Clinical Trials /

Pembrolizumab and BCG Solution in Treating Patients With Recurrent Non-Muscle-Invasive Bladder Cancer

NCT02808143

Description:

The purpose of this study is to evaluate the efficacy (the effect of drug on tumor) and the tolerability (the effect of drug on the body) of pembrolizumab, when given as a single agent in patients with bladder tumors. Another purpose of the study is to see what tumor characteristics are associated with increased efficacy of the pembrolizumab. Pembrolizumab (MK-3475) is an antibody (a human protein that sticks to a part of the tumor and/or immune cells) designed to allow the body's immune system to work against tumor cells. Pembrolizumab is Food and drug Administration (FDA) approved for the treatment of advanced melanoma (a type of skin cancer) and some types of lung cancer. It is not yet approved by the United States Food and Drug Administration (USFDA) for bladder cancer, hence it is considered an investigational agent for this disease.

Related Conditions:
  • Bladder Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and BCG Solution in Treating Patients With Recurrent Non-Muscle-Invasive Bladder Cancer
  • Official Title: A Phase 1 Dose-Escalation Study of Intravesical MK-3475 and Bacillus Calmette-Guerin (BCG) in Subjects With High Risk and BCG-Refractory Non-Muscle-Invasive Bladder Cancer

Clinical Trial IDs

  • ORG STUDY ID: NU 15U06
  • SECONDARY ID: STU00202754
  • SECONDARY ID: NU 15U06
  • SECONDARY ID: P30CA060553
  • SECONDARY ID: NCI-2016-00664
  • NCT ID: NCT02808143

Conditions

  • Recurrent Bladder Carcinoma
  • Stage 0a Bladder Urothelial Carcinoma
  • Stage 0is Bladder Urothelial Carcinoma
  • Stage I Bladder Cancer

Interventions

DrugSynonymsArms
BCG SolutionBacillus Calmette-Guerin Solution, TICE BCG SolutionTreatment (pembrolizumab, BCG solution)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, BCG solution)

Purpose

The purpose of this study is to evaluate the efficacy (the effect of drug on tumor) and the tolerability (the effect of drug on the body) of pembrolizumab, when given as a single agent in patients with bladder tumors. Another purpose of the study is to see what tumor characteristics are associated with increased efficacy of the pembrolizumab. Pembrolizumab (MK-3475) is an antibody (a human protein that sticks to a part of the tumor and/or immune cells) designed to allow the body's immune system to work against tumor cells. Pembrolizumab is Food and drug Administration (FDA) approved for the treatment of advanced melanoma (a type of skin cancer) and some types of lung cancer. It is not yet approved by the United States Food and Drug Administration (USFDA) for bladder cancer, hence it is considered an investigational agent for this disease.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) of the study drug (pembrolizumab [MK-3475])
      when administered intravesically in combination with BCG in patients with high risk or
      BCG-refractory non-muscle-invasive bladder cancer (up to the individual maximum tolerated
      dose of each drug alone).

      SECONDARY OBJECTIVES:

      I. To describe the dose limiting toxicities (DLTs) of MK-3475 in combination with BCG in this
      population.

      II. To assess the safety and tolerability of the combination of MK-3475 and BCG in subjects
      with high risk or BCG-refractory non-muscle-invasive bladder cancer.

      TERTIARY OBJECTIVES:

      I. To characterize the pharmacokinetics (PK) of MK-3475 in both blood and urine when
      administered intravesically in combination with BCG.

      II. To measure humoral and cellular responses to tumor antigens on serum and urine samples by
      measuring the levels of cytokines (ie, interleukin [IL]-2, IL-6, IL-8, IL-10, IL-18,
      interferon gamma [IFN-gamma] and tumor necrosis factor alpha [TNF-alpha]) and peripheral
      blood lymphocyte phenotype throughout treatment.

      III. To determine the response rate in terms of complete pathologic response in this
      population assessed when patient undergoes cystoscopies (weeks 17, 25, 33, 41, and 49 if
      applicable).

      IV. To document the progression rate associated with the combination of intravesical MK-3475
      and BCG in patients with high risk or BCG-refractory non-muscle-invasive bladder cancer.

      V. To evaluate the relationship between tumor biomarkers programmed cell death (PD)-ligand
      (L)1, PD-L2, PD-1 as defined by immunohistochemistry (IHC) and adverse effects and recurrence
      rate.

      OUTLINE: This is a dose-escalation study of pembrolizumab.

      PRE-INDUCTION PHASE: Patients receive pembrolizumab intravesically once on day -14.

      INDUCTION PHASE: Patients receive BCG solution intravesically once weekly for 6 weeks at
      weeks 0-5 and pembrolizumab intravesically every 2 weeks at weeks 0, 2, and 4.

      MAINTENANCE PHASE: Beginning 2 weeks after the last dose of BCG solution, patients receive
      pembrolizumab intravesically every 2 weeks for 12 weeks at weeks 7, 9, 11, 13, 15, and 17 for
      a total of 6 doses. Patients then receive pembrolizumab intravesically every 4 weeks at weeks
      21, 25, 29, 33, 37, 41, 45, and 49 for a total of 8 doses.

      After completion of study treatment, patients are followed up every 3 months for 2 years,
      every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, BCG solution)ExperimentalPRE-INDUCTION PHASE: Patients receive pembrolizumab intravesically once on day -14. INDUCTION PHASE: Patients receive BCG solution intravesically once weekly for 6 weeks at weeks 0-5 and pembrolizumab intravesically every 2 weeks at weeks 0, 2, and 4. MAINTENANCE PHASE: Beginning 2 weeks after the last dose of BCG solution, patients receive pembrolizumab intravesically every 2 weeks for 12 weeks at weeks 7, 9, 11, 13, 15, and 17 for a total of 6 doses. Patients then receive pembrolizumab intravesically every 4 weeks at weeks 21, 25, 29, 33, 37, 41, 45, and 49 for a total of 8 doses.
  • BCG Solution
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a histologically documented recurrence of non-muscle-invasive
             bladder carcinoma (T1HG, T1HG after repeat transurethral resection [reTUR]) or BCG
             refractory; if patient has received BCG they can be Ta, Tis, or T1)

          -  Patients must have persistent high grade disease OR be BCG refractory, defined as
             either:

               -  Recurrence within 6 months of receiving at least 2 courses of intravesical BCG
                  (at least 5 or 6 inductions and at least 2 or 3 maintenance doses) or

               -  T1 high grade disease at the first evaluation following induction BCG alone (at
                  least 5 of 6 induction doses)

          -  Patients must agree to provide tissue from archival biopsy samples or newly obtained
             excisional biopsy of a tumor lesion

               -  NOTE: Patients who do not have available specimens from previous biopsy or do not
                  agree to provide this tissue are not eligible; cytological specimens will not be
                  acceptable; availability of tissue must be confirmed at the time of registration,
                  but the actual sample does not have to be received in order to complete
                  registration

          -  Patients must have received one course of induction treatment with BCG (4-6 weekly
             doses), irrespective of the interval since last treatment; patients are allowed to
             have received any number of prior chemotherapy instillations

               -  NOTE: Patients may have received prior intravesical interferon

          -  All patients must have imaging (computed tomography [CT] scan or magnetic resonance
             imaging [MRI]) documenting normal upper urinary tracts and absence of locally advanced
             bladder cancer within 60 days prior to study registration

          -  Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL within 14 days prior to registration

          -  Platelets >= 100,000 / mcL within 14 days prior to registration

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L within 14 days prior to registration

          -  Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
             (creatinine clearance should be calculated per institutional standard) creatinine
             clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or
             creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X
             institutional ULN within 14 days prior to registration

          -  Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN within 14 days prior to registration

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
             ULN within 14 days prior to registration

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants within 14
             days prior to registration

          -  Activated PTT (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as
             long as PT or PTT is within therapeutic range of intended use of anticoagulants within
             14 days prior to registration

          -  Females of child-bearing potential (FOCBP) and males must agree to use adequate
             contraception (e.g. hormonal or barrier method of birth control; abstinence) prior to
             study entry, for the duration of study participation, and for 120 days following
             completion of therapy; should a female patient become pregnant or suspect she is
             pregnant while participating in this study, she should inform her treating physician
             immediately;

               -  NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a
                  tubal ligation, or remaining celibate by choice) who meets the following criteria

               -  Has not undergone a hysterectomy or bilateral oophorectomy

               -  Has had menses at any time in the preceding 12 consecutive months (and therefore
                  has not been naturally postmenopausal for > 12 months)

          -  FOCBP must have a negative urine or serum pregnancy test within 7 days prior to
             receiving the first dose of study medication; if the urine test is positive or cannot
             be confirmed as negative, a serum pregnancy test will be required

          -  Patients must have the ability to understand and the willingness to sign a written
             informed consent prior to registration on study

        Exclusion Criteria:

          -  Patients who have had chemotherapy, targeted small molecule therapy, or radiation
             therapy within 2 weeks prior to study day -14 or who have not recovered (to =< grade 1
             or baseline) from adverse events due to a previously administered agent are not
             eligible

               -  Note: subjects with =< grade 2 neuropathy are an exception to this criterion and
                  do qualify for the study

               -  Note: if subject received major surgery within 4 weeks prior to day -14, they
                  must have recovered adequately from the toxicity and/or complications per PI
                  discretion

          -  Patients may not be receiving any other investigational agents within 4 weeks of the
             first dose of treatment

          -  Patients who have received a prior monoclonal antibody within 4 weeks prior to study
             day -14 or who have not recovered (to =< grade 1 or baseline) from adverse events due
             to agents administered more than 4 weeks earlier are not eligible

          -  Patients who have a diagnosis of immunodeficiency (per PI discretion) or who have
             received treatment with systemic immunosuppressive medications (including but not
             limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-TNF agents within 2 weeks prior to study registration are not eligible

               -  NOTE: patients who have received acute, low-dose, systemic immunosuppressant
                  medications (eg, one-time dose of dexamethasone for nausea) may be enrolled in
                  the study; the use of inhaled corticosteroids and mineralocorticoids (eg,
                  fludrocortisone) is allowed

          -  Patients who have a history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to MK-3475 are not eligible AND/OR patients who have
             had prior exposure to compounds of similar chemical or biologic composition to MK-3475
             are not eligible

          -  Patients who have documentation of an uncontrolled intercurrent illness (as noted in
             their medical records) including, but not limited to any of the following, are not
             eligible

               -  Ongoing or active infection requiring systemic treatment

               -  Symptomatic congestive heart failure (New York Heart Association cardiac disease
                  class III or IV)

               -  Unstable angina pectoris

               -  Myocardial infarction within the previous 3 months

               -  Unstable cardiac arrhythmias

               -  Psychiatric illness/social situations that would limit compliance with study
                  requirements

               -  Any other illness or condition that the treating investigator feels would
                  interfere with study compliance or would compromise the patient's safety or study
                  endpoints

          -  Female patients who are pregnant or nursing are not eligible

          -  Patients who have a history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to BCG are not eligible

          -  Patients who have had an active infection requiring systemic therapy within 1 week
             prior to day -14 are not eligible UNLESS they are symptom-free and have a negative
             culture at the time of dosing on day -14

          -  Patients who received a live, attenuated vaccine within 4 weeks before study
             registration or are anticipated to require such a live attenuated vaccine are not
             eligible; NOTE: Influenza vaccination should be given during influenza season only
             (approximately October to March); patients must not receive live, attenuated influenza
             vaccine (e.g., FluMist) within 4 weeks prior to study registration or at any time
             during the study

          -  Patients who are known to be (i.e. documented in medical records) human
             immunodeficiency virus (HIV) positive are not eligible

          -  Patients with active tuberculosis are not eligible

          -  Patients with known active hepatitis B (chronic or acute; defined as having a positive
             hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C are not eligible

               -  NOTE: patients with past hepatitis B virus (HBV) infection or resolved HBV
                  infection (defined as the presence of hepatitis B core antibody [HBc Ab] and
                  absence of HBsAg) are eligible; HBV deoxyribonucleic acid (DNA) must be obtained
                  in these patients 14 days prior to study registration

               -  NOTE: patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction is negative for HCV ribonucleic acid (RNA)

          -  Patients who have a history of severe allergic, anaphylactic, or other
             hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins are
             not eligible

          -  Patients with an active autoimmune disease requiring systemic treatment within the
             past 2 years (i.e. with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs); replacement therapy (eg. thyroxine, insulin, or physiologic
             corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
             not considered a form of systemic treatment

          -  Patients with a documented history of clinically severe autoimmune disease, or a
             syndrome that requires systemic steroids or immunosuppressive agents; subjects with
             vitiligo or resolved childhood asthma/atopy would be an exception to this rule;
             subjects that require intermittent use of bronchodilators or local steroid injections
             would not be excluded from the study; subjects with hypothyroidism stable on hormone
             replacement or Sjogren's syndrome will not be excluded from the study

          -  Patients with history of interstitial lung disease or active, non-infectious
             pneumonitis are not eligible

               -  NOTE: history of radiation pneumonitis in the radiation field (fibrosis) is
                  permitted

          -  Treatment with systemic immunostimulatory agents (including but not limited to IFNs,
             IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to
             study registration are not eligible

          -  Patients who received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2,
             anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody
             (including ipilimumab or any other antibody or drug specifically targeting T-cell
             co-stimulation or checkpoint pathways) are not eligible

          -  Patients who have a history of prior malignancy are not eligible; please NOTE the
             following exceptions when patient has undergone potentially curative therapy with no
             evidence of that disease recurrence for 5 years since initiation of that therapy

               -  Basal cell carcinoma of the skin

               -  Squamous cell carcinoma of the skin

               -  In situ cervical cancer

          -  Patients who have a history of an allogeneic tissue/solid organ transplant are not
             eligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:Up to 9 weeks
Safety Issue:
Description:Determine the MTD of the study drug (MK-3475) when administered intravesically in combination with BCG in patients with high risk or BCG-refractory non-muscle-invasive bladder cancer (up to the individual maximum tolerated dose of each drug alone). The MTD will be defined as the highest dose that causes dose limiting toxicities (DLTs) in <2 of 6 patients graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Secondary Outcome Measures

Measure:Dose Limiting Toxicities (DLTs)
Time Frame:Up to 9 weeks
Safety Issue:
Description:Evaluate the DLTs of MK-3475 in combination with BCG in this population. DLTs will be defined as significant adverse events occurring during the DLT observation period (2 week pre-induction phase and the 7 weeks of induction phase) that is related to either drug or the combination. DLT will be evaluated according to CTCAE v 4.03 criteria.
Measure:Incidence of adverse events
Time Frame:Up to 30 days from the last dose of study drug
Safety Issue:
Description:Determine the safety and tolerability of the combination of MK-3475 and BCG in subjects with high risk or BCG-refractory non-muscle-invasive bladder cancer by evaluating number, frequency, and severity of adverse events using CTCAE v 4.03.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Northwestern University

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