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.