| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Muscle-invasive urothelial bladder cancer before cystectomy |
| Carcinoma uroteliale della vescica muscolo-infiltrante candidati a cistectomia radicale. |
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| E.1.1.1 | Medical condition in easily understood language |
| Bladder cancer |
| Tumore alla vescica |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess whether pembrolizumab (MK-3475) results in pathological complete response rates (herein referred to as either ¿pT0¿ or ¿pCR¿) in T2-T4a N0M0 UC of the bladder according to the assumptions provided below.
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| Valutare l¿attivit¿ del trattamento neoadiuvante con Pembrolizumab in pazienti affetti da carcinoma uroteliale della vescica muscolo-infiltrante |
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| E.2.2 | Secondary objectives of the trial |
To evaluate radiological response on those patients with measurable disease (at baseline). Response (CR and PR) after 3 cycles of treatment with the study drug.
Safety of MK-3475.
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| Valutare la sicurezza e la tollerabilit¿ Pembrolizumab somministrato ad una popolazione di pazienti con neoplasia organo-confinata ad alto rischio. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetics
Version: 1.0
Date: 12/11/2015
Title: PURE-01 ¿ An open label, single-arm, phase 2 study of neoadjuvant pembrolizumab (MK-3475) before cystectomy for patients with muscle-invasive urothelial bladder cancer
Objectives: Tumour and blood samples will be collected before, during, and after treatment with pembrolizumab. These biomarker assessments will potentially aid in understanding the drug effect. All patients will be consented for the collection and use of research blood and tissue samples. All samples will be linked anonymised and only identified by the trial ID and unique sample number allocated by the trial center of the sponsor (Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
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Farmacogenetica
Versione: 1.0
Data: 12/11/2015
Titolo: PURE-01: Studio di Fase 2, in aperto, a singolo braccio, con anticorpo monoclonale anti-PD1 MK-3475 (Pembrolizumab) in pazienti con carcinoma uroteliale della vescica muscolo-infiltrante candidati a cistectomia radicale.
Obiettivi: Questo studio prevede anche uno studio a latere di tipo biologico, che consiste nello studio dell¿espressione di alcuni geni e in analisi molecolari ed immunologiche che potrebbero essere utili in futuro per definire con maggiore precisione la popolazione di pazienti che maggiormente pu¿ beneficiare di un trattamento immunoterapico come quello a lei proposto.
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| E.3 | Principal 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 defined by the following laboratory results obtained within 28 days prior to the first study treatment:
11. Absolute Neutrophil Count = 1,500 cells/µL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1).
12. Lymphocyte count = 500/µL.
13. Platelet count = 100,000/µL (without transfusion within 2 weeks prior to Cycle 1, Day 1).
14. Haemoglobin = 9.0 g/dL - Patients may be transfused or receive erythropoietic treatment to meet this criterion.
15. AST, ALT, and alkaline phosphatase = 2.5 times the upper limit of normal (ULN), with the following exceptions:
a. Patients with known Gilbert disease who have serum bilirubin level = 3 × ULN may be enrolled.
16. INR and aPTT = 1.5 × ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
17. Calculated creatinine clearance = 30 mL/min (Cockcroft-Gault formula).
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• Consenso informato scritto.
• Età = 18 anni.
• Diagnosi istologicamente confermata (TURB) di carcinoma a cellule transizionali della vescica.
• TCC pT¿2 confermato alla TURB (pazienti T2 non saranno arruolabili senza una documentazione istologica di malattia muscolo-infiltrante). La conferma dell’istologia di TCC dovrà avvenire tramite revisione centralizzata all’INT Milano in tutti i casi prima dell’arruolamento.
• Linfonodi clinicamente negativi (cN0).
• Nessuna precedente terapia sistemica (le pregresse instillazioni intravescicali di chemioterapia per malattia superficiale sono ammesse).
• Adeguata funzione midollare, epatica e renale in accordo ai seguenti valori di laboratorio:
o Conta assoluta dei neutrofili (ANC) = 1500/µL.
o Piastrine (PLT) = 100000/µL.
o Emoglobina = 9 g/dL (in assenza di trasfusioni e di trattamento con eritropoietina).
• Bilirubina totale = 1,5 volte il limite superiore di normalità
• AST e ALT = 2,5 volte il limite superiore di normalità.
• Fosfatasi alcalina = 4 volte il limite superiore di normalità.
• Creatinina sierica = 1,5 mg/dL o alternativamente creatinina clearance ¿ 50 mL/min.
• PT-INR/PTT < 1,5 volte il limite superiore di normalità (i pazienti che necessitano di assumere terapia anticoagulante con farmaci come coumadin o eparina potranno partecipare allo studio previa documentata assenza di alterazione dei suddetti parametri)
• ECOG performance status di 0 o 1.
• Soggetti che accettino di praticare un’effettiva contraccezione durante l’intera durata dello studio, a meno che esista documentazione di infertilità (un test di gravidanza negativo eseguito entro 7 giorni precedenti l’inizio dello studio è necessario per tutte le donne in età fertile).
• Possibilità e disponibilità a seguire le procedure previste dal protocollo.
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| E.4 | Principal 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
• Pregnant female patients
• Significant cardiovascular disease
• Severe infections within 4 weeks prior to enrolment in the study
• Major surgical procedure within 4 weeks prior to enrolment
• Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to randomization
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• History of autoimmune disease
• 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 (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan
• Positive test for HIV.
• Patients with active hepatitis infection
• Patients with active tuberculosis.
• Prior treatment with CD137 agonists, 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 (including but not limited to interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment.
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• Evidenza clinica e/o strumentale di adenopatie patologiche o di metastasi a distanza.
• TCC delle alte vie urinarie.
Co-morbidità escluse:
• Importanti patologie cardiovascolari nei 6 mesi che precedono l’inizio dell’assunzione di Pembrolizumab, quali:
o Infarto miocardico (IM), angina instabile (l’IM a più di 6 mesi dall’ingresso nello studio è ammesso), scompenso cardiaco di grado = 2 secondo i criteri NYHA, aritmie di qualsiasi natura che richiedano l’uso di farmaci (beta-bloccanti o digossina sono permessi), ipertensione (PA media > 140/90 mm/Hg) non controllata, prolungamento dell’intervallo QT (QTc) > 450 msec.
o Storia di infarti cerebro-vascolari, embolia polmonare o trombosi venosa profonda non trattata entro i 6 mesi che precedono l’inizio del protocollo.
• Infezione da HIV o epatite cronica attiva di tipo B e C.
• Diagnosi di immunodeficienza o sta ricevendo una terapia steroidea per via sistemica o qualsiasi altra forma di terapia immunosoppressiva nei 7 giorni precedenti la prima dose del trattamento sperimentale. L’uso di dosi fisiologiche di corticosteroidi può essere approvato previa consultazione con lo Sponsor.
• Presenza di una malattia autoimmune in fase attiva per cui si è reso necessario un trattamento per via sistemica nei 3 mesi precedenti o di una storia documentata di malattia autoimmune clinicamente grave o una sindrome che richiede una terapia per via sistemica o con agenti immunosoppressori. Soggetti con vitiligo, diabete di tipo I o asma/atopia infantile risoltesi faranno eccezione a questa regola. Soggetti che richiedono un utilizzo intermittente di broncodilatatori, steroidi per via inalatoria o iniezioni locali di steroidi non saranno esclusi dallo studio. Soggetti con ipotiroidismo stabile in terapia ormonale sostitutiva o con sindrome di Sjøgren non saranno esclusi dallo studio.
• Infezioni clinicamente serie in fase attiva (di grado > 2 dei CTCAE v.4.0).
• Anamnesi positiva per crisi epilettiche che richiedono specifico trattamento medico (come cortico-steroidi e anti-epilettici).
• Seconda neoplasia pregressa o concomitante fatta eccezione per il carcinoma in situ della cervice, il carcinoma basocellulare o qualsiasi altra neoplasia trattata in modo radicale ad un tempo > 5 anni rispetto alla data di ingresso nello studio.
• Gravidanza e allattamento.
• Impossibilità ad assumere farmaci per via orale.
• Presenza di infezione non controllata.
• Nota ipersensibilità a farmaci chimicamente correlabili a Pembrolizumab.
• Presenza di qualsiasi condizione medica, disfunzione metabolica o psichiatrica che possa limitare la piena osservanza delle procedure dello studio.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Pathologic complete response (pCR) is the primary endpoint. |
| Il numero di risposte patologiche complete (pCR) è l’endpoint primario |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| at the end of the study |
| fine studio |
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| E.5.2 | Secondary end point(s) |
All toxicities will be evaluated and recorded based on the NCI common toxicity criteria (CTCAE v4.03) described by frequency and grade, by cycle and over all cycles, with the maximum grade over all cycles used as the summary measure per patient.
; PFS time will be calculated as the interval between the date of enrollment and that of first disease progression or death regardless of the cause, with censoring at the date of last follow-up visit for patients alive and without progression. ; OS will be calculated from the date of enrollment to that of death/last follow-up. ; Secondary endpoints will include downstaging to non-muscle invasive disease |
Valutazione della sicurezza e della tollerabilit¿ del trattamento:
- Numero di pazienti che hanno avuto eventi avversi.
- Tipo, frequenza, severit¿ e correlazione al trattamento degli eventi avversi, valutati secondo i Common Toxicity Criteria (CTC) for adverse events v 4.0.
; Sopravvivenza libera da progressione (PFS).; Sopravvivenza globale (OS).; Risposta maggiore, definita come il downstaging a TCC non infiltrante (pT<2) nei pazienti radicalmente operati. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at the end of the study; at the end of the study; at the end of the study; at the end of the study |
| fine studio; fine studio; fine studio; fine studio |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Nessun Comparatore |
| No Comparator |
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| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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