Clinical Trials /

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

NCT03609216

Description:

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.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dose Dense Gemcitabine and Cisplatin Without Cystectomy for Patients With Muscle Invasive Bladder Urothelial Cancer and Select Genetic Alterations
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: A031701
  • SECONDARY ID: NCI-2018-01531
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT03609216

Conditions

  • Infiltrating Bladder Urothelial Carcinoma
  • Stage II Bladder Urothelial Carcinoma
  • Stage III Bladder Urothelial Carcinoma

Interventions

DrugSynonymsArms
Gemcitabine HydrochlorideArm I (gemcitabine, cisplatin, bladder sparing)
CisplatinArm I (gemcitabine, cisplatin, bladder sparing)
PegfilgrastimArm I (gemcitabine, cisplatin, bladder sparing)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (gemcitabine, cisplatin, bladder sparing)ExperimentalParticipants 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.
  • Gemcitabine Hydrochloride
  • Cisplatin
  • Pegfilgrastim
Arm II (gemcitabine, cisplatin, cystectomy, chemoradiotherapy)ExperimentalParticipants 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.
  • Gemcitabine Hydrochloride
  • Cisplatin
  • Pegfilgrastim

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients who are recurrence-free within the DDR mutated group who undergo the bladder sparing approach
Time Frame:At 3 years
Safety Issue:
Description: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

Measure:Clinical response rate for patients harboring deleterious DDR gene alterations
Time Frame:After 6 courses (84 days)
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Will be estimated with Kaplan-Meier estimators and corresponding 95% confidence intervals.
Measure:Overall survival
Time Frame:Time from study registration up to 5 years
Safety Issue:
Description:Will be estimated with Kaplan-Meier estimators and corresponding 95% confidence intervals.
Measure:Pathologic response (pT0) rate at cystectomy in participants without DDR gene alterations
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Recurrence-free survival
Time Frame:Time from study registration up to 5 years
Safety Issue:
Description: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.
Measure:The rate of cystectomies in patients with a DDR alteration and with a cT0/CIS/Ta response
Time Frame:Within 3 years
Safety Issue:
Description: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.
Measure:Proportion of patients in the bladder-sparing group who undergo local therapy
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Alliance for Clinical Trials in Oncology

Last Updated

November 19, 2019