Transitional Cell Carcinoma of the Bladder
Conditions
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.
Interventions
DRUGDasatinib
Dasatinib 100 mg administered orally once daily for 4 weeks duration (+/- 1 week)
PROCEDURERadical 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.
Sponsors
Bristol-Myers Squibb
Hoosier Cancer Research Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility | From enrollment to completion of radical cystectomy | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reduced pSFK Expression | Baseline to post dasatinib therapy | pSFK levels were analyzed pre and post treatment |
| Pathologic Complete Response (pCR) Rate | 24 months | Pathologic complete response (pCR) rate is defined as no residual evidence of muscle-invasive disease at cystectomy (\< pT0). |
| Grade 3/4 Toxicities | Time of consent through 30 days after treatment discontinuation | Report grade 3/4 toxicities during treatment with dasatinib prior to radical cystectomy in patients with muscle invasive transitional cell carcinoma of the bladder. |
| Reduced Ki-67 Expression | Baseline to post dasatinib therapy | Ki-67 levels were analyzed pre and post treatment |
| Increase in Cas3 Expression | Baseline to post dasatinib therapy | Cas3 levels were analyzed pre and post treatment |
| Post-Cystectomy Pathologic Stage | Staged Post-Cystectomy and dasatinib treatment | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy Dasatinib 100 mg PO qd x 4 weeks followed by radical cystectomy 8-24 hours post last administered dasatinib dose
Dasatinib: Dasatinib 100 mg administered orally once daily for 4 weeks duration (+/- 1 week)
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. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Dasatinib Administration | Ineligible after start of therapy | 1 |
| Dasatinib Administration | Withdrawal by Subject | 1 |
| Radical Cystectomy | Deemed unresectable upon exploration | 1 |
Baseline characteristics
| Characteristic | Experimental: Neoadjuvant Dasatinib + Radical Cystectomy |
|---|---|
| Age, Continuous | 62 years |
| ECOG PS ECOG PS 0 | 19 participants |
| ECOG PS ECOG PS 1 | 6 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 20 Participants |
| T-Stage at Study Entry T2 | 17 participants |
| T-Stage at Study Entry T3 | 7 participants |
| T-Stage at Study Entry T4a | 0 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 24 / 25 |
| serious Total, serious adverse events | 4 / 25 |
Outcome results
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)
Time frame: From enrollment to completion of radical cystectomy
Population: All patients who completed dasatinib
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Feasibility | DLT | 8 participants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Feasibility | Absence of DLT | 15 participants |
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 frame: Time of consent through 30 days after treatment discontinuation
Population: 24 patients received treatment, 1 patient ineligible due to small cell histology after starting dasatinib treatment and was not evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Anemia | 4 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Fatigue | 8 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Diarrhea | 4 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Nausea | 4 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Anorexia | 4 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Abdominal Pain | 4 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Dyspnea | 8 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Hematuria | 4 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Superventricular and Nodal Arrythmia | 4 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Enteric Fistula | 8 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Grade 3/4 Toxicities | Deep Vein Thrombosis \ Pulmonary Embolism | 8 percentage of particpants |
Secondary
Increase in Cas3 Expression
Cas3 levels were analyzed pre and post treatment
Time frame: Baseline to post dasatinib therapy
Population: Sufficient tumor suitable for Immuno-Histochemistry (IHC) analysis was available from 20 patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Increase in Cas3 Expression | 3 participants |
p-value: 0.42paired t-test
Secondary
Pathologic Complete Response (pCR) Rate
Pathologic complete response (pCR) rate is defined as no residual evidence of muscle-invasive disease at cystectomy (\< pT0).
Time frame: 24 months
Population: 23 participants completed treatment and underwent radical cystectomy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Pathologic Complete Response (pCR) Rate | 0 participants |
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
Time frame: Staged Post-Cystectomy and dasatinib treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Post-Cystectomy Pathologic Stage | T4 | 9 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Post-Cystectomy Pathologic Stage | T1\Tis | 23 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Post-Cystectomy Pathologic Stage | T2 | 27 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Post-Cystectomy Pathologic Stage | T3 | 41 percentage of particpants |
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Post-Cystectomy Pathologic Stage | Unresectable | 5 percentage of particpants |
Secondary
Reduced Ki-67 Expression
Ki-67 levels were analyzed pre and post treatment
Time frame: Baseline to post dasatinib therapy
Population: Sufficient tumor suitable for Immuno-Histochemistry (IHC) analysis was available from 20 patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Reduced Ki-67 Expression | 4 participants |
p-value: 0.2paired t-test
Secondary
Reduced pSFK Expression
pSFK levels were analyzed pre and post treatment
Time frame: Baseline to post dasatinib therapy
Population: Sufficient tumor suitable for Immuno-Histochemistry (IHC) analysis was available from 20 patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Neoadjuvant Dasatinib + Radical Cystectomy | Reduced pSFK Expression | 16 participants |
Comparison: Tumor samples from 20 patients were analyzed for expression of pSFK. A paired t-Test was used to calculate the significance of the difference in expression levels before and after treatment.p-value: 0.003paired t-test