Gemcitabine and Cisplatin Without Cystectomy for Patients With Muscle Invasive Bladder Urothelial Cancer and Select Genetic Alterations

Phase 2

Recruiting

• Conditions: Stage III Bladder Urothelial Carcinoma; Stage II Bladder Urothelial Carcinoma; Infiltrating Bladder Urothelial Carcinoma
• Interventions: Drug: Gemcitabine Hydrochloride; Drug: Cisplatin; Biological: Pegfilgrastim; Procedure: Conventional Surgery; Procedure: Radical Cystectomy; Other: Chemoradiotherapy

• Registration Number: NCT03609216
• Lead Sponsor: Alliance for Clinical Trials in Oncology

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.

Study Timeline

• Study First Submitted: 2018-07-25
• Study First Submitted QC: 2018-07-25
• Study First Posted: 2018-08-01
• Study Start: 2018-12-10
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-24
• Last Update Posted: 2025-06-26
• Primary Completion: 2027-02-01
• Study Completion: 2029-02-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 271

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

• No major surgery or radiation therapy =< 4 weeks of registration (TURBT is allowed).

• Not pregnant and not nursing. This study involves an agent that has known genotoxic, mutagenic and teratogenic effects. For women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Absolute neutrophil count (ANC) >= 1,000/mm^3

• Platelet count >= 100,000/mm^3

• Calculated creatinine clearance ≥ 55 mL/min using formula per institutional standard or investigator's discretion. The same formula should be used to calculate all subsequent creatinine clearances.

• Total bilirubin =< 1.5 x upper limit of normal (ULN)

  * (For patients with documented Gilbert's syndrome Total Bilirubin =< 3 x ULN)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN

• Alkaline phosphatase =< 2.5 x ULN

• No evidence of New York Heart Association (NYHA) functional class III or IV heart disease

• No ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade >= 2

• No pre-existing sensory grade >= 2 neuropathy

• No pre-existing grade >= 2 hearing loss

• No serious intercurrent medical or psychiatric illness, including serious active infection

• None of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack

• No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the drugs used in this trial. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy, when indicated

• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to the agents used in this study

• No concurrent treatment on another clinical trial; supportive care trials or non-therapeutic trials (e.g., quality of life) are allowed

• No prior malignancy except for: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years. Patients with localized prostate cancer who are being followed by an active surveillance program are also eligible

• Step 2 Patient Registration Eligibility Criteria

• Patients must have completed 4 or more cycles of protocol-directed chemotherapy and DDR gene results must be available

• Step 3 Patient Registration Eligibility Criteria (only patients with a DDR gene alteration)

• Deleterious alteration within 1 or more of 9 pre-defined DDR genes within the pre-treatment TURBT deoxyribonucleic acid (DNA)

• Cystoscopy and imaging performed to determine stage/treatment assignment

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (gemcitabine, cisplatin, bladder sparing)	Gemcitabine Hydrochloride	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.
Arm I (gemcitabine, cisplatin, bladder sparing)	Conventional Surgery	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.
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)	Gemcitabine Hydrochloride	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.
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)	Pegfilgrastim	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.
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)	Radical Cystectomy	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.
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)	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.
Arm I (gemcitabine, cisplatin, bladder sparing)	Cisplatin	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.
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)	Cisplatin	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.
Arm I (gemcitabine, cisplatin, bladder sparing)	Pegfilgrastim	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.

Primary Outcome Measures

Name	Time	Method
Proportion of patients who are recurrence-free within the DDR mutated group who undergo the bladder sparing approach	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 Outcome Measures

Name	Time	Method
Overall survival	Time from study registration up to 5 years	Will be estimated with Kaplan-Meier estimators and corresponding 95% confidence intervals.
Proportion of patients in the bladder-sparing group who undergo local therapy	Up to 5 years	Will be estimated with a binomial point estimate and 95% binomial confidence interval. The estimate will be determined as the number of patients who undergo local treatment (BCG or resection of non-invasive disease) in the bladder-sparing group divided by the total number of patients in the bladder-sparing group.
Bladder-intact survival in DDR-altered patients with < cT1 responses who selected the bladder sparing approach	Time from registration up to 5 years	Will be estimated with Kaplan-Meier estimators and corresponding 95% confidence intervals.
Pathologic response (pT0) rate at cystectomy in participants without DDR gene alterations	Up to 5 years	This will be the number of patients without DDR gene alterations with pT0 at cystectomy divided by the number of patients without DDR gene alterations who underwent cystectomy following the completion of dose dense gemcitabine and cisplatin treatment. Will be estimated with a binomial point estimate and corresponding 95% binomial confidence intervals.
The rate of cystectomies in patients with a DDR alteration and with a cT0/CIS/Ta response	Within 3 years	Will be computed as the number of patients with a DDR alteration and with a cT0/CIS/Ta response who undergo a cystectomy within 3 years divided by the total number of patients with a DDR alteration and with a cT0/CIS/Ta response. Will be estimated with a binomial point estimate and corresponding 95% binomial confidence intervals.
Recurrence-free survival	Time from study registration up to 5 years	The Kaplan-Meier estimator will be used to estimate the proportion of patients who are recurrence-free success at three years under the two alternative definitions of recurrence-free success above. The point estimate for the three-year recurrence free survival rate will be reported with a 95% confidence interval. These analyses will also be repeated for 5-year recurrence free survival.
Clinical response rate for patients harboring deleterious DDR gene alterations	After 6 courses (84 days)	Will be defined as the number of patients with less than a cT1 response divided by the total number of patients harboring deleterious DDR gene alterations who completed 6 cycles of dose dense gemcitabine and cisplatin.

Trial Locations

Locations (418)

Fairbanks Memorial Hospital; 🇺🇸 Fairbanks, Alaska, United States

CTCA at Western Regional Medical Center; 🇺🇸 Goodyear, Arizona, United States

Cancer Center at Saint Joseph's; 🇺🇸 Phoenix, Arizona, United States

Mercy Hospital Fort Smith; 🇺🇸 Fort Smith, Arkansas, United States

CHI Saint Vincent Cancer Center Hot Springs; 🇺🇸 Hot Springs, Arkansas, United States

University of Arkansas for Medical Sciences; 🇺🇸 Little Rock, Arkansas, United States

Mission Hope Medical Oncology - Arroyo Grande; 🇺🇸 Arroyo Grande, California, United States

Mercy Cancer Center - Carmichael; 🇺🇸 Carmichael, California, United States

Mercy San Juan Medical Center; 🇺🇸 Carmichael, California, United States

Mercy Cancer Center - Elk Grove; 🇺🇸 Elk Grove, California, United States

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