A Phase II Study of Gemcitabine Plus Cisplatin Chemotherapy in Patients With Muscle-invasive Bladder Cancer With Bladder Preservation for Those Patients Whose Tumors Harbor Deleterious DNA Damage Response (DDR) Gene Alterations
Overview
- Phase
- Phase 2
- Intervention
- Cisplatin
- Conditions
- Infiltrating Bladder Urothelial Carcinoma
- Sponsor
- Alliance for Clinical Trials in Oncology
- Enrollment
- 237
- Locations
- 1197
- Primary Endpoint
- Proportion of patients who are recurrence-free within the DDR mutated group who undergo the bladder sparing approach
- Status
- Active, Not Recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
This phase II trial studies how well gemcitabine hydrochloride and cisplatin work in treating participants with invasive bladder urothelial cancer. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the 3-year event free survival, defined as the proportion of patients without invasive or metastatic recurrence following definitive gemcitabine hydrochloride (gemcitabine) and cisplatin (standard or dose-dense) chemotherapy in those patients whose pre-treatment transurethral resection of bladder tumor (TURBT) tumors harbor deleterious DDR gene alterations and who achieve \< cT1 response to chemotherapy. SECONDARY OBJECTIVES: I. To determine the clinical response rate (\< cT1) for patients harboring deleterious DDR gene alterations following dose dense gemcitabine and cisplatin. II. To determine the bladder-intact and overall survival for DDR-altered patients with \< cT1. III. For DDR gene altered patients who elect radical cystectomy despite \< cT1, to determine the pT0 rate in this patient population. IV. To determine the pathologic response rate at cystectomy and 3-year recurrence-free and overall survival for patients without DDR mutations who are registered onto this trial. V. To assess the local treatment burden (Bacillus Calmette-Guerin \[BCG\] therapy, resection of non-invasive disease, checkpoint blockade) over time in the bladder-sparing group. VI. To determine the bladder-intact disease-free survival in patients who elect to undergo chemoradiation therapy in the DDR mutant group and the DDR wild-type group. OUTLINE: Participants receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim subcutaneously (SC) on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants are then assigned to 1 of 2 arms. ARM I: Participants with DDR gene alteration and disease stage \< cT1 undergo bladder sparing. ARM II: Participants with DDR gene alteration and disease stage \>= cT1 or participants without DDR gene alteration undergo radical cystectomy or chemoradiotherapy. After completion of study treatment, participants are followed up for 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Step 1 Patient Registration Eligibility Criteria
- •Histologically confirmed muscle-invasive urothelial carcinoma of the bladder. Urothelial carcinoma invading into the prostatic stroma with no histologic muscle invasion is allowed, provided the extent of disease is confirmed via imaging and/or examination under anesthesia (EUA). The diagnostic TURBT sample must have been obtained within 60 days prior to registration
- •20 unstained slides (10 micron thickness) of formalin-fixed paraffin-embedded (FFPE) pre-treatment diagnostic transurethral resection (TUR) specimen available (for sequencing), with 2 (5 micron) slides at the start and end of the 20 slides, for a total of 22 unstained slides. An FFPE block is also acceptable
- •Clinical stage T2-T4aN0/xM0 disease
- •Medically appropriate candidate for radical cystectomy as assessed by surgeon
- •No concomitant multifocal carcinoma in situ; a single focus is allowed
- •A single muscle-invasive bladder tumor measuring ≤5 cm in size as defined by the surgeons at cystoscopic evaluation. When documented, pathologic size at cystoscopy and TURBT will take precedence over radiographic measurements of tumor size.
- •No clinical or radiographic evidence for locally advanced or metastatic disease
- •No prior anti-PD-1 or anti PD-L1 therapies, or systemic chemotherapy within the past 5 years (prior intravesical induction immunotherapy for non-muscle invasive disease is allowed, defined as BCG x6 doses and maintenance therapy); BCG refractory disease, defined as disease recurrence within 3 months of BCG therapy, is not allowed. Intravesical chemotherapy is allowed.
- •No prior radiation therapy to the bladder or prostate
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I (gemcitabine, cisplatin, bladder sparing)
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage \< cT1 undergo bladder sparing.
Intervention: Cisplatin
Arm I (gemcitabine, cisplatin, bladder sparing)
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage \< cT1 undergo bladder sparing.
Intervention: Pegfilgrastim
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage \>= cT1 or participants without DDR gene alteration undergo radical cystectomy or chemoradiotherapy.
Intervention: Cisplatin
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage \>= cT1 or participants without DDR gene alteration undergo radical cystectomy or chemoradiotherapy.
Intervention: Pegfilgrastim
Arm I (gemcitabine, cisplatin, bladder sparing)
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage \< cT1 undergo bladder sparing.
Intervention: Conventional Surgery
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage \>= cT1 or participants without DDR gene alteration undergo radical cystectomy or chemoradiotherapy.
Intervention: Radical Cystectomy
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage \>= cT1 or participants without DDR gene alteration undergo radical cystectomy or chemoradiotherapy.
Intervention: Chemoradiotherapy
Arm I (gemcitabine, cisplatin, bladder sparing)
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage \< cT1 undergo bladder sparing.
Intervention: Gemcitabine Hydrochloride
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)
Participants receive gemcitabine hydrochloride IV over 30 minutes on day 1, cisplatin IV on days 1 and 2, and pegfilgrastim SC on day 3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unaccepted toxicity. Participants with DDR gene alteration and disease stage \>= cT1 or participants without DDR gene alteration undergo radical cystectomy or chemoradiotherapy.
Intervention: Gemcitabine Hydrochloride
Outcomes
Primary Outcomes
Proportion of patients who are recurrence-free within the DDR mutated group who undergo the bladder sparing approach
Time Frame: At 3 years
Will use Kaplan Meier survival analysis to estimate the proportion of patients who are recurrence-free at three years. Will use a one-sided 90% confidence interval.
Secondary Outcomes
- Overall survival(Time from study registration up to 5 years)
- Proportion of patients in the bladder-sparing group who undergo local therapy(Up to 5 years)
- Bladder-intact survival in DDR-altered patients with < cT1 responses who selected the bladder sparing approach(Time from registration up to 5 years)
- Pathologic response (pT0) rate at cystectomy in participants without DDR gene alterations(Up to 5 years)
- The rate of cystectomies in patients with a DDR alteration and with a cT0/CIS/Ta response(Within 3 years)
- Recurrence-free survival(Time from study registration up to 5 years)
- Clinical response rate for patients harboring deleterious DDR gene alterations(After 6 courses (84 days))