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Trial record 1 of 1 for:    a031803
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Testing the Addition of an Anti-cancer Drug, Pembrolizumab, to the Usual Intravesical Chemotherapy Treatment (Gemcitabine) for the Treatment of BCG-Unresponsive Non-muscle Invasive Bladder Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04164082
Recruitment Status : Recruiting
First Posted : November 15, 2019
Last Update Posted : February 19, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well gemcitabine together with pembrolizumab works in treating patients with non-muscle invasive bladder cancer who are unresponsive to the BCG vaccine. Drugs used in chemotherapy, such as gemcitabine, 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. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Adding pembrolizumab to gemcitabine may delay the return of bladder cancer for longer than gemcitabine alone.

Condition or disease Intervention/treatment Phase
Bladder Urothelial Carcinoma In Situ High Risk Non-Muscle Invasive Bladder Urothelial Carcinoma Infiltrating Bladder Mixed Carcinoma Stage 0a Bladder Cancer AJCC v8 Stage 0is Bladder Cancer AJCC v8 Stage I Bladder Cancer AJCC v8 Drug: Gemcitabine Drug: Gemcitabine Hydrochloride Biological: Pembrolizumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Intravesical Gemcitabine and MK-3475 (Pembrolizumab) in the Treatment of Patients With BCG-Unresponsive Non-Muscle Invasive Bladder Cancer
Actual Study Start Date : January 6, 2020
Estimated Primary Completion Date : March 31, 2023
Estimated Study Completion Date : March 31, 2023


Arm Intervention/treatment
Experimental: Treatment (pembrolizumab, gemcitabine hydrochloride)

INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1 and 4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Gemcitabine
Given intravesically
Other Names:
  • dFdC
  • dFdCyd
  • Difluorodeoxycytidine

Drug: Gemcitabine Hydrochloride
Given intravesically
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • FF 10832
  • FF-10832
  • FF10832
  • Gemcitabine HCI
  • Gemzar
  • LY-188011
  • LY188011

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Complete response rate in the carcinoma in situ (CIS) subpopulation [ Time Frame: At 6 months ]
    A complete response, only for patients with a CIS component, is a cystoscopy without evidence of bladder tumor, negative biopsy (including directed biopsies to any suspicious areas and in addition random bladder biopsies including trigone, left lateral wall, right lateral wall, posterior bladder, dome of bladder, and the prostatic urethra in men) and negative cytology for high grade disease at 6 months (end of cycle 8, week 25).

  2. Event-free survival at 18 months [ Time Frame: From the date of study registration to the first documentation of an event or death whichever comes first, assessed up to 18 months ]
    EFS will be measure from the date of study registration to the first documentation of an event or death whichever comes first. For patients without a documented event and who are still alive, they will be censored at last disease assessment. For patients who start any subsequent ant-cancer therapy without any reported events will be censored at their last disease assessment. will be obtained with a Kaplan-Meier estimator (using the Greenwood formula to estimate the variance) for the entire 155 patient group consisting of patients with CIS, CIS with Ta/T1 or Ta or T1 disease. A 90% confidence interval will be generated for the 18-month EFS estimate.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 5 years post treatment ]
    Adverse events will be assessed based on the National Cancer Institute (NCI) common toxicity criteria (Common Terminology Criteria for Adverse Events [CTACAE] version [v] 5.0).

  2. Duration of response (DOR) [ Time Frame: From the time a patient had a documented response that had been confirmed (the time would start at the time a response was first noted) until disease-progression, assessed up to 5 years ]
    Analysis will only include those patients with a confirmed response. Patients who are alive and without a documented progression at the time of analysis will be censored at the time of the last disease status evaluation. The Kaplan-Meier product-limit estimator will be used to estimate DOR, medians and 95% confidence intervals (CI).

  3. Progression-free survival (PFS) [ Time Frame: From the date of study registration to the date of progression or death due to any cause, whichever occurs first, assessed up to 5 years ]
    Surviving patients without any documented progressions will be censored at the date of last known contact. Progression will be defined as the development of muscle invasive bladder cancer or metastatic urothelial cancer (nodal and/or distant). The Kaplan-Meier product-limit estimator will be used to estimate PFS, medians and 95% CI.

  4. Overall survival (OS) [ Time Frame: From the date of study registration to date of death due to any cause, assessed up to 5 years ]
    Surviving patients will be censored at the date of last known contact. The Kaplan-Meier product-limit estimator will be used to estimate OS, medians and 95% CI.

  5. Cystectomy-free survival [ Time Frame: From the date of study registration to the date of cystectomy for all patients ]
    The Kaplan-Meier product-limit estimator will be used to estimate cystectomy-free survival, medians and 95% CI.

  6. Recurrence free survival (RFS) [ Time Frame: From the date of study registration to the first documentation of recurrence or death due to any cause, assessed up to 5 years ]
    Surviving patients without any documented recurrence will be censored at the date of last known contact. Recurrence will be defined as the development of high-grade bladder cancer for patients with a CIS component only and those without a CIS component. The Kaplan-Meier product-limit estimator will be used to estimate RFS, medians and 95% CI.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • High grade Ta, T1 or CIS urothelial carcinoma. Accrual of patients with Ta or T1 disease may be closed to ensure adequate patients enrollment to meet the primary endpoint
  • Persistent disease after completing therapy with at least induction BCG (>= 5 doses) and the first round of maintenance or second induction course (>= 2 doses)

    • Persistent high risk NMIBC (T1, high grade Ta and/or CIS) must be within 9 months of the last BCG instillation despite having received adequate BCG as defined above
  • High grade T1 after completing therapy with at least induction BCG (>= 5 doses) or after completing therapy with at least induction BCG (≥5 doses) and first round of maintenance or second induction course (>= 2 doses)

    • Persistent high risk NMIBC (T1, high grade Ta and/or CIS) must be within 9 months of the last BCG instillation despite having received adequate BCG as defined above
  • Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but pure variant histology is ineligible
  • Patients who are disease free at 6 months after starting BCG but have high grade recurrence (T1, Ta, CIS) while on maintenance therapy would be eligible

    • The recurrence must be within 6 months of the last BCG dose
  • Patients must be deemed unfit for radical cystectomy by the treating physician or refuse radical cystectomy
  • All visible tumor must be completely resected 60 days prior to registration (residual pure CIS is permitted)

    • All patients must have histologically confirmed urothelial cancer of the bladder within 60 days prior to registration.

All patients must have had a cystoscopy without papillary tumor and negative urinary cytology within 21 days of registration. (positive cytology is allowed in patients with pure CIS)

  • All patients with T1 tumors must undergo a re-staging transurethral resection of bladder tumor (TURBT) within 60 days of registration. There must be uninvolved muscularis propria present in the re-staging TURBT. The initial TURBT prior to re-staging TURBT may be greater than 60 days prior to registration
  • Patients must have had imaging with computed tomography (CT) or magnetic resonance imaging (MRI) abdomen/pelvis within 90 days of registration demonstrating no evidence of metastasis.
  • Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects

    • Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelet count >= 100,000/mm^3
  • Hemoglobin >= 9.0 g/dL
  • Creatinine =< 1.5 x upper limit of normal (ULN)

    • In patients with creatinine > 1.5 x ULN, if measured or calculated creatinine clearance > 30 mL/min, then patient is eligible
  • Total Bilirubin =< 1.5 x ULN

    • In patients with a total bilirubin > 1.5 x ULN, if direct bilirubin < 1.0 X ULN, then patient is eligible
  • Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 2.5 x ULN
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN

    • Unless patient is receiving anticoagulant therapy, then PT or partial thromboplastin time (PTT) must be within the therapeutic range of intended use of the anticoagulant(s)
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN

    • Unless patient is receiving anticoagulant therapy, then PT or PTT must be within the therapeutic range of intended use of the anticoagulant(s)
  • Patients with human immunodeficiency virus (HIV) are eligible with the following:

    • On stable regimen of anti-retroviral therapy (highly active anti-retroviral therapy [HAART]).
    • No requirement for antibiotic or antifungal for prevention of opportunistic infections.
    • A CD4 count about 250 cells/mcl and undetectable HIV viral load by PCR
  • Has no known additional malignancy that has had progression or has required active treatment in the last three years. Exceptions include basal or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with definitive intent is allowed, provided that the prostate-specific antigen (PSA) is undetectable for at least 1 year while off androgen deprivation therapy
  • No live vaccines or BCG within 30 days prior to registration
  • Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Include as applicable: Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom).

Exclusion Criteria:

  • Patients cannot have had a history of urothelial carcinoma in the ureters or prostatic urethra 24 months prior to registration
  • Patients must not have received any prior or concurrent systemic chemotherapy or immunotherapy (prior intravesical chemotherapy and interferon is permitted). Single dose chemotherapy post TURBT is permitted
  • Patients must not have received any prior bladder radiation
  • Patients must not have had an active autoimmune disease requiring systemic treatment within 24 months prior to registration. Autoimmune diseases include, but not limited to, lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
  • Patients must not have undergone prior organ or bone marrow transplant
  • Patients must not have active tuberculosis
  • Patients must not have been treated with antibiotics for an active infection within 14 days prior to registration. Prophylactic antibiotics are permitted
  • Patients must not have a history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or active pneumonitis
  • Patients must not have active hepatitis B or C (resolved disease with positive anti-hepatitis B core [HBc] antibody or negative polymerase chain reaction [PCR] for hepatitis C [HCV] RNA permitted)
  • Glucocorticoids for any purpose other than to modulate symptoms from an adverse event of suspected immunologic etiology. Physiologic doses of corticosteroids are allowed
  • Physicians should consider whether any of the following may render the patient inappropriate for this protocol:

    • Psychiatric illness which would prevent the patient from giving informed consent.
    • Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04164082


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Michael E Woods Alliance for Clinical Trials in Oncology

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04164082    
Other Study ID Numbers: NCI-2019-07573
NCI-2019-07573 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A031803 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A031803 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: November 15, 2019    Key Record Dates
Last Update Posted: February 19, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Carcinoma in Situ
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Gemcitabine
Pembrolizumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological