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
Conditions
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.
Interventions
DRUGpazopanib hydrochloride
800 mg Given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
China, South Korea, United States
Participant flow
Recruitment details
Nineteen participants were accrued between October 2008 and December 2009.
Pre-assignment details
Of the 19 participants accrued, one participant canceled prior to treatment evaluation, and therefore was excluded from toxicity analysis. This participant was included in the primary endpoint analysis.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Enzyme Inhibitor Therapy) 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. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment (Enzyme Inhibitor Therapy) |
|---|---|
| Age, Continuous | 66 years |
| Region of Enrollment Australia | 2 participants |
| Region of Enrollment Hong Kong | 2 participants |
| Region of Enrollment Korea, Republic of | 1 participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 3 / 18 |
Outcome results
Primary
Best Tumor Response (Complete [CR] or Partial Response [PR] by Response Evaluation Criteria in Solid Tumors [RECIST])
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.
Time frame: Participants will be evaluated every 8 weeks during treatment and up to 1 year after completion of treatment.
Population: All participants meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluated for response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Best Tumor Response (Complete [CR] or Partial Response [PR] by Response Evaluation Criteria in Solid Tumors [RECIST]) | Partial Response (PR) | 0 participants |
| Treatment (Enzyme Inhibitor Therapy) | Best Tumor Response (Complete [CR] or Partial Response [PR] by Response Evaluation Criteria in Solid Tumors [RECIST]) | Complete Response (CR) | 0 participants |
Secondary
Adverse Events Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0
The maximum grade for each adverse event considered to be at least possibly related to treatment will be recorded. Frequency tables will be constructed.
Time frame: Every 4 weeks during treatment (maximum duration was 44 weeks)
Population: Eighteen of the 19 participants accrued to the study were evaluable for adverse events.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Adverse Events Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | Grade 3 Adverse Events | 7 participants |
| Treatment (Enzyme Inhibitor Therapy) | Adverse Events Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | Grade 4 or Higher Adverse Events | 0 participants |
Secondary
Confirmed Tumor Response (CR and PR)
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 frame: Documented on 2 consecutive evaluations 8 weeks apart from the start of the treatment until disease progression/recurrence, assessed up to 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Confirmed Tumor Response (CR and PR) | Confirmed Partial Response (PR) | 0 participants |
| Treatment (Enzyme Inhibitor Therapy) | Confirmed Tumor Response (CR and PR) | Confirmed Complete Response (CR) | 0 participants |
Secondary
Duration of Response
The distribution of response durations will be estimated using the Kaplan-Meier method.
Time frame: 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
Population: There were no responses.
Secondary
Survival Time
The distribution of survival times will be estimated using the Kaplan-Meier method.
Time frame: Time from registration until death due to any cause, assessed every 6 months after PD for up to 2 years after registration
Population: all participants were evaluable for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Survival Time | 5.83 months |
Secondary
Time to Disease Progression
The distribution of progression-free survival times will be estimated using the Kaplan-Meier method.
Time frame: Every 3 months from registration until progressive disease (PD), assessed up to 2 years after registration
Population: All participants were evaluable for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Time to Disease Progression | 1.85 months |