Trial of Lapatinib and Weekly Paclitaxel for Advanced Urothelial Cancer

Bladder cancer caused 14,680 deaths in 2010 in the US. In advanced bladder cancer, MVAC
(methotrexate, vinblastine, adriamycin and cisplatin) and GC (gemcitabine, cisplatin)
combination chemotherapy demonstrate comparable efficacy with response rates of 45%- 50%.
Despite the reasonable initial response to platinum based chemotherapy, median time to
progression on first line therapy is only 7 months and median survival approximately 15
months. There is no standard second line therapy after platinum based chemotherapy in the US
and no survival benefit has been noted with any agent. Median progression free survival
(PFS) is around 2 months in platinum refractory urothelial cancer (PRUC) and overall
survival (OS) is 6 - 8 months with single agent second line therapy. Combination
chemotherapy does not prolong overall survival. Given the dire prognosis in PRUC and the
lack of efficacy of conventional chemotherapy, preclinical investigations and clinical
research have focused on identification of novel molecular targets.

Lapatnib is approved by the FDA for the treatment of breast cancer. Paclitaxel is approved
by the FDA for the treatment of sarcoma, breast and lung cancers. Lapatinib and paclitaxel
are not approved for advanced urothelial cancer; however, the FDA allows the use of these
drugs in this study for research purposes.

Inclusion Criteria:

- Male and female patients must be at least 18 years of age.

- Diagnosis of urothelial carcinoma that is locally advanced, recurrent or metastatic
is required.

- Patients must have progressed on prior regimens (1-2 allowed) of systemic
chemotherapy for any stage of urothelial carcinoma (including peri-operative
chemotherapy alone in which case they must have progressed within 12 months of
peri-operative chemotherapy), with one of the regimens including a platinum agent.

- Patients must have adequate tumor tissue (primary or metastatic tumor; fresh or
archived) available for EGFR and HER2 expression analysis at baseline as determined
by the study pathologist.

- EGFR and HER2 status by Immunohistochemistry of a potential patient's urothelial
tumor must be determined at baseline before registration or therapy. A potential
patient's eligibility will depend on his/her tumor's EGFR and HER2 category AND the
available open slots in that category at that time.

- Patients must be able to care for themselves and must be up and about more than 50%
of waking hours.

- Patients must have measurable disease.

- Prior chemotherapy or radiation therapy must have been completed prior to
registration (at least 4 weeks prior for chemotherapy and at least 2 weeks prior for
radiation). Patients must have recovered from any reversible side effects and must
not have had more than 25% of the bone marrow irradiated.

- Ability of the heart to pump blood must be adequate for this study. This will be
determined by a screening test.

- Patients must have adequate organ and marrow function as determined by screening
tests.

- All patients must be informed of the investigational nature of this study and must
sign an informed consent document.

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

Exclusion Criteria:

- No prior use of anti-HER2 (including trastuzumab) or anti-EGFR (including erlotinib,
gefitinib, cetuximab) therapy, paclitaxel, nanoparticle bound paclitaxel or docetaxel
for any reason.

- Must not have history of or known spinal cord compression, or carcinomatous
meningitis, or evidence of symptomatic brain or leptomeningeal disease. Patients with
known brain metastases would be excluded from this clinical trial.

- Known HIV positive patients may not participate.

- No malignancy for which systemic therapy, surgery or radiation is ongoing or
anticipated within the next 3 months as assessed by the investigator.

- In situ carcinoma of any site including CIS of the urothelial tract [or]
adequately treated basal cell or squamous cell skin cancer is allowed.

- Patients with history of non-metastatic prostate cancer who have a PSA <2 ng/mL
with or without androgen deprivation therapy are eligible.

- Patients with serious cardiac illness or medical conditions are excluded.

- Patients must not receive treatment on another therapeutic clinical trial. Supportive
care trials and non-interventional trials, e.g. quality of life (QOL) trials are
allowed..

- Herbal medications or supplements are not allowed.

- Female patients must be surgically sterile or be postmenopausal as per the
investigator's discretion, or must agree to use effective contraception during the
period of therapy. All female patients with reproductive potential must have a
negative pregnancy test (serum or urine) prior to registration. Male patients must be
surgically sterile or must agree to use effective contraception during the period of
therapy.

- Must not have malabsorption syndrome, any disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel, or unable to
swallow oral medication.

- No history of allergic reactions to compounds of similar chemical or biologic
composition to lapatinib.

- Use of strong CYP3A4 inhibitors or inducers is prohibited on study.