Gemcitabine, Carboplatin, and Lenalidomide for Treatment of Advanced/Metastatic Urothelial Cancer and Other Solid Tumors

BACKGROUND:

- Gemcitabine plus carboplatin is an accepted first-line therapy in patients unfit for
cisplatin chemotherapy with metastatic urothelial carcinoma or other solid tumor
malignancies.

- Both non-clinical and clinical data support targeting angiogenesis in urothelial
carcinoma and other solid tumors.

- Both non-clinical and clinical data support targeting the immune system in urothelial
carcinoma and other solid tumors.

- Lenalidomide has both anti-angiogenic and potent immunomodulatory properties.

- Lenalidomide has been safely coadministered with cytotoxic therapy in patients with
solid tumors and non-clinical studies demonstrate possible synergy with gemcitabine.

OBJECTIVES:

Primary

- To establish the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of
lenalidomide which can be safely combined with gemcitabine and carboplatin in patients with
advanced/metastatic UC and other solid tumors that are unfit for cisplatin.

Secondary

- To preliminarily evaluate the progression free survival, response rate and overall
survival in patients with advanced/metastatic UC and other solid tumors treated with the
combination of lenalidomide, gemcitabine, and carboplatin.

- To determine the effects of treatment on a set of 4 laboratory parameters (including
Treg, sIL-2R, VEGF and CTC.) in the expansion cohort of patients with bladder cancer
treated at the MTD.

ELIGIBILITY:

- Adult patients with histologic documentation of an advanced solid tumor with
unresectable or metastatic disease.

- Urothelial cancer patients should be ineligible for cisplatin based on one or more of
the following:

- Calculated creatinine clearance of < 60 mL/min (but greater than or equal to 30 mL/min)

- Solitary kidney

- Karnofsky Performance Status < 80%

- No prior combination systemic chemotherapy for metastatic disease allowed for patients
with UC, except single agent radiosensitizing chemotherapy (not considered prior
systemic therapy), or prior neoadjuvant or adjuvant systemic chemotherapy (including
cisplatin-based) is allowed provided if it was completed (Bullet) 6 months prior to
diagnosis of metastatic disease; or prior intravesical therapy is permitted. Up to 1
line of chemotherapy in the metastatic setting is permitted for non UC patients.

- Laboratory evaluation must meet safety requirements, including a creatinine clearance
greater than 30 using the Cockroft-Gault formula; may not be pregnant or breast-feeding.

DESIGN:

- This is a single-institution phase I study of gemcitabine (1000 mg/m2 on days 1 and 8)
and carboplatin (AUC 5 on day 1) plus escalating doses of lenalidomide (GCL) in patients
with advanced/metastatic UC and other solid tumors ineligible for cisplatin therapy.
Lenalidomide will be administered once daily on days 1 through 14 every 21 days at
escalating dose. An expansion cohort at the MTD of an additional 15 patients with
bladder cancer will be enrolled in order to determine whether there are differences
between pre-treatment and post-treatment levels of the following parameters: Treg, sIL-
2R, VEGF and CTC.

- Patients will receive a total of 6 cycles of gemcitabine and carboplatin in combination
with lenalidomide unless disease progression or unacceptable toxicity occurs. Patients
who achieve stable disease, a partial response, or a complete response after completion
of 6 cycles will be eligible to continue lenalidomide alone at the same dose and
schedule until disease progression. Restaging evaluations will occur after every 3
cycles of treatment (approximately 9 weeks).

- Based on a standard 3+3 design with 4 dose levels per cohort, a maximum of 24 patients,
with the potential for an additional 3 patients with CrCl>60 mL/min, may need to be
evaluated to determine the dose limiting toxicities (DLTs) and maximum tolerated dose
(MTD) of lenalidomide in this combination therapy. With an expansion cohort of 15
patients at MTD, a total of 42 subjects may be enrolled over 1.5 -3 years.

- INCLUSION CRITERIA:

Dose Escalation cohort only

- Adult patients with histologic documentation of an advanced solid tumor for whom
gemcitabine and carboplatin would be appropriate first line therapy, including but not
limited to urothelial cancer, non-small cell lung cancer, pancreatic and ovarian carcinoma.

Expansion cohort only

Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the
bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA
certified lab.

OR

-Patient must have a histologically confirmed diagnosis of non-transitional cell carcinoma
of the bladder, urethra, ureter, or renal pelvis including but not limited to squamous
cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid. Confirmation may be
obtained from any CLIA certified lab.

All patients

- Unresectable or metastatic disease

- Urothelial cancer patients should be ineligible for cisplatin based on one or more of
the following:

- Calculated creatinine clearance of < 60 mL/min (but greater than or equal to 30
mL/min)

- Solitary kidney

- Karnofsky Performance Status < 80%

- Age greater than or equal to 18 years of age; UC is not a common cancer in children
and without proven benefit, this combination of chemotherapy agents presents too great
a risk for conducting as a phase I study in children.

- Karnofsky Performance Status greater than or equal to 60%

- Required Initial Laboratory Values:

- Absolute neutrophil count greater than or equal to 1.2 x 10(9)/L

- Platelets greater than or equal to 100 x 10(9)/L

- Bilirubin less than or equal to 1.5 times the upper limit of normal for the
institution or less than or equal to 3 mg/dl in a subject with Gilbert Syndrome

- Aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 3
times the ULN for the institution (less than or equal to 5 times the ULN is acceptable
if liver has tumor involvement).

- Serum creatinine < 2 or calculated creatinine clearance (CrCl) greater than or equal
to 30 mL/min

- Ability to understand and willingness to sign the written informed consent document.

- Patients must be able to swallow whole capsules. Capsules must not be crushed or
chewed; capsules must not be opened.

EXCLUSION CRITERIA:

- For urothelial cancer patients, no prior combination systemic chemotherapy for
metastatic disease, except:

- Single-agent radiosensitizing chemotherapy is not considered prior systemic therapy

- Prior neoadjuvant or adjuvant systemic chemotherapy (including cisplatin-based) is
allowed provided it was completed greater than or equal to 6 months prior to the
diagnosis of metastatic disease

- Prior intravesical therapy is permitted

- For non-urothelial cancer patients, no more than 1 prior line of combination systemic
chemotherapy for metastatic disease is allowed

- Less than or equal to 2 weeks since radiation therapy

- Unstable angina

- New York Heart Association (NYHA) Grade II or greater congestive heart failure

- History of myocardial infarction within 6 months

- History of stroke within 6 months

- Clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy. Patients that are on anticoagulation
therapy for DVT will be allowed to enroll and continue on the treatment dose of
enoxaparin or other anticoagulation such a warfarin.

- Patients with contraindications to anticoagulation therapy for deep venous thrombosis
such as:

- Patients on full treatment dose of anticoagulation such as those patients being
treated for a deep vein thrombosis or pulmonary embolus.

- Presence of central nervous system or brain metastases

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1

- Anticipation of need for major surgical procedure during the course of the study

Those patients that develop DVTs during the study will be treated with anticoagulants and
in certain cases, will continue on the protocol.

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 25 mIU/mL within 10 14 days and again within 24
hours prior to starting Cycle 1 of lenalidomide. Further, they 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 starting 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. A FCBP is a sexually mature
woman 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). All patients must be
counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal
exposure.

- Inability to comply with study and/or follow-up procedures

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to lenalidomide, gemcitabine or carboplatin, or other agents used in
study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Due to the possibility of infection reactivation, patients who are known seropositive
for or who have active viral infection with human immunodeficiency virus (HIV) are NOT
eligible.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women of all races and ethnic groups are eligible for this trial.