Sorafenib in Treating Patients With Regional or Metastatic Cancer of the Urothelium

Phase 2

Terminated

Conditions: Adenocarcinoma of the Bladder
Distal Urethral Cancer
Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter
Proximal Urethral Cancer
Recurrent Bladder Cancer
Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter
Recurrent Urethral Cancer
Regional Transitional Cell Cancer of the Renal Pelvis and Ureter
Squamous Cell Carcinoma of the Bladder
Stage III Bladder Cancer

Interventions: Drug: sorafenib tosylate
Other: laboratory biomarker analysis

Registration Number: NCT00112905

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial is studying how well sorafenib works in treating patients with progressive regional or metastatic cancer of the urothelium. Sorafenib 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. To evaluate the 4-month progression-free survival rate, response rate and toxicity of BAY 43-9006 in patients with progressing regional or metastatic transitional cell carcinoma (or mixed histologies containing a component of TCC) of the urothelium who have progressed on one and only one prior systemic chemotherapy regimen for metastatic disease.

SECONDARY OBJECTIVES:

I. To determine the time to disease progression and overall survival with BAY 43-9006.

II. To evaluate the frequency of polymorphisms in drug metabolizing enzymes and to correlate these polymorphisms with variations in BAY 43-9006 pharmacokinetics.

III. To evaluate the frequency of raf kinase mutations in tumor specimens and correlate these with response rate.

IV. To evaluate serum VEGF levels as potential markers of angiogenesis inhibition by BAY 43-9006.

V. To evaluate markers of apoptosis and kinase inhibition in peripheral blood mononuclear cells as potential biomarkers of BAY 43-9006 activity.

VI. To determine if there are proteins differentially translated from the genome in patients who respond to treatment with BAY 43-9006 versus patients who do not respond to BAY 43-9006.

OUTLINE: This is a multicenter study.

Patients receive oral sorafenib twice daily on days 1-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months until 2 years from study entry and then every 6 months until 3 years from study entry.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 27

Inclusion Criteria

Histologically confirmed transitional cell carcinoma or mixed histologies containing a component of transitional cell carcinoma of the urothelium (renal pelvis, ureter, bladder, urethra) with manifestations of progressing regional or metastatic cancer; or (2) Nontransitional cell histologies include patients with adenocarcinoma or squamous cell carcinomas representing greater than 90% of specimen; patients with small cell carcinoma, soft tissue sarcomas, or carcinosarcomas are excluded
Measurable disease, as defined in the RECIST criteria; all sites of disease must be evaluated within 4 weeks prior to registration
Patients must have progressed on one and only one prior systemic chemotherapy for metastatic disease; prior chemotherapy administered in the adjuvant or neoadjuvant setting is permitted (i.e. does not count as 1 prior regimen) provided that it was completed greater than 12 months prior to the start of the first chemotherapy regimen administered in the metastatic setting
Patients must not have had prior systemic biologic response modifier therapy; patients must not have had chemotherapy, hormonal or biologic therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or have recovered from adverse events due to agents administered more than 4 weeks earlier
Prior radiotherapy is allowed; patients must be >= 2 weeks post-radiotherapy at time of registration; a previously irradiated lesion can only be used as a marker lesion if there is unequivocal evidence of progression demonstrated on serial imaging studies; patients must have recovered from all toxicities associated with prior radiotherapy
Patients must be >= 4 weeks post-major surgery at time of registration; patients must have recovered from all toxicities associated with prior surgery
ECOG performance status of 0 or 1
No history of severe cardiovascular disease (AHA Class III or IV), uncontrolled CHF, uncontrolled hypertension, or ventricular dysrhythmias
Patients with previously resected and irradiated CNS metastases with evidence of stable disease are eligible
Patients with a history of prior malignancy are eligible provided they were treated with curative intent and have been disease free for >= 5 years; curatively treated basal cell or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix must have been treated with curative intent; patients with clinically unsuspected organ confined prostate cancer found at the time of cystoprostatectomy are eligible
Creatinine < 1.5 mg/dL
Granulocytes >= 1500/mm^3
Platelets >= 100,000/mm^3
AST =< 2.5 x institutional upper limit of normal
Bilirubin < 1.5 mg/dl
No active unresolved infection requiring parenteral antibiotics < 7 days prior to study entry
Patients must not have a swallowing dysfunction which would prevent the ingesting of pills
Patients must not have any evidence of bleeding diathesis
Patients must not be on therapeutic anticoagulation; prophylactic anticoagulation (i.e. low dose warfarin) of venous or arterial access devices is allowed provided that the requirements for PT, INR or PTT are met
Patients must not be taking the cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, and phenobarbital), rifampin, or St. John's Wort
Women of childbearing potential must not be pregnant (as proven by a negative pregnancy test within 14 days prior to registration) or breast feeding because the effects of this treatment on the fetus and breast-fed infants is unknown
Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (sorafenib tosylate)	sorafenib tosylate	Patients receive oral sorafenib twice daily on days 1-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.
Treatment (sorafenib tosylate)	laboratory biomarker analysis	Patients receive oral sorafenib twice daily on days 1-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Kaplan-Meier Estimate of Progression-free Survival at 4 Months	Assessed every cycle while on treatment; after being off-treatment, assessed every 3 months for 2 years, then every 6 months for 1 year.	Survival estimate from the Kaplan-Meier curve of the proportion of patients alive and progression-free at 4 months. Progression-free survival is defined as the time from registration to progression or death, whichever occurs first. Progression is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s) or unequivocal progression of existing nontarget lesions.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	Assessed every cycle while on treatment; after being off-treatment, assessed every 3 months for 2 years, then every 6 months for 1 year.	Time from registration to the earlier of disease progression or death. Patients alive and progression-free at last follow-up were censored. Progression is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s) or unequivocal progression of existing nontarget lesions.
Overall Survival	Assessed every cycle while on treatment; after being off-treatment, assessed every 3 months for 2 years, then every 6 months for 1 year.	Time from registration to death. Patients alive at last follow-up were censored.
Best Overall Response by RECIST	Assessed every cycle while on treatment; after being off-treatment, assessed every 3 months for 2 years, then every 6 months for 1 year.	This outcome measure reports the best response a patient has ever experienced. \<Target Lesions\> Complete Response (CR): The disappearance of all target lesions, confirmed by assessments \>=4 weeks (wks) later. Partial Response: \>=30% decrease in the sum of the longest diameters of target lesions from baseline, confirmed by assessments \>=4 wks later. Progressive Disease (PD): \>=20% increase in the sum of the longest diameters of target lesions from the smallest sum longest diameter since baseline, or the appearance of new lesions. Stable Disease (SD): Neither response criteria nor progressive disease criteria are met for \>=8 wks. \<Nontarget Lesions\> CR: The disappearance of all nontarget lesions and normalization of tumor marker levels, confirmed by assessments \>=4 wks later. SD: Persistence of nontarget lesions or maintenance of tumor marker levels above the normal limits for \>=8 wks. PD: The appearance of new lesions or unequivocal progression of existing lesions.