Gemcitabine, Cisplatin, and Lenalidomide for Bladder Cancer

• Determine optimal dose of gemcitabine, cisplatin, and lenalidomide. [ Time Frame: 2-3 years ] [ Designated as safety issue: Yes ]
  
• Determine the 1 year progression-free survival on combination. [ Time Frame: 2-3 years ] [ Designated as safety issue: Yes ]
  

• Objective response rate by RECIST of gem, cis, lenalidomide combination; safety of combination per CTCAE; evaluate lenalidomide as maintenance treatment; treatment impact on peripheral immune cell subsets and circulating tumos cells. [ Time Frame: 2-3 years ] [ Designated as safety issue: Yes ]
  
• Safety of combination per CTCAE. [ Time Frame: 2-3 years ] [ Designated as safety issue: Yes ]
  
• Evaluate lenalidomide as maintenance treatment. [ Time Frame: 2-3 years ] [ Designated as safety issue: Yes ]
  
• Treatment impact on peripheral immune cell subsets and circulating tumos cells. [ Time Frame: 2-3 years ] [ Designated as safety issue: Yes ]
  

Drug: Lenalidomide
N/A
Drug: Cisplatin
N/A
Drug: Gemcitabine
N/A

Background

• Urothelial carcinoma of the urinary bladder is the second most common genitourinary malignancy. Each year in the United States, more than 60,000 patients will develop urothelial carcinoma and over 12,000 will die of their disease.
• Gemcitabine plus cisplatin is standard first-line therapy in patients with metastatic urothelial carcinoma. While treatment of this patient population has been made more tolerable over the past 20 years, there have been no improvements in efficacy.
• Lenalidomide has both anti-angiogenic and potent immunomodulatory properties, and has been safely coadministered with cytotoxic therapy in patients with solid tumors and non-clinical studies demonstrate possible synergy with gemcitabine.

Objectives

• To determine the recommended phase II dose of gemcitabine, cisplatin, and lenalidomide.
• To determine the 1 year progression-free survival in patients with advanced/metastatic urothelial carcinoma treated with gemcitabine, cisplatin, plus lenalidomide.

Eligibility

• Patients greater than or equal to 18 years of age with histological or cytological confirmation of transitional cell carcinoma of the urothelial tract (urethra, bladder, ureters, or renal pelvis), who have measurable disease or unresectable disease (cT4b).
• Must be registered with the mandatory RevAssist(Registered Trademark) program, and be willing and able to comply with the requirements of RevAssist(Registered Trademark).
• Safety laboratory values and performance status must meet specified limits. Females of childbearing potential must have a negative serum or urine pregnancy test. Males and females must be will to use effective birth control measures (when applicable).
• Must be able to take aspirin.
• May not have had prior treatment with systemic chemotherapy for metastatic disease, prior lenalidomide, or surgery (within 30 days of starting study treatment).
• HIPAA authorization for the release of personal health information is not required for subjects participating at NCI

Design

Phase Ib

-Patients will receive gemcitabine 1000 mg/m2 IV on days 1 + 8 and cisplatin 70 mg/m2 IV on day 1 of each 21 day cycle. Lenalidomide will be given orally on days 1-14 and the dose will be escalated in four successive cohorts (10 mg, 15 mg, 20 mg, 25 mg) to define the recommended phase II dose. Patients will continue gemcitabine, cisplatin, plus lenalidomide for up to 6 cycles, in the absence of disease progression or prohibitive toxicity. After completion of 6 cycles of therapy, patients who have achieved at least stable disease will proceed with maintenance lenalidomide given at patient's phase 1b dose level orally on days 1-21 of each 28-day cycle.

Phase II

• During cycle 1 only of the phase II portion, subjects will have a lead-in period where lenalidomide will be administered orally as a single-agent at 10 mg once per day, the dose defined from the phase Ib portion of the study, for 14 consecutive days followed by 7 days of rest(for a total lead-in period of 21 days) prior to starting combination treatment.
• Patients will receive gemcitabine 1000 mg/m2 IV on days 1 + 8 and cisplatin 70 mg/m(2) IV on day 1 of each 21 day cycle starting with cycle 2. Lenalidomide will be given orally on days 1-14 at 10 mg once per day, the dose defined from the phase Ib portion of the study. Patients will continue gemcitabine, cisplatin, plus lenalidomide for up to 6 cycles, in the absence of disease progression or prohibitive toxicity. After completion of 6 cycles of therapy, patients who have achieved at least stable disease will proceed with maintenance lenalidomide given orally at 10 mg once per day on days 1-21 of each 28-day cycle.
• A CT scan of the chest, abdomen, and pelvis will be performed after every 2 cycles (or sooner if there is evidence of disease progression) while on combination therapy until disease progression. At the NCI site, subjects enrolled in phase Ib will be assessed after cycles 2, 4 and 6 while those enrolled in phase II, which features the cycle 1 lead in , will be assessed after cycles 3, 5, and 7. During the maintenance phase CT scans will be performed after every 3 cycles.
• The phase II portion will be conducted using a single-stage, single-arm, design. The primary endpoint will be Progression Free Survival (PFS) at one year. Data indicate that patients treated with gemcitabine and cisplatin experience 28% PFS at 1-year. The goal is to see if the addition of lenalidomide will increase PFS by an absolute amount of 20%, i.e., from 28% to 48%.
• Approximately 12-15 patients will be enrolled in the phase 1b portion and approximately 43 patients will be enrolled in the phase II portion for a total of 67 patients. Enrollment will proceed for approximately 36 months. 15 - 20 patients will be enrolled at the NCI, NIH.