Neoadjuvant Dasatinib and Radical Cystectomy for Transitional Cell Carcinoma of the Bladder

OUTLINE: This is a multi-center study.

This is a pilot study designed to determine the safety and feasibility of treatment with
dasatinib 100 mg administered orally once daily for 4 weeks duration prior to radical
cystectomy for patients with muscle-invasive transitional cell carcinoma of the bladder
ineligible for and/or willing to forgo neoadjuvant cisplatin-based combination chemotherapy.
If surgery delay is imperative, dasatinib therapy should continue until at least 24 hours
before planned surgery.

ECOG Performance Status 0-1

Life Expectancy: Not specified

Hematopoietic:

- Absolute Neutrophil Count (ANC) > 1.5 K/mm3

- Platelets > 100 K/mm3

- INR < 1.2

Hepatic:

- Total bilirubin < 2.0 X Upper Limit of Normal (ULN)

- Aspartate aminotransferase (AST) ≤ 2.5 X ULN.

- Alanine aminotransferase (ALT ) ≤ 2.5 X ULN

Renal:

- Serum creatinine < 2 X ULN

Cardiovascular:

- No uncontrolled angina, congestive heart failure or MI within 6 months prior to
registration on study.

- No diagnosed congenital long QT syndrome (a congenital disorder characterized by a
prolongation of the QT interval on ECG and a propensity to ventricular
tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death).

- No history of clinically significant ventricular arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or Torsades de Pointes).

- No prolonged QTc interval on pre-entry electrocardiogram (> 450 msec), obtained within
28 days prior to being registered on study.

Inclusion Criteria:

- Histological proof of muscle-invasive transitional cell carcinoma of the bladder
(stage II-IVa) with no evidence of metastatic disease (focal squamous and/or
adenocarcinoma differentiation defined as ≤ 10% of tumor volume allowed, sarcomatoid
and small-cell components not allowed). Patient with any degree of fixation of the
pelvic sidewall are not eligible.

- Patients must be willing to undergo a Cystoscopy, prior to registration on study if
tumor block is not available.

- Eligible for radical cystectomy as per the attending urologist.

- All patients must be willing to forego neoadjuvant cisplatin-based combination
chemotherapy and understand it is an option post-surgery or must be deemed ineligible
for cisplatin-based combination chemotherapy by the attending medical oncologist.

- Prior radiation therapy is allowed provided that no radiation therapy was
administered to the urinary bladder.

- Written informed consent and HIPAA authorization for release of personal health
information.

- Age > 18 years at the time of consent.

- Females of childbearing potential and males must be willing to use an effective
method of contraception (hormonal or barrier method of birth control; abstinence)
from the time consent is signed until 4 weeks after treatment discontinuation.

- Females of childbearing potential must have a negative pregnancy test within 7 days
prior to being registered for protocol therapy.

- Females must not be breastfeeding.

- Ability to take oral medication (dasatinib must be swallowed whole).

Exclusion Criteria:

- No prior malignancy is allowed except for adequately treated basal cell or squamous
cell skin cancer, in situ cervical cancer, Gleason < grade 7 prostate cancers, or
other cancer for which the patient has been disease-free for at least 5 years.

- No treatment with any investigational agent within 30 days prior to being registered
for protocol therapy.

- No prior systemic chemotherapy for transitional cell carcinoma of the bladder( prior
intravesical therapy is allowed). Any other prior chemotherapy must have been
completed > 5 years prior to initiation of therapy.

- Following concomitant medications must be discontinued 7 days prior to registration
on study and for the duration of dasatinib therapy: Bisphosphonates - due to risk of
hypocalcemia; Drugs that are generally accepted to have a risk of causing Torsades de
Pointes; any prohibited CYP3A4 inhibitors/inducers/substrates; Anti-coagulation
and/or anti-platelet therapies to avoid potential bleeding risks.

- No clinically significant infections as judged by the treating investigator.

- No pleural or pericardial effusion of any grade.

- history of diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

- No history of diagnosed acquired bleeding disorder (e.g., acquired anti-factor VIII
antibodies) within one year prior to registration on protocol therapy.

- No history of ongoing or recent (within <3 months prior to registration on protocol
therapy) significant gastrointestinal bleeding.

- No known history of hypokalemia that cannot be corrected prior to registration on
protocol therapy.

- No known history of hypomagnesemia that cannot be corrected prior to registration on
protocol therapy.