Clinical Trials Dashboard

BRIEF 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

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

Org Study ID: A031701
Secondary ID: NCI-2018-01531,U10CA180821
NCT ID: NCT03609216
NCT Alias:

Sponsor: Alliance for Clinical Trials in Oncology - Other
Source: 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 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.

Overal Status	Start Date	Phase	Study Type
Recruiting	August 1, 2018	Phase 2	Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Proportion of patients who are recurrence-free within the DDR mutated group who undergo the bladder sparing approach

Primary Outcome 1 - Time Frame: At 3 years

Condition:

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

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
Show More

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Gopa Iyer, MD

Role: Study Chair

Affiliation: Memorial Sloan Kettering Cancer Center

Overall Contact