Gemzar, Cisp, Sunitinib Urothelial Ca

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Urothelial Cancer

Intervention / Treatment
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* Drug: Gemcitabine, Cisplatin, Sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Has unresectable or metastatic disease Has a Karnofsky Performance Status greater than or equal 60 percent Is 18 years of age or older Has laboratory values as defined by the protocol 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 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. 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]) Is not currently breastfeeding 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. Has signed a Patient Informed Consent Form, Has signed a Patient Authorization Form Exclusion Criteria: Has had prior treatment with systemic chemotherapy (prior intravesical therapy is permitted) Has had major surgery or radiation therapy within 4 weeks of starting the study treatment Has had NCI CTCAE (Version 3.0) Grade 3-4 hemorrhage within 4 weeks of starting the study treatment 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. 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 Has ongoing cardiac dysrhythmias of NCI CTCAE (Version 3.0) Grade 2 Has prolonged QTc interval on baseline EKG Has uncontrolled hypertension (grater than 150/100 mm Hg despite optimal medical therapy) Has pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication Has known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection Is receiving concomitant use of any other investigational drugs or has received such drug within 28 days prior to registration Is receiving concurrent treatment on another clinical trial, including supportive care 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. 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) 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) Is currently on CYP3A4 inducers (see Section 5) within 14 days prior to Day 1 of Cycle 1 (dosing) 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) Has a serious uncontrolled intercurrent medical or psychiatric illness, including serious infection 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. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Arm<br>Gemcitabine, Cisplatin, Sunitinib | Drug: Gemcitabine, Cisplatin, Sunitinib<br>* Patients will receive gemcitabine 800 mg/m2 IV (Days 1 and 8), cisplatin 60 mg/m2 IV (Day 1), and sunitinib 37.5 mg PO daily (Days 1-14) of each 21-day cycle. 2. One cycle of treatment is defined as 21 days (3 weeks). Restaging studies will be performed after every 3 cycles of therapy. 3. Successive cycles will be initiated every 3 weeks, and will be continued through 6 cycles unless a patient shows evidence of disease progression or intolerable toxicity.<br>* Other names: Gemzar, Sutent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR, CR+PR) in Patients With Advanced/Metastatic UC Treated With the Combination of Gemcitabine, Cisplatin, and Sunitinib. | Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | PFS is measured from the date of randomization to the date of first documented disease progression or date of death, whichever comes first. If a patient neither progresses nor dies, this patient will be censored at last contact date. Progression (PD) is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. | 2 years | 
| Ovarall Survival (OS) | OS is measured from the date of randomization to the date of death for a dead patient. If a patient is still alive or is lost to follow up, the patient will be censored at the last contact date. | 2 years |