Purpose

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.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

- One focus of muscle-invasive bladder cancer and/or a tumor < 5 cm in size

- No clinical or radiographic evidence for locally advanced or metastatic disease

- No prior anti-PD-1, anti PD-L1 therapies, or systemic chemotherapy (prior intravesical
induction immunotherapy for non-muscle invasive disease is allowed, defined as BCG x 6
treatments; BCG refractory disease, defined as disease recurrence within 3 months of
BCG therapy, is not allowed)

- No prior radiation therapy to the bladder

- No major surgery or radiation therapy =< 4 weeks of registration

- 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

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

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

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

- Alkaline phosphatase =< 2.5 x ULN

- No hydronephrosis refractory to urinary diversion

- 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

- 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

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
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.
  • Drug: Gemcitabine Hydrochloride
    Given IV
  • Drug: Cisplatin
    Given IV
  • Biological: Pegfilgrastim
    Given SC
  • Procedure: Conventional Surgery
    Undergo bladder sparing
Experimental
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.
  • Drug: Gemcitabine Hydrochloride
    Given IV
  • Drug: Cisplatin
    Given IV
  • Biological: Pegfilgrastim
    Given SC
  • Procedure: Radical Cystectomy
    Undergo radical cystectomy
  • Other: Chemoradiotherapy
    Undergo chemoradiotherapy

Recruiting Locations

Central Maryland Radiation Oncology in Howard County
Columbia, Maryland 21044
Contact:
Site Public Contact
443-546-1300

More Details

Status
Recruiting
Sponsor
Alliance for Clinical Trials in Oncology

Study Contact

Gopa Iyer, MD
646-888-4737
iyerg@mskcc.org

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 dose dense gemcitabine hydrochloride (gemcitabine) and cisplatin 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) over time in the bladder-sparing 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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.