Clinical trial NCT00706641: Neoadjuvant Dasatinib and Radical Cystectomy for Transitional Cell Carcinoma of the Bladder
Official title: A Pilot Study of Neoadjuvant Dasatinib Followed by Radical Cystectomy for Transitional Cell Carcinoma of the Bladder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Transitional Cell Carcinoma of the Bladder
Lead sponsor: Hoosier Cancer Research Network
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2008-06-27
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This pilot study is designed to determine feasibility and safety of treatment with dasatinib administered orally once daily for 4 weeks duration prior to radical cystectomy for urothelial carcinoma of the bladder.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Feasibility
timeFrame: From enrollment to completion of radical cystectomy
Secondary outcomes:
measure: Grade 3/4 Toxicities
timeFrame: Time of consent through 30 days after treatment discontinuation
measure: Reduced pSFK Expression
timeFrame: Baseline to post dasatinib therapy
measure: Pathologic Complete Response (pCR) Rate
timeFrame: 24 months
measure: Post-Cystectomy Pathologic Stage
timeFrame: Staged Post-Cystectomy and dasatinib treatment
measure: Reduced Ki-67 Expression
timeFrame: Baseline to post dasatinib therapy
measure: Increase in Cas3 Expression
timeFrame: Baseline to post dasatinib therapy
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University Simon Cancer Center
state: Indiana
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
Study officials:
affiliation: Hoosier Oncology Group, Inc.
name: Noah Hahn, M.D.
role: STUDY_CHAIR
References:
citation: Hahn NM, Knudsen BS, Daneshmand S, Koch MO, Bihrle R, Foster RS, Gardner TA, Cheng L, Liu Z, Breen T, Fleming MT, Lance R, Corless CL, Alva AS, Shen SS, Huang F, Gertych A, Gallick GE, Mallick J, Ryan C, Galsky MD, Lerner SP, Posadas EM, Sonpavde G. Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity. Urol Oncol. 2016 Jan;34(1):4.e11-7. doi: 10.1016/j.urolonc.2015.08.005. Epub 2015 Sep 9.