Clinical Trials /

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

NCT04164082

Description:

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.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-07573
  • SECONDARY ID: NCI-2019-07573
  • SECONDARY ID: A031803
  • SECONDARY ID: A031803
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT04164082

Conditions

  • 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

Interventions

DrugSynonymsArms
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineTreatment (pembrolizumab, gemcitabine hydrochloride)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Treatment (pembrolizumab, gemcitabine hydrochloride)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, gemcitabine hydrochloride)

Purpose

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.

Detailed Description

      CO-PRIMARY OBJECTIVES:

      I. Estimate the 6-month complete response rate of treatment with intravesical gemcitabine
      hydrochloride (gemcitabine) in combination with MK-3475 (pembrolizumab) in patients with
      BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) that have a carcinoma in situ
      (CIS) component.

      II. Estimate the 18 month event-free survival (EFS) rate for all patients with
      BCG-unresponsive NMIBC receiving intravesical gemcitabine in combination with MK-3475
      (pembrolizumab).

      SECONDARY OBJECTIVES:

      I. To characterize the safety profile of the combination of intravesical gemcitabine with
      MK-3475 (pembrolizumab) with BCG-unresponsive NMIBC (CIS or high grade Ta and T1 with or
      without a CIS component).

      II. To estimate progression-free survival (PFS) of patients with BCG-unresponsive NMIBC
      treated with intravesical gemcitabine in combination with MK-3475 (pembrolizumab).

      III. To estimate overall survival (OS) of patients with BCG-unresponsive NMIBC treated with
      intravesical gemcitabine in combination with MK-3475 (pembrolizumab).

      IV. To estimate cystectomy-free survival of patients with BCG-unresponsive NMIBC treated with
      intravesical gemcitabine in combination with MK-3475 (pembrolizumab).

      V. To estimate recurrence-free survival (RFS) for patients with a CIS component only and
      those without a CIS component.

      EXPLORATORY OBJECTIVES:

      I. To assess correlation between tumor mutation burden (TMB) and EFS and 6-month complete
      response (CR) rate.

      II. To assess correlation between specific genomic alterations (single nucleotide variant
      [SNV] and copy number gains/loss) and EFS and 6-month complete response rate.

      III. To assess correlation between APOBEC mutational signature and EFS and 6-month complete
      response rate.

      IV. To assess correlation between immune gene signatures (IGS) and EFS and 6-month complete
      response rate.

      V. To assess correlation between PD-L1 ribonucleic acid (RNA) levels and EFS and 6-month
      complete response rate.

      VI. To assess correlation between RNA molecular subtype and EFS and 6-month complete response
      rate.

      VII. To assess correlation between intratumoral T-cell receptor (TCR) clonality and EFS and
      6-month complete response rate.

      VIII. To assess correlation between changes in peripheral blood TCR clonality and EFS and
      6-month complete response rate.

      IX. To assess EFS in patients with urine cell free deoxyribonucleic acid (DNA) (cfDNA) +
      versus (vs.) patients with cfDNA.

      OUTLINE:

      INDUCTION: Patients receive pembrolizumab intravenously (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.

      After completion of study treatment, patients are followed every 3 months for 2 years and
      then every 6 months for up to 5 years from study registration or until disease progression or
      recurrence. After documentation of disease progression or recurrence, patients are followed
      every 6 months for up to 5 years total from study registration.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, gemcitabine hydrochloride)ExperimentalINDUCTION: 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.
  • Gemcitabine
  • Gemcitabine Hydrochloride
  • Pembrolizumab

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

Primary Outcome Measures

Measure:Complete response rate in the carcinoma in situ (CIS) subpopulation
Time Frame:At 6 months
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 5 years post treatment
Safety Issue:
Description: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).
Measure: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
Safety Issue:
Description: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).
Measure: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
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:From the date of study registration to date of death due to any cause, assessed up to 5 years
Safety Issue:
Description: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.
Measure:Cystectomy-free survival
Time Frame:From the date of study registration to the date of cystectomy for all patients
Safety Issue:
Description:The Kaplan-Meier product-limit estimator will be used to estimate cystectomy-free survival, medians and 95% CI.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

November 18, 2019