Docetaxel and Lapatinib in Metastatic Transitional Cell Carcinoma in Bladder

PRIMARY OBJECTIVES:

I. To assess the efficacy of 1250 mg of lapatinib (lapatinib ditosylate) given in combination
with docetaxel in prolonging progression-free survival of subjects with metastatic,
previously treated transitional cell carcinoma (TCC) relative to historical controls.

SECONDARY OBJECTIVES:

I. To assess the efficacy of 1250 mg of Lapatinib given in combination with docetaxel in the
objective response rates and overall survival.

II. To study the tolerability and safety of 1250 mg of lapatinib given in combination with
docetaxel by assessing the incidence and nature of Grade 3, 4 and serious adverse events
(AEs).

TERTIARY OBJECTIVES:

I. To assess the expression status of epidermal growth factor receptor (EGFR) or human
epidermal growth factor receptor 2 (HER-2) in tumor tissue and/or circulating tumor cells
(CTCs) as potential predictors of response to therapy.

II. To evaluate the number of CTC's present in 7.5mLs of peripheral blood as a predictor for
disease progression and response of treatment in bladder cancer in the setting of combination
therapy of lapatinib and docetaxel.

III. To evaluate the effect of lapatinib in human at molecular level by targeting the
phosphorylation activity of the AKT/extracellular-regulated kinase (ERK) on pathway prior and
during the treatment with lapatinib.

OUTLINE: Patients receive docetaxel intravenously (IV) over 1 hour on day 1 and lapatinib
ditosylate orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 2
years.

Inclusion Criteria:

- Histologically or cytologically confirmed transitional cell carcinoma of the
urothelium (also called urothelial cancer); mixed histologies are allowed as long as
the predominant histology is TCC; in addition, tumor tissue must be available for
evaluation for EGFR and HER2/neu status

- Locally recurrent or advanced, non-resectable or stage IV transitional cell carcinoma

- Must have had prior platinum salt-based chemotherapy for TCC; other prior systemic
chemotherapeutic or investigational treatment regimens for TCC are allowed; patient
may have had up to three lines of chemotherapy for advanced disease; may have had
paclitaxel provided their cancer did not progress while on it, and it was part of an
adjuvant or neoadjuvant regimen; prior targeted or biological therapy is permitted
except for drugs targeting EGFR and/or HER2; specifically, subjects must meet one or
more of the following criteria: (a). Progression after treatment with a regimen that
includes a platinum salt (e.g. carboplatin or cisplatin) for Stage IV or recurrent
disease OR (b). Disease recurrence within two years (from the date of last dose of
chemotherapy or surgery until day the informed consent is signed) of neoadjuvant or
adjuvant treatment with a regimen that includes a platinum salt

- Measurable or evaluable disease, as defined by Response Evaluation Criteria In Solid
Tumors (RECIST) 1.1; if all sites of measurable or evaluable disease have been
irradiated, one site must have demonstrated growth after irradiation

- A left ventricular ejection fraction (LVEF) within normal range as measured by
echocardiogram or multi-gated acquisition (MUGA) scan

- Adequate contraceptive method for subjects with reproductive potential (females with
reproductive potential must have a negative serum pregnancy test within 7 days of
study entry)

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- A signed written informed consent

- Due to the experimental nature of lapatinib, female subjects must be one year
postmenopausal, surgically sterile, or using an acceptable method of contraception
(oral contraceptives, barrier methods, approved contraceptive implant, long-term
injectable contraception, intrauterine device or tubal ligation); male subjects must
be surgically sterile or using an acceptable method of contraception during their
participation in this study

Exclusion Criteria:

- History of treatment of TCC (in any setting - neoadjuvant, adjuvant or for metastatic
disease) with docetaxel

- History of treatment with an EGFR or HER2 targeted agent

- Serum bilirubin more than 1.5 x the upper limit of normal (ULN) except in patients
with diagnosis of Gilbert's disease

- Creatinine clearance less than 20 mL/minute (calculated by the Cockcroft-Gault
formula)

- Potassium, less than institutional normal level despite supplementation; serum calcium
(ionized or adjusted for albumin,) or magnesium below lower limits of normal despite
supplementation

- Baseline liver function test including AST or ALT greater than 2.5 x institutional
upper limits of normal.

- Absolute neutrophil count (ANC) less than 1500/uL

- Platelets less than 100/uL

- Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the Investigator's opinion makes it undesirable for the subject to participate in
the trial or which would jeopardize compliance with the protocol

- An abnormal left ventricular ejection fraction LVEF as measured by echocardiogram or
MUGA scan or other suitable technique

- Clinically significant cardiac event such as myocardial infarction; New York Heart
Association (NYHA) classification of heart disease more than class 2 within 3 months
before entry; or presence of cardiac disease that, in the opinion of the Investigator,
increases the risk of ventricular arrhythmia

- History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy,
trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is
symptomatic or requires treatment (Common Terminology Criteria for Adverse Events
[CTCAE] grade 3) or asymptomatic sustained ventricular tachycardia; atrial
fibrillation controlled on medication is not exclusion nor are infrequent or unifocal
ectopic beats

- Current QTc prolongation as a result of medication will require discontinuation of
that medication; the patient can be reassessed after discontinuation, provided this is
medically appropriate, after 2 weeks or five half-lives of the drug have passed
whichever is longer

- Congenital long QT syndrome or 1st degree relative with unexplained sudden death under
40 years of age

- Presence of left bundle branch blocks (LBBB)

- QTc with Bazett's correction that is unmeasurable, or exceeds 480 msec on screening
electrocardiogram (ECG); if a subject has QTc > 480 msec on screening ECG, the screen
ECG may be repeated twice (at least 24 hours apart); the average QTc from the three
screening ECGs must be < 480 msec in order for the subject to be eligible for the
study

- Any concomitant medication that may cause QTc prolongation, induce Torsades de Pointes
or induce cytochrome P450 3A4 (CYP3A4) function

- Hypertension not controlled by medical therapy

- Currently active diarrhea

- Women who are currently pregnant or breast feeding

- Receipt of any investigational agent, chemotherapy or radiation therapy within 21 days
prior to Study Day 1

- Any unresolved non-hematologic toxicity greater than CTCAE grade 1 from previous
anti-cancer therapy (other than alopecia)

- Major surgery within 4 weeks or incompletely healed surgical incision before starting
study therapy

- Grade 2 or greater peripheral neuropathy

- Previous or current malignancies within the last 3 years, with the exception of in
situ carcinoma of the cervix, adequately treated carcinoma of the skin, small renal
masses, and adequately treated localized prostate cancer; other cancers that are
highly likely to be cured (cure rate of 75% or greater) may be included at the
discretion of the Principal Investigator

- History of severe hypersensitivity reaction to drugs formulated with polysorbate 80

- Patients with brain metastasis can only be included if they were treated more than 4
weeks prior to enrollment; subjects with treated brain metastases must have a post
treatment brain magnetic resonance imaging (MRI) showing no further progression of
prior lesions AND no new metastatic lesions; subjects will be ineligible if they have
any ongoing symptoms from brain metastases or if there continues to be radiographic
evidence of cerebral edema