Neoadjuvant Pembrolizumab for Muscle-invasive Urothelial Bladder Carcinoma

NCT02736266 | Completed Phase 2 DMC

• 2 other identifiers: INT 101/162015-002055-10
• Study Type: interventional
• Target: 174
• Locations: 1 country
• Sites: 1

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.

Conditions

Urothelial Bladder Carcinoma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Pathologic complete response

  Absence of residual viable tumor in the radical cystectomy specimen

  At the time of radical cystectomy (within 9 weeks of the first dose of pembrolizumab)

Secondary Outcomes (3)

• Adverse events

  Up to 2 years

• Percentage of treatment-related delay in surgery

  Starting at week 9

• Frequency of treatment-related adverse events

  Up to 1 year

Study Arms (1)

Pembrolizumab (MK-3475)

EXPERIMENTAL

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)

Interventions

Pembrolizumab (MK-3475) DRUG

Pembrolizumab given intravenously in 30 min. infusion every 3 weeks

Also known as: Keytruda

Pembrolizumab (MK-3475)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent.
• Ability to comply with the protocol.
• Age ≥ 18 years.
• Histopathologically confirmed transitional cell carcinoma. Patients with mixed histologies are required to have a dominant (i.e. 50% at least) transitional cell pattern.
• Fit and planned for cystectomy (according to local guidelines).
• Clinical stage T2-T4a N0 M0 disease by CT (or MRI) + PET/CT (within 4 weeks of randomization by RECIST v1.1).
• Residual disease after TURB (surgical opinion, cystoscopy or radiological presence).
• 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.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Adequate hematologic and end-organ function tests.

You may not qualify if:

• 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

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Mi, 20133, Italy

Location

Related Publications (17)

• Necchi A, Basile G, Gibb EA, Raggi D, Calareso G, de Padua TC, Patane D, Crupi E, Mercinelli C, Cigliola A, Tateo V, Giannatempo P, Moschini M, Briganti A, Montorsi F, Messina A, Ross JS, Pavlick D, De Cobelli F, Brembilla G. Vesical Imaging-Reporting and Data System use predicting the outcome of neoadjuvant pembrolizumab in muscle-invasive bladder cancer. BJU Int. 2024 Feb;133(2):214-222. doi: 10.1111/bju.16191. Epub 2023 Oct 16.

  PMID: 37803523 DERIVED

• Basile G, Bandini M, Gibb EA, Ross JS, Raggi D, Marandino L, Costa de Padua T, Crupi E, Colombo R, Colecchia M, Luciano R, Nocera L, Moschini M, Briganti A, Montorsi F, Necchi A. Neoadjuvant Pembrolizumab and Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Cancer: 3-Year Median Follow-Up Update of PURE-01 Trial. Clin Cancer Res. 2022 Dec 1;28(23):5107-5114. doi: 10.1158/1078-0432.CCR-22-2158.

  PMID: 36190522 DERIVED

• Martini A, Raggi D, Marandino L, Montorsi F, Ross JS, Gibb EA, Necchi A. The Paradoxical Role of Body Mass Index in Patients with Muscle-invasive Bladder Cancer Receiving Neoadjuvant Immunotherapy. Eur Urol Oncol. 2022 Jun;5(3):370-372. doi: 10.1016/j.euo.2022.02.004. Epub 2022 Mar 10. No abstract available.

  PMID: 35283158 DERIVED

• Necchi A, Martini A, Raggi D, Cucchiara V, Colecchia M, Luciano R, Villa L, Mazzone E, Basile G, Scuderi S, Pederzoli F, Bandini M, Barletta F, Larcher A, Capitanio U, Salonia A, Briganti A, Ross JS, Messina A, Montorsi F. A feasibility study of preoperative pembrolizumab before radical nephroureterectomy in patients with high-risk, upper tract urothelial carcinoma: PURE-02. Urol Oncol. 2022 Jan;40(1):10.e1-10.e6. doi: 10.1016/j.urolonc.2021.05.014. Epub 2021 Jun 17.

  PMID: 34147313 DERIVED

• Trevisani F, Di Marco F, Raggi D, Bettiga A, Vago R, Larcher A, Cinque A, Salonia A, Briganti A, Capitanio U, Necchi A, Montorsi F. Renal function outcomes in patients with muscle-invasive bladder cancer treated with neoadjuvant pembrolizumab and radical cystectomy in the PURE-01 study. Int J Cancer. 2021 Jul 1;149(1):186-190. doi: 10.1002/ijc.33554. Epub 2021 Mar 26.

  PMID: 33720424 DERIVED

• Marandino L, Capozza A, Bandini M, Raggi D, Fare E, Pederzoli F, Gallina A, Capitanio U, Bianchi M, Gandaglia G, Fossati N, Colecchia M, Giannatempo P, Serafini G, Padovano B, Salonia A, Briganti A, Montorsi F, Alessi A, Necchi A. Incidence and Clinical Impact of Inflammatory Fluorodeoxyglucose Positron Emission Tomography Uptake After Neoadjuvant Pembrolizumab in Patients with Organ-confined Bladder Cancer Undergoing Radical Cystectomy. Eur Urol Focus. 2021 Sep;7(5):1092-1099. doi: 10.1016/j.euf.2020.10.003. Epub 2020 Nov 7.

  PMID: 33172772 DERIVED

• Marandino L, Capozza A, Bandini M, Raggi D, Fare E, Pederzoli F, Gallina A, Capitanio U, Bianchi M, Gandaglia G, Fossati N, Colecchia M, Giannatempo P, Serafini G, Padovano B, Salonia A, Briganti A, Montorsi F, Alessi A, Necchi A. [18F]Fluoro-Deoxy-Glucose positron emission tomography to evaluate lymph node involvement in patients with muscle-invasive bladder cancer receiving neoadjuvant pembrolizumab. Urol Oncol. 2021 Apr;39(4):235.e15-235.e21. doi: 10.1016/j.urolonc.2020.09.035. Epub 2020 Oct 16.

  PMID: 33071107 DERIVED

• Bandini M, Gibb EA, Gallina A, Raggi D, Marandino L, Bianchi M, Ross JS, Colecchia M, Gandaglia G, Fossati N, Pederzoli F, Luciano R, Colombo R, Salonia A, Briganti A, Montorsi F, Necchi A. Does the administration of preoperative pembrolizumab lead to sustained remission post-cystectomy? First survival outcomes from the PURE-01 study☆. Ann Oncol. 2020 Dec;31(12):1755-1763. doi: 10.1016/j.annonc.2020.09.011. Epub 2020 Sep 23.

  PMID: 32979511 DERIVED

• Pederzoli F, Bandini M, Marandino L, Raggi D, Giannatempo P, Salonia A, Gallina A, Briganti A, Montorsi F, Necchi A. Neoadjuvant Chemotherapy or Immunotherapy for Clinical T2N0 Muscle-invasive Bladder Cancer: Time to Change the Paradigm? Eur Urol Oncol. 2021 Dec;4(6):1006-1010. doi: 10.1016/j.euo.2020.07.006. Epub 2020 Aug 23.

  PMID: 32847746 DERIVED

• Bandini M, Calareso G, Raggi D, Marandino L, Colecchia M, Gallina A, Giannatempo P, Pederzoli F, Gandaglia G, Fossati N, Capitanio U, Colombo R, Salonia A, Briganti A, Montorsi F, De Cobelli F, Messina A, Necchi A. The Value of Multiparametric Magnetic Resonance Imaging Sequences to Assist in the Decision Making of Muscle-invasive Bladder Cancer. Eur Urol Oncol. 2021 Oct;4(5):829-833. doi: 10.1016/j.euo.2020.06.004. Epub 2020 Jun 27.

  PMID: 32605888 DERIVED

• Bandini M, Ross JS, Raggi D, Gallina A, Colecchia M, Luciano R, Giannatempo P, Fare E, Pederzoli F, Bianchi M, Colombo R, Gandaglia G, Fossati N, Marandino L, Capitanio U, Deho' F, Ali SM, Madison R, Chung JH, Salonia A, Briganti A, Montorsi F, Necchi A. Predicting the Pathologic Complete Response After Neoadjuvant Pembrolizumab in Muscle-Invasive Bladder Cancer. J Natl Cancer Inst. 2021 Jan 4;113(1):48-53. doi: 10.1093/jnci/djaa076.

  PMID: 32516377 DERIVED

• Necchi A, Raggi D, Giannatempo P, Marandino L, Fare E, Gallina A, Colecchia M, Luciano R, Salonia A, Gandaglia G, Fossati N, Bandini M, Pederzoli F, Dittamore R, Liu Y, Davicioni E, Ross JS, de Jong JJ, Briganti A, Montorsi F, Gibb EA. Can Patients with Muscle-invasive Bladder Cancer and Fibroblast Growth Factor Receptor-3 Alterations Still Be Considered for Neoadjuvant Pembrolizumab? A Comprehensive Assessment from the Updated Results of the PURE-01 Study. Eur Urol Oncol. 2021 Dec;4(6):1001-1005. doi: 10.1016/j.euo.2020.04.005. Epub 2020 May 14.

  PMID: 32417369 DERIVED

• Necchi A, Raggi D, Gallina A, Ross JS, Fare E, Giannatempo P, Marandino L, Colecchia M, Luciano R, Bianchi M, Colombo R, Salonia A, Gandaglia G, Fossati N, Bandini M, Pederzoli F, Capitanio U, Montorsi F, de Jong JJ, Dittamore R, Liu Y, Davicioni E, Boormans JL, Briganti A, Black PC, Gibb EA. Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer. Eur Urol. 2020 Jun;77(6):701-710. doi: 10.1016/j.eururo.2020.02.028. Epub 2020 Mar 9.

  PMID: 32165065 DERIVED

• Necchi A, Bandini M, Calareso G, Raggi D, Pederzoli F, Fare E, Colecchia M, Marandino L, Bianchi M, Gallina A, Colombo R, Fossati N, Gandaglia G, Capitanio U, Deho F, Giannatempo P, Luciano R, Salonia A, Madison R, Ali SM, Chung JH, Ross JS, Briganti A, Montorsi F, De Cobelli F, Messina A. Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study. Eur Urol. 2020 May;77(5):636-643. doi: 10.1016/j.eururo.2019.12.016. Epub 2019 Dec 25.

  PMID: 31882281 DERIVED

• Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Luciano R, Montironi R, Giannatempo P, Fare E, Pederzoli F, Bandini M, Bianchi M, Colombo R, Gandaglia G, Fossati N, Marandino L, Capitanio U, Deho F, Ali SM, Chung JH, Ross JS, Salonia A, Briganti A, Montorsi F. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. Eur Urol. 2020 Apr;77(4):439-446. doi: 10.1016/j.eururo.2019.10.026. Epub 2019 Nov 8.

  PMID: 31708296 DERIVED

• Necchi A, Montorsi F. Reply to S. Zhang. J Clin Oncol. 2019 Apr 10;37(11):940-941. doi: 10.1200/JCO.18.02448. Epub 2019 Feb 27. No abstract available.

  PMID: 30811283 DERIVED

• Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Luciano R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Fare E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Dec 1;36(34):3353-3360. doi: 10.1200/JCO.18.01148. Epub 2018 Oct 20.

  PMID: 30343614 DERIVED

MeSH Terms

Interventions

pembrolizumab

Study Officials

• Filippo G. de Braud, MD

  Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: April 9, 2016
• First Posted: April 13, 2016
• Study Start: February 27, 2017
• Primary Completion: October 20, 2018
• Study Completion: September 23, 2022
• Last Updated: July 18, 2023

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)