Gemzar, Cisp, Sunitinib Urothelial Ca

Phase II Trial of Gemcitabine, Cisplatin, and Sunitinib in Patients With Advanced/Metastatic Urothelial Carcinoma

The primary objective of this nonrandomized Phase II study is to evaluate the objective response rate (ORR, CR+PR) in patients with advanced/metastatic UC treated with the combination of gemcitabine, cisplatin, and sunitinib.

Given the strong preclinical rationale for targeting angiogenesis in urothelial carcinoma (UC), the evidence supporting co-targeting of VEGFR2 and PDGF, the safety and efficacy of single-agent sunitinib in patients with UC, and preclinical evidence of synergy with the combination of sunitinib and cisplatin, the evaluation of sunitinib in combination with gemcitabine plus cisplatin in previously untreated patients with metastatic UC is warranted.

Inclusion Criteria:

1. Has histological documentation of diagnosis of transitional cell carcinoma (TCC) of the bladder, urethra, ureter, or renal pelvis (histology may be mixed, but still requires a component of TCC; measurable disease only)
2. Has unresectable or metastatic disease
3. Has a Karnofsky Performance Status greater than or equal 60 percent
4. Is 18 years of age or older
5. Has laboratory values as defined by the protocol
6. Has resolution of all acute toxic effects of prior chemotherapy or radiotherapy or surgical procedures to NCI CTCAE (v3.0) Grade less than or equal to 1
7. Has normal cardiac function as evidenced by a LVEF greater than or equal to 50 percent, as determined by multiple gated acquisition (MUGA) scan or an echocardiogram (ECHO). The same method must be used throughout the study to evaluate LVEF.
8. Has a negative serum pregnancy test within 7 calendar days prior to registration (female patients of childbearing potential [not surgically sterilized and between menarche and 1 year postmenopausal])
9. Is not currently breastfeeding
10. If fertile, patient (male or female) has agreed to use an acceptable method of birth control to avoid pregnancy for the duration of the study and for a period of 3 months thereafter.
11. Has signed a Patient Informed Consent Form, Has signed a Patient Authorization Form

Exclusion Criteria:

1. Has had prior treatment with systemic chemotherapy (prior intravesical therapy is permitted)
2. Has had major surgery or radiation therapy within 4 weeks of starting the study treatment
3. Has had NCI CTCAE (Version 3.0) Grade 3-4 hemorrhage within 4 weeks of starting the study treatment
4. Has a history of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening CT or MRI scan. However treated, stable and asymptomatic brain metastases are allowed.
5. Has had any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism
6. Has ongoing cardiac dysrhythmias of NCI CTCAE (Version 3.0) Grade 2
7. Has prolonged QTc interval on baseline EKG
8. Has uncontrolled hypertension (grater than 150/100 mm Hg despite optimal medical therapy)
9. Has pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication
10. Has known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection
11. Is receiving concomitant use of any other investigational drugs or has received such drug within 28 days prior to registration
12. Is receiving concurrent treatment on another clinical trial, including supportive care
13. Has ongoing treatment with therapeutic doses of warfarin (low dose warfarin up to 2 mg PO daily for thromboembolic prophylaxis allowed). Patients on warfarin (greater than 2mg) for thrombosis must be switched to low molecular weight heparin (ie, Lovenox), prior to registration for protocol therapy.
14. Is currently taking drugs having proarrhythmic potential (terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide and flecainide) within 7 days prior to Day 1 of Cycle 1 (dosing) (and throughout study)
15. Is currently on CYP3A4 inhibitors (see Section 5) within 7 days prior to Day 1 of Cycle 1 (dosing), with the exception of amiodarone, which should be discontinued within 6 months prior to Day 1 of Cycle 1 (dosing)
16. Is currently on CYP3A4 inducers (see Section 5) within 14 days prior to Day 1 of Cycle 1 (dosing)
17. Has been taking herbal or alternative medications within the past 7 days or refuses to discontinue the use of herbal or alternative therapies within 7 days prior to Day 1 of Cycle 1 (dosing)
18. Has a serious uncontrolled intercurrent medical or psychiatric illness, including serious infection
19. Has a history of other malignancy within the last 5 years (except cured basal cell carcinoma of skin and carcinoma in situ of uterine cervix), which could affect the diagnosis or assessment of any of the study drugs.
20. Is a pregnant or nursing woman. Patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the Study Investigator or Treating Physician. Male patients must be surgically sterile or agree to use effective contraception.

Is unable to comply with requirements of study