Gemcitabine, Cisplatin, Plus Lenalidomide as First-line Therapy for Patients With Metastatic Urothelial Carcinoma

The primary objectives of this study are (Phase 1) to determine in subjects with unresectable or metastatic bladder cancer who have never had chemotherapy, the dose of lenalidomide that is well-tolerated when given in combination with gemcitabine plus cisplatin and (Phase 2) to study this recommended dose in subjects to evaluate progression-free survival at 1 year. The secondary objectives will be to determine the objective response rate to treatment, and the safety of combination therapy with gemcitabine, cisplatin and lenalidomide as well as to evaluate lenalidomide as maintenance treatment in subjects achieving objective response or stable disease.

Urothelial carcinoma of the urinary bladder is the second most common genitourinary malignancy. Based on the results of a large randomized study comparing MVAC with gemcitabine plus cisplatin, the latter regimen became a treatment standard based on improved tolerability. While the tolerability of chemotherapy for patients with advanced urothelial carcinoma has improved, there have been no significant improvements in efficacy since the advent of MVAC in the 1980's and novel approaches are clearly needed.

The current study will explore the safety and activity of lenalidomide in combination with gemcitabine plus cisplatin as first line chemotherapy in subjects with metastatic urothelial carcinoma.

The primary objective of the phase Ib portion will be to determine the recommended phase II dose of the combination of gemcitabine, cisplatin, plus lenalidomide in patients with advanced/metastatic urothelial carcinoma. The primary objective of the phase II portion will be the progression-free survival at 1 year. The secondary objectives are to evaluate the activity (as determined by objective response rate); and to determine the safety (per the Common Terminology for Adverse Events version 4.0) of combination therapy with gemcitabine, cisplatin plus lenalidomide; to evaluate lenalidomide as maintenance treatment in patients achieving an objective response or stable disease following completion of 6 cycles of combination therapy and; to determine the impact of treatment on peripheral blood immune cell subsets and circulating tumor cells.

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 successive cohorts during the phase Ib portion 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 orally on days 1-21 of each 28-day cycle. Treatment will continue, in the absence of prohibitive toxicity, until the time of disease progression.

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
2. Age \> 18 years at the time of consent.
3. Karnofsky Performance Status of ≥ 70%.
4. Histological or cytological proof of transitional cell carcinoma of the urothelial tract. The primary site may include: urethra, bladder, ureters, and renal pelvis. Patients with mixed histologies may be enrolled provided that transitional cell carcinoma is the predominant histology.
5. Measurable disease according to RECIST or unresectable disease (cT4b).
6. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
7. Females of childbearing potential (FCBP)\* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control.
8. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).
9. Adequate organ function as determined by the following laboratory values:

   * Hemoglobin (Hgb) \> 9 g/dL
   * Platelets \> 100 x 1,000,000,000/L
   * Absolute neutrophil count (ANC) \> 1.5 x 1,000,000,000/L
   * Calculated creatinine clearance of \> 60 cc/min using the Cockcroft-Gault formula
   * Bilirubin \< 1.5 x ULN
   * Aspartate aminotransferase (AST, SGOT) \< 1.5 X ULN (\< 5 X ULN if patient has hepatic metastases)

Exclusion Criteria:

1. Has had prior treatment with systemic chemotherapy for metastatic disease (prior intravesical therapy is permitted; prior neoadjuvant/adjuvant chemotherapy permitted if completed ≥ 1 year from study entry)
2. Has received prior lenalidomide.
3. Has had major surgery within 30 days of starting the study treatment
4. 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
5. Has active CNS metastases. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis.
6. Has a history of a prior malignancy
7. Has received anticancer therapy, radiation, or any investigational agent within 30 days prior to being registered for protocol therapy.
8. Pregnant or breastfeeding.
9. Has a clinically significant infection as judged by the treating investigator.
10. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).