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Trial record 1 of 2 for:    PURE-01
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Neoadjuvant Pembrolizumab for Muscle-invasive Urothelial Bladder Carcinoma

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ClinicalTrials.gov Identifier: NCT02736266
Recruitment Status : Recruiting
First Posted : April 13, 2016
Last Update Posted : May 13, 2021
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Urothelial Bladder Carcinoma Drug: Pembrolizumab (MK-3475) Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : February 27, 2017
Estimated Primary Completion Date : September 27, 2021
Estimated Study Completion Date : December 27, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: Pembrolizumab (MK-3475)
Pembrolizumab (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.
Drug: Pembrolizumab (MK-3475)
Pembrolizumab given intravenously in 30 min. infusion every 3 weeks
Other Name: Keytruda

Primary Outcome Measures :
  1. Pathologic complete response [ Time Frame: At the time of radical cystectomy (within 9 weeks of the first dose of pembrolizumab) ]
    Absence of residual viable tumor in the radical cystectomy specimen

Secondary Outcome Measures :
  1. Adverse events [ Time Frame: Up to 2 years ]
    Number of patients developing side effects

  2. Percentage of treatment-related delay in surgery [ Time Frame: Starting at week 9 ]
    Number of patients undergoing cystectomy later than 12 weeks after pembrolizumab treatment

  3. Frequency of treatment-related adverse events [ Time Frame: Up to 1 year ]
    Number of patients developing side effects

Information from the National Library of Medicine

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

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.

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): NCT02736266

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Contact: Liana Bevilacqua, PhD +390223903766 liana.bevilacqua@istitutotumori.mi.it

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Fondazione IRCCS Istituto Nazionale dei Tumori Recruiting
Milano, Mi, Italy, 20133
Contact: Patrizia giannatempo, MD    +390223902402    patrizia.giannatempo@istitutotumori.mi.it   
Principal Investigator: Patrizia giannatempo, MD         
Sponsors and Collaborators
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Merck Sharp & Dohme LLC
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Principal Investigator: Patrizia Giannatempo, MD Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Andrea Necchi, Dr, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
ClinicalTrials.gov Identifier: NCT02736266    
Other Study ID Numbers: PURE-01
2015-002055-10 ( EudraCT Number )
First Posted: April 13, 2016    Key Record Dates
Last Update Posted: May 13, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No formal plan

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:
Urothelial bladder carcinoma
Neoadjuvant therapy
Radical cystectomy
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents