| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| muscle-invasive bladder cancer |
| carcinoma uroteliale della vescica muscolo-infiltrante |
|
| E.1.1.1 | Medical condition in easily understood language |
| Tumor pathology of the bladder in advanced stage |
| Patologia tumorale della vescica in stadio avanzato. |
|
| 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 | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 nab-paclitaxel plus nivolumab results in pathological complete response (herein referred to as either “ypT0N0M0” or “pCR”) in patients with clinical T2-4aN0M0 MIBC who cannot receive or refuse to receive cisplatin-based chemotherapy. |
| Valutare l’attività del trattamento neoadiuvante con nab-paclitaxel+nivolumab, seguito da trattamento adiuvante con solo nivolumab, in pazienti affetti da carcinoma uroteliale della vescica muscolo-infiltrante |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate safety and tolerability of nab-paclitaxel+nivolumab administered in study population with high risk organ-confined neoplasia |
| Valutare la sicurezza e la tollerabilità di nab-paclitaxel+nivolumab somministrato ad una popolazione di pazienti con neoplasia organo-confinata ad alto rischio. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
2. Female or male subjects, >18 years of age, able to understand and give written informed consent.
3. Histopathologically confirmed urothelial carcinoma. Patients with mixed histologies are required to have a dominant (i.e. 50% at least) transitional cell pattern.
4. Fit and planned for RC (according to local guidelines).
5. ECOG performance status score of 0 or 1.
6. Adequate hematologic counts without transfusional or growth factor support within 2 weeks of study drug initiation (Hemoglobin = 9 g/dL, ANC = 1,500/ mm3, and Platelets = 100,000/ µL).
7. Adequate hepatic function (Bilirubin = 1.5 IULN, AST and ALT = 2.5 x IULN or = 5 x IULN if known liver metastases and serum albumin >3 g/dl).
8. Creatinine clearance =30 mL/min as assessed by the Cockcroft-Gault equation.
9. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication, and must not be lactating. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 4 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >2 years.
11. Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy.
12. Clinical stage T2-T4aN0M0 MIBC, assessed by CT + PET/CT + mpMRI.
13. The patient accepts to undergo RC.
14. Ineligibility to receive cisplatin-based neoadjuvant chemotherapy based on Galsky’s criteria (Galsky MD, et al. J Clin Oncol. 2011 Jun 10;29(17):2432-8) OR refusal to receive neoadjuvant cisplatin-based chemotherapy. |
• Consenso informato scritto.
• Età = 18 anni.
• Diagnosi istologicamente confermata (TURB) di carcinoma a cellule transizionali della vescica.
• Prevalente istologia uroteliale. La presenza di varianti istologiche non uroteliali è ammessa purchè esse non rappresentino la componente maggioritaria del tumore.
• Stadio clinico T2-4N0M0 confermato alla TURB e alle indagini radiologiche.
• Nessuna precedente terapia sistemica (le pregresse instillazioni intravescicali di chemioterapia per malattia superficiale sono ammesse).
• Adeguata funzione midollare, epatica e renale.
• Eleggibilità per l’intervento chirurgico di cistectomia radicale.
• Rifiuto della chemioterapia neoadiuvante cisplatino-contenente oppure ineleggibilità alla stessa in base ai criteri di Galsky. Tali criteri includono almeno 1 dei seguenti elementi: filtrato glomerulare calcolato di <60 ml/min, ECOG-performance status >1, pregressa co-morbidità cardiologica classificata come cardiopatia classe NYHA III-IV, pregressa neuropatia o deficit audiometrico di grado 3-4.
• 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. |
|
| E.4 | Principal exclusion criteria |
1.A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2.Prior immunotherapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
3.Has received prior systemic anti-cancer therapy including investigational agents.
4.Has received prior radiotherapy on the bladder tumor.
5.Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
6.Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
7.Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
8. Has severe hypersensitivity (=Grade 3) to nivolumab or nab-paclitaxel and/or any of its excipients.
9. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or GI perforation within 6 months of enrollment.
12. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
13. Has received any antibiotics within 30 days prior to the first dose of study drug.
14. Has a known history of Human Immunodeficiency Virus (HIV).
15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
16. Has a known history of active TB (Bacillus Tuberculosis).
17. Has active autoimmune disease that has required systemic treatment in 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.
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
19. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
20. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of trial treatment. |
• Evidenza clinica e/o strumentale di adenopatie patologiche o di metastasi a distanza.
• Co-morbidità escluse:
• Importanti patologie cardiovascolari, quali:
• Patologie autoimmuni ad esclusione della tiroidite di Hashimoto e della vitiligo.
• 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 (betabloccanti o digossina sono permessi), ipertensione (PA media > 140/90 mm/Hg) non controllata, prolungamento dell’intervallo QT (QTc) > 450 msec.
• 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.
• Infezioni clinicamente serie in fase attiva (di grado > 2 dei CTCAE v.5.0).
• 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.
• Presenza di infezione non controllata.
• Nota ipersensibilità a farmaci chimicamente correlabili a nab-paclitaxel e/o nivolumab.
• Presenza di qualsiasi condizione medica, disfunzione metabolica o psichiatrica che possa limitare la piena osservanza delle procedure dello studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Pathologic complete response number, defined as absence of viable tumor cells in cystectomy histological examination. evidence of in situ carcinoma or non muscle-invesive disease does not define a pathologic complete responce. Two independent pathologists, blinded to the study findings, with >10 years of experience in genitourinary tumors will independently evaluate the response. To assess whether nab-paclitaxel plus nivolumab results in pathological complete response (herein referred to as either "ypT0N0M0" or "pCR") in patients with clinical T2-4aN0M0 MIBC who cannot receive or refuse to receive cisplatin-based chemotherapy. Absence of any residual viable tumor in the radical cystectomy specimen. |
| numero di risposte patologiche complete, definite come assenza di cellule tumorali vitali all’esame istologico della cistectomia, due patologi indipendenti con più di 10 anni di esperienza in tumori genitourinari, non a conoscenza delle scoperte dello studio, valuteranno indipendentemente la risposta. L’evidenza di carcinoma in situ o malattia non muscolo-infiltrante non definisce una risposta patologica completa. Per valutare se i risultati di nab-paclitaxel + nivolumab nella risposta patologica completa (qui riferita a o "ypT0N0M0" o "pCR") in pazienti con clinico T2-4aN0M0 MIBC che non possono ricevere o rifiutano di ricevere chemioterapia basata sul cisplatino. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Change from Screening after radical cystectomy |
| Cambiamento da Screening dopo la cistectomia radicale |
|
| E.5.2 | Secondary end point(s) |
| Radiologica response. To evaluate radiological response on those patients with measurable disease. Response (CR and PR) will be assessed after the full neoadjuvant course of 4 cycles.; Number of participants with treatment-related adverse events as assessed by CTCAE v 5.0 and EAU recommandations. To evaluate the surgical and medical safety of neoadjuvant combination therapy, as well as of the adjuvant nivolumab therapy.; survival outcomes. To assess event-free survival in the total population and in the subgroups according to the pathological response.; pathological downstaging; survival outcomes. To assess overall survival in the total population and in the subgroups according to the pathological response. |
| risposta radiologica. Valutare la risposta radiologica in quei pazienti con patologia misurabile. la risposta (completa o parziale) sarà valutata dopo l'intero percorso neoadivante di 4 cicli; Numero di pazienti con eventi avversi correlati al trattamento come descritto da CTCAE v5.0 e raccomandazioni EAU. Valutare la sicurezza chirurgica e medica della terapia combinata neodiuvante e anche la terapia adiuvante con nivolumab; sopravvivenza. Valutare la sopravvivenza libera da eventi nella popolazione totale e nei sottogruppi secondo la risposta patologica; regressione patologica. Valutare la porzione di pazienti che hanno una regressione patologica ypT<=1N0M0; sopravvivenza. Valutare la sopravvivenza generale nella popolazione totale e nei sottogruppi secondo la risposta patologica |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| screening, 14 days after final combined treatment, Q3 weeks until 12 months post-radical cystectomy, Q3 months until 12 months post-adjuvant nivolumab; From date of Screening until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 40 months; From date of Screening until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 40 months; screening, 14 days after final combined treatment, Q3 weeks until 12 months post-radical cystectomy, Q3 months until 12 months post-adjuvant nivolumab; From date of Screening until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 40 months |
| Screening, 14 giorni dopo il trattamento combinato finale, Q3 settimane fino a 12 mesi dopo la cistectomia radicale, Q3 mesi fino a 12 mesi dopo il nivolumab adiuvante; Dalla data di screening fino alla data della prima progressione documentata o data di morte per qualsiasi causa, quale sopravvenga prima, fino a 40 mesi; Dalla data di screening fino alla data della prima progressione documentata o data di morte per qualsiasi causa, quale sopravvenga prima, fino a 40 mesi; Screening, 14 giorni dopo il trattamento combinato finale, Q3 settimane fino a 12 mesi dopo la cistectomia radicale, Q3 mesi fino a 12 mesi dopo il nivolumab adiuvante; Dalla data di screening fino alla data della prima progressione documentata o data di morte per qualsiasi causa, quale sopravvenga prima, fino a 40 mesi |
|
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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 | No |
| 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.8.6 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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