Multi-Center Phase Ib/II Trial of Gemcitabine, Cisplatin, Plus Lenalidomide as First-line Therapy for Patients With Metastatic Urothelial Carcinoma

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, one highly
effective method and one additional effective method AT THE SAME TIME, at least 28
days before she starts taking lenalidomide. FCBP must also agree to ongoing
pregnancy testing. Men must agree to use a latex condom during sexual contact with a
FCBP even if they have had a successful vasectomy.

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:

- Males: (140 - Age in years) × Actual Body Weight in kg

72 × Serum Creatinine (mg/dL)

- Females: Estimated creatinine clearance for males × 0.85

- Bilirubin < 1.5 x ULN

- Aspartate aminotransferase (AST, SGOT) < 1.5 X ULN (< 5 X ULN if patient has
hepatic metastases)

FCBP* A female of childbearing potential is a sexually mature female who: 1) has not
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the
preceding 24 consecutive months).

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.

i) NOTE: A subject with prior brain metastasis may be considered if they have
completed their treatment for brain metastasis, no longer require corticosteroids,
and are asymptomatic

6. Has a history of a prior malignancy with the exception of: adequately treated basal
cell or squamous cell skin cancer, in situ cervical cancer, clinically localized
prostate cancer treated with definitive local therapy and without evidence of
recurrent disease without the need for androgen deprivation therapy, or other cancer
for which the subject has been disease-free for at least 5 years.

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). Patients who are
seropositive because of hepatitis B virus vaccine are eligible.