
Shatin, Hong Kong, China
Cox Medical Center
🇺🇸
Springfield, Missouri, United States
Mayo Clinic in Florida
🇺🇸
Jacksonville, Florida, United States
Metro-Minnesota CCOP
🇺🇸
Saint Louis Park, Minnesota, United States
Gangnam Severance Hospital
🇰🇷
Seoul, Korea, Republic of
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Wayne State University
🇺🇸
Detroit, Michigan, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States