Trial Information

Multi-Center Phase 1B/II Trial of Gemcitabine, Cisplatin, Plus Lenalidomide as First Line Therapy for Patients With Metastatic Urothelial Carcinoma

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.