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Trial record 1 of 1 for:    a031701
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Dose Dense Gemcitabine and Cisplatin Without Cystectomy for Patients With Muscle Invasive Bladder Urothelial Cancer and Select Genetic Alterations

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ClinicalTrials.gov Identifier: NCT03609216
Recruitment Status : Recruiting
First Posted : August 1, 2018
Last Update Posted : November 12, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Tracking Information
First Submitted Date  ICMJE July 25, 2018
First Posted Date  ICMJE August 1, 2018
Last Update Posted Date November 12, 2020
Actual Study Start Date  ICMJE August 1, 2018
Estimated Primary Completion Date February 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 25, 2018)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2018)
  • Clinical response rate for patients harboring deleterious DDR gene alterations [ Time Frame: 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.
  • Bladder-intact survival in DDR-altered patients with < cT1 responses who selected the bladder sparing approach [ Time Frame: Time from registration up to 5 years ]
    Will be estimated with Kaplan-Meier estimators and corresponding 95% confidence intervals.
  • Overall survival [ Time Frame: Time from study 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 [ Time Frame: 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.
  • Recurrence-free survival [ Time Frame: 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.
  • The rate of cystectomies in patients with a DDR alteration and with a cT0/CIS/Ta response [ Time Frame: 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.
  • Proportion of patients in the bladder-sparing group who undergo local therapy [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose Dense Gemcitabine and Cisplatin Without Cystectomy for Patients With Muscle Invasive Bladder Urothelial Cancer and Select Genetic Alterations
Official Title  ICMJE A Phase II Study of Dose-Dense Gemcitabine Plus Cisplatin (ddGC) in Patients With Muscle-Invasive Bladder Cancer With Bladder Preservation for Those Patients Whose Tumors Harbor Deleterious DNA Damage Response (DDR) Gene Alterations
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Infiltrating Bladder Urothelial Carcinoma
  • Stage II Bladder Urothelial Carcinoma
  • Stage III Bladder Urothelial Carcinoma
Intervention  ICMJE
  • Drug: Gemcitabine Hydrochloride
    Given IV
  • Drug: Cisplatin
    Given IV
  • Biological: Pegfilgrastim
    Given SC
  • Procedure: Conventional Surgery
    Undergo bladder sparing
  • Procedure: Radical Cystectomy
    Undergo radical cystectomy
  • Other: Chemoradiotherapy
    Undergo chemoradiotherapy
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Gemcitabine Hydrochloride
    • Drug: Cisplatin
    • Biological: Pegfilgrastim
    • Procedure: Conventional Surgery
  • 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.
    Interventions:
    • Drug: Gemcitabine Hydrochloride
    • Drug: Cisplatin
    • Biological: Pegfilgrastim
    • Procedure: Radical Cystectomy
    • Other: Chemoradiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 25, 2018)
271
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2029
Estimated Primary Completion Date February 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Gopa Iyer, MD 646-888-4737 iyerg@mskcc.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03609216
Other Study ID Numbers  ICMJE A031701
NCI-2018-01531 ( Registry Identifier: NCI Clinical Trial Reporting Program )
U10CA180821 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Alliance for Clinical Trials in Oncology
Study Sponsor  ICMJE Alliance for Clinical Trials in Oncology
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: Gopa Iyer, MD Memorial Sloan Kettering Cancer Center
PRS Account Alliance for Clinical Trials in Oncology
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP