Clinical Trials /

Neoadjuvant Pembrolizumab for Muscle-invasive Urothelial Bladder Carcinoma

NCT02736266

Description:

Patients with T2-T4a N0 urothelial bladder carcinoma (UBC) with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence) will receive 3 cycles of pembrolizumab (MK-3475) at the dose of 200mg 3 weekly prior to surgery (radical cystectomy). Cystectomy will be planned to be done within 3 weeks of the last dose (accounting for a total of 9 weeks). Computed tomography (CT) scan and fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan will be done during screening and before surgery. After cystectomy, patients with the evidence of pathologic stage T3-4 (pT3-4) and/or pathologically node-positive disease will be managed according to local guidelines. Further anti programmed-death (PD)-1 or anti PD-ligand 1 (PD-L1) therapy will not be given post-operatively. PD-L1 status will be centralized and assessed on TURB specimen using an anti-PD-L1 antibody (Ab) and a prototype immunohistochemical (IHC) assay. PD-L1 positivity will be defined as any staining in the stroma or in ≥1% of tumor cells. Pathologic complete response (pCR) is the primary endpoint. All patients enrolled who receive at least 1 cycle of study drug will be includes in the intention-to-treat (ITT) analysis. The alternative hypothesis (H1) is pCR ≥20% and null hypothesis (H0) pCR≤10%. A 2-stage design will be used to estimate the number of pts required. Out of 90 pts overall, with the first stage of 49 pts, ≥6 pCR will be required in the first stage, and ≥13 pCR in the whole study population (80% power and a 2-sided test of significance at the 10% level). Correlative research on tissue/blood samples will include immune-cell profiling in tumor and blood during Pembrolizumab, cytokine assessment, and molecular profiling of tumor samples.

Related Conditions:
  • Transitional Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Pembrolizumab for Muscle-invasive Urothelial Bladder Carcinoma
  • Official Title: An Open Label, Single-arm, Phase 2 Study of Neoadjuvant Pembrolizumab (MK-3475) Before Cystectomy for Patients With Muscle-invasive Urothelial Bladder Cancer.

Clinical Trial IDs

  • ORG STUDY ID: PURE-01
  • SECONDARY ID: 2015-002055-10
  • NCT ID: NCT02736266

Conditions

  • Urothelial Bladder Carcinoma

Interventions

DrugSynonymsArms
Pembrolizumab (MK-3475)KeytrudaPembrolizumab (MK-3475)

Purpose

Patients with T2-T4a N0 urothelial bladder carcinoma (UBC) with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence) will receive 3 cycles of pembrolizumab (MK-3475) at the dose of 200mg 3 weekly prior to surgery (radical cystectomy). Cystectomy will be planned to be done within 3 weeks of the last dose (accounting for a total of 9 weeks). Computed tomography (CT) scan and fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan will be done during screening and before surgery. After cystectomy, patients with the evidence of pathologic stage T3-4 (pT3-4) and/or pathologically node-positive disease will be managed according to local guidelines. Further anti programmed-death (PD)-1 or anti PD-ligand 1 (PD-L1) therapy will not be given post-operatively. PD-L1 status will be centralized and assessed on TURB specimen using an anti-PD-L1 antibody (Ab) and a prototype immunohistochemical (IHC) assay. PD-L1 positivity will be defined as any staining in the stroma or in ≥1% of tumor cells. Pathologic complete response (pCR) is the primary endpoint. All patients enrolled who receive at least 1 cycle of study drug will be includes in the intention-to-treat (ITT) analysis. The alternative hypothesis (H1) is pCR ≥20% and null hypothesis (H0) pCR≤10%. A 2-stage design will be used to estimate the number of pts required. Out of 90 pts overall, with the first stage of 49 pts, ≥6 pCR will be required in the first stage, and ≥13 pCR in the whole study population (80% power and a 2-sided test of significance at the 10% level). Correlative research on tissue/blood samples will include immune-cell profiling in tumor and blood during Pembrolizumab, cytokine assessment, and molecular profiling of tumor samples.

Detailed Description

      Patients with T2-T4a N0 urothelial bladder carcinoma (UBC) with residual disease after
      transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological
      presence) will receive 3 cycles of pembrolizumab (MK-3475) at the dose of 200mg 3 weekly
      prior to surgery (radical cystectomy). Cystectomy will be planned to be done within 3 weeks
      of the last dose (accounting for a total of 9 weeks).
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab (MK-3475)ExperimentalPembrolizumab (MK-3475) will be administered at the dose of 200mg, as a 30-minute intravenous infusion, every 3 weeks, for a total of 3 cycles prior to radical cystectomy.
  • Pembrolizumab (MK-3475)

Eligibility Criteria

        Inclusion Criteria:

          1. Willing and able to provide written informed consent.

          2. Ability to comply with the protocol.

          3. Age ≥ 18 years.

          4. Histopathologically confirmed transitional cell carcinoma. Patients with mixed
             histologies are required to have a dominant (i.e. 50% at least) transitional cell
             pattern.

          5. Fit and planned for cystectomy (according to local guidelines).

          6. Clinical stage T2-T4a N0 M0 disease by CT (or MRI) + PET/CT (within 4 weeks of
             randomization by RECIST v1.1).

          7. Residual disease after TURB (surgical opinion, cystoscopy or radiological presence).

          8. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (blocks
             preferred) or at least 15 unstained slides, with an associated pathology report, for
             testing at the study sponsor site and determined to be evaluable for tumor PD-L1
             expression prior to study enrolment; patients with fewer than 15 unstained slides
             available at baseline (but no fewer than 10) may be eligible following discussion with
             Merck representatives.

          9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

         10. Adequate hematologic and end-organ function tests.

        Exclusion Criteria:

          -  Patients taking regular oral steroids, above the allowed limit of 10mg/day
             methylprednisolone or analogues, for any reason. Patients must not have had steroids
             for 28 days prior to study entry.

          -  Previously intravenous chemotherapy bladder cancer. Patients who have previously had
             radiotherapy or concurrent chemo-radiation would be eligible.

          -  Malignancies other than UBC within 5 years prior to Cycle 1, Day 1, with the exception
             of those with a negligible risk of metastasis or death and treated with expected
             curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or
             squamous cell skin cancer, or ductal carcinoma in situ treated surgically with
             curative intent) or localized prostate cancer treated with curative intent and absence
             of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason
             score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive).

          -  Evidence of measurable nodal or metastatic disease.

          -  Evidence of significant uncontrolled concomitant disease that could affect compliance
             with the protocol or interpretation of results, including significant liver disease
             (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava
             syndrome).

          -  Pregnant female patients. All female patients of childbearing potential with a
             positive pregnancy test within 2 weeks prior to the first dose of study treatment will
             be excluded from the study.

          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease
             (Class II or greater), myocardial infarction within 3 months prior to enrolment,
             unstable arrhythmias, or unstable angina.

          -  Severe infections within 4 weeks prior to enrolment in the study including but not
             limited to hospitalization for complications of infection, bacteraemia, or severe
             pneumonia.

          -  Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for
             a major surgical procedure during the course of the study other than for diagnosis.

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or any component of the pembrolizumab formulation

          -  History of autoimmune disease including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
             syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
             multiple sclerosis, vasculitis, or glomerulonephritis.

          -  Patients with a history of autoimmune-related hypothyroidism, unless on a stable dose
             of thyroid-replacement hormone.

          -  Patients with uncontrolled Type 1 diabetes mellitus

          -  Uncontrolled hypercalcemia

          -  Patients with prior allogeneic stem cell or solid organ transplantation.

          -  History of idiopathic pulmonary fibrosis

          -  Positive test for HIV.

          -  Patients with active hepatitis infection

          -  Patients with active tuberculosis.

          -  Prior treatment with anti−programmed death−1 (PD-1), or anti−PD-L1 therapeutic
             antibody or pathway-targeting agents.

          -  Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or
             anticipation that such a live, attenuated vaccine will be required during the study

          -  Treatment with any other investigational agent or participation in another clinical
             trial with therapeutic intent within 28 days prior to enrolment

          -  History of severe immune-related adverse effects from anti−CTLA-4 (CTCAE Grade 3 and
             4).

          -  Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of
             the drug, whichever is shorter, prior to enrolment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic complete response
Time Frame:At the time of radical cystectomy (within 9 weeks of the first dose of pembrolizumab)
Safety Issue:
Description:Absence of residual viable tumor in the radical cystectomy specimen

Secondary Outcome Measures

Measure:Adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Number of patients developing side effects
Measure:Percentage of treatment-related delay in surgery
Time Frame:Starting at week 9
Safety Issue:
Description:Number of patients undergoing cystectomy later than 12 weeks after pembrolizumab treatment
Measure:Frequency of treatment-related adverse events
Time Frame:Up to 1 year
Safety Issue:
Description:Number of patients developing side effects

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Trial Keywords

  • Muscle-invasive
  • Urothelial bladder carcinoma
  • Neoadjuvant therapy
  • Radical cystectomy

Last Updated

April 9, 2019