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

Transitional Cell Carcinoma of the Bladder Clinical Trial

Official title:

A Pilot Study of Neoadjuvant Dasatinib Followed by Radical Cystectomy for Transitional Cell Carcinoma of the Bladder

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00706641
• Other study ID #: GU07-122
• Status: Completed
• Phase: N/A
• First received: June 25, 2008
• Last updated: December 10, 2015
• Start date: June 2008
• Est. completion date: December 2012

Study information

• Verified date: December 2015
• Source: Hoosier Cancer Research Network
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Transitional Cell
• Transitional Cell Carcinoma of the Bladder
• Urinary Bladder Neoplasms

Intervention

Drug:
• Dasatinib
Dasatinib 100 mg administered orally once daily for 4 weeks duration (+/- 1 week)

Procedure:
• Radical Cystectomy
Radical cystectomy should be performed no sooner than 8 hours but preferably within 24 hours of the last administered Dasatinib dose. All attempts should be made for the patient to have their surgery after 8 hours but within 24 hours of their last dose of dasatinib. If surgery delay is imperative, dasatinib therapy should continue until at least 24 hours before planned surgery.

Locations

Country	Name	City	State
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University Simon Cancer Center	Indianapolis	Indiana
United States	Virginia Oncology Associates	Norfolk	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
Hoosier Cancer Research Network	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility	Feasibility for this trial is defined as at least 60% (>=14 of 23) of patients completing study therapy in the absence of Dose Limiting Toxicity (DLT)	From enrollment to completion of radical cystectomy	Yes
Secondary	Grade 3/4 Toxicities	Report grade 3/4 toxicities during treatment with dasatinib prior to radical cystectomy in patients with muscle invasive transitional cell carcinoma of the bladder.	Time of consent through 30 days after treatment discontinuation	Yes
Secondary	Reduced pSFK Expression	pSFK levels were analyzed pre and post treatment	Baseline to post dasatinib therapy	No
Secondary	Pathologic Complete Response (pCR) Rate	Pathologic complete response (pCR) rate is defined as no residual evidence of muscle-invasive disease at cystectomy (< pT0).	24 months	No
Secondary	Post-Cystectomy Pathologic Stage	Tumor Node Metastasis (TNM) Staging. This system classifies tumors by size and extent of the primary tumor (T), involvement of regional lymph nodes (N), and the presence or absence of distant metastases (M) T0=No evidence of primary tumor, Tis=Carcinoma in situ, and T1, T2, T3, T4=Increasing size and/or local extension of the primary tumor, TX=Not assessed N0=No Regional lymph node metastases, N1, N2, N3=Increasing number or extent of regional lymph node involvement, NX=not assessed M0=No distant metastases, M1=Distant metastases present	Staged Post-Cystectomy and dasatinib treatment	No
Secondary	Reduced Ki-67 Expression	Ki-67 levels were analyzed pre and post treatment	Baseline to post dasatinib therapy	No
Secondary	Increase in Cas3 Expression	Cas3 levels were analyzed pre and post treatment	Baseline to post dasatinib therapy	No

External Links

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