| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Renal cell carcinoma (RCC) |
| Carcinoma a cellule renali |
|
| E.1.1.1 | Medical condition in easily understood language |
| RCC is the most common type of kidney cancer in adults (responsible for approximately 90-95% of cases) |
| RCC è il tipo più comune di carcinoma renale negli adulti (responsabile di circa il 90-95% dei casi) |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073251 |
| E.1.2 | Term | Clear cell renal cell carcinoma |
| 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 evaluate the efficacy of atezolizumab in combination with cabozantinib (i.e. atezolizumab + cabozantinib arm) compared with cabozantinib alone (cabozantinib arm) in the intention-to-treat population |
| L’obiettivo primario di efficacia dello studio consiste nel valutare l’efficacia di atezolizumab in associazione a cabozantinib rispetto a cabozantinib in monoterapia nella popolazione intent-to-treat (ITT) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of atezolizumab in combination with cabozantinib compared with cabozantinib alone in the intent-to-treat population
• To evaluate the safety of atezolizumab in combination with cabozantinib compared with cabozantinib alone in the intent-to-treat population
• To characterize the pharmacokinetics profile of atezolizumab and cabozantinib administered in combination
• To evaluate the immune response to atezolizumab (for atezolizumab+ cabozantinib arm)
|
Per valutare l'efficacia di atezolizumab in associazione con cabozantinib rispetto al solo cabozantinib nella popolazione intent-to-treat
• Valutare la sicurezza di atezolizumab in associazione con cabozantinib rispetto al solo cabozantinib nella popolazione intent-to-treat
• Caratterizzare il profilo farmacocinetico di atezolizumab e cabozantinib somministrati in associazione
• Valutare la risposta immunitaria ad atezolizumab (per braccio atezolizumab + cabozantinib) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age >= 18 years
• Histologically confirmed locally advanced or metastatic clear cell or non-clear cell RCC (RCC with sarcomatoid features is allowed)
• Radiographic disease progression during or following treatment with immune checkpoint inhibitors (ICI) for locally advanced or metastatic RCC either in first- or second-line treatment. Only patients for whom the immediate preceding line of therapy was an ICI are allowed. ICI is defined by anti¿PD-L1 or anti¿PD1 antibody including atezolizumab, avelumab, pembrolizumab, or nivolumab. Ipilimumab monotherapy is not considered an anti¿PD L1 or anti¿PD1 therapy.
• Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1
• Evaluable International Metastatic Renal Cell Carcinoma Database Consortium risk score
• Two representative pretreatment tumor specimen for exploratory biomarker research: archival tumor specimen, and pretreatment tumor tissue from fresh biopsy at screening, if clinically feasible.
• Karnofsky Performance Status score of >= 70
• Adequate hematologic and end-organ function
• Negative hepatitis B testing at screening
• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
• Negative HIV test at screening
• For women of childbearing potential: agreement to remain abstinent or use contraception and agree to refrain from donating eggs for 4 months after the final dose of cabozantinib and for 5 months after the final dose of atezolizumab
• For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm for 4 months after the final dose of cabozantinib to avoid exposing the embryo
|
Età> = 18 anni
• RCC a cellule chiare o non a cellule chiare (solo sottotipi papillare o non classificato) localmente avanzato o metastatico confermato dall’esame istologico.
• Progressione radiografica di malattia durante o dopo trattamento con un ICI per RCC localmente avanzato o metastatico nel trattamento di prima o seconda linea
•Malattia misurabile secondo i criteri RECIST v1.1.
• Punteggio di rischio IMDC valutabile
• Due campioni tumorali rappresentativi pre-trattamento per la ricerca sui biomarcatori esplorativi.
• KPS >= 70.
• Adeguata funzione ematologica e degli organi terminali
• Test negativo per il virus dell’immunodeficienza umana (HIV) allo screening.
•Test negativo per l’epatite B allo screening
• Test di anticorpi negativi per virus dell'epatite C (HCV) allo screening o test di anticorpi HCV positivo seguito da test di RNA HCV negativo allo screening
• Per le donne in età fertile: accordo per rimanere in astinenza o usare la contraccezione e concordare di astenersi dal donare uova per 4 mesi dopo la dose finale di cabozantinib e per 5 mesi dopo la dose finale di atezolizumab
• Per gli uomini: accordo per rimanere in astinenza o usare un preservativo e accordo per astenersi dalla donazione di sperma per 4 mesi dopo la dose finale di cabozantinib per evitare di esporre l'embrione |
|
| E.4 | Principal exclusion criteria |
| •Treat with anti-cancer therapy within 28d prior to initiation of study treatment•Pz received cabozantinib (Cabo) at any time prior to screening•Pz who received more than 1 regimen of ICIs•Pz who received more than 2 prior lines of therapy in the advanced or metastatic setting•Pz who received ICI in the adjuvant setting•Pz who have received a mammalian target of rapamycin inhibitor in the advanced or metastatic setting•Symptomatic, untreated, or actively progressing CNS metastases•History of leptomeningeal disease•Uncontrolled tumor-related pain, pleural effusion, pericardial effusion,or ascites requiring recurrent drainage procedures, uncontrolled or symptomatic hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab•Active tuberculosis•Major surgical procedure, other than for diagnosis, within 4w prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study•Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5m after the final dose of atezolizumab (Atezo) and 4m after the final dose of Cabo•Severe infection within 4w prior to initiation of study treatment•Treat with systemic immunostimulatory agents within 4w or 5 drug-elimination half-lives prior to initiation of study treat•Treat with systemic immunosuppressive medication within 2w prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment•Treat with therapeutic oral or IV antibiotics within 2w prior to initiation of study treat•Prior allogeneic stem cell or solid organ transplantation•Any other disease,metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications•Current treat with anti-viral therapy for HBV or HCV •Active or history of autoimmune disease or immune deficiency•History of idiopathic pulmonary fibrosis,organizing pneumonia drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan•Pat with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption•Uncontrolled hypertension defined as sustained blood pressure (BP)>150mmHg systolic or>90mmHg diastolic despite optimal antihypertensive treat•Stroke,myocardial infarction (MI), or other symptomatic ischemic event,or thromboembolic event within 6m before first dose•cardiovascular disease within 3m prior to initiation of study treatment, unstable arrhythmia, or unstable angina•History of clinically significant ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease,coronary heart disease,clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome•History of congenital QTsyndrome•History or presence of an abnormal ECG that is clinically significant in the investigator's opinion•QTinterval corrected through use of Fridericia's formula>48 ms per ECG within 14 d before randomiz•Significant vascular disease within 6 m prior to D1 of C1•Evidence of bleeding diathesis or significant coagulopathy•History abdominal or tracheoesophageal fistula or gastroint perfor within 6 m prior to D1 of C1•Concom anticoagulation with coumarin agents, direct thrombin inhibitor dabigatran, direct factor Xa inhibitor betrixaban, or platelet inhibitors•Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding•Evidence of abdominal free air not explained by paracentesis or recent surgical procedure•Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture•Prior history of hypertensive crisis or hypertensive encephalopathy• |
| •Trattamento con terapia antitumorale nei 28 g precedenti l’inizio del trattamento in studio.•Pazienti trattati con cabozantinib in qualsiasi momento prima dello screening. •Pazienti sottoposti a più di 1 regime di ICI .•Pz sottoposti a più di 2 linee precedenti di terapia nel setting avanzato o metastatico.•Pazienti trattati con ICI nel setting adiuvante .•Pz trattati con un inibitore del bersaglio della rapamicina nei mammiferi (mTOR) nel setting avanzato o metastatico•Metastasi a carico del sistema nervoso centrale (SNC) sintomatiche, non trattate o in progressione attiva•Anamnesi positiva per malattia leptomeningea.•Dolore non controllato correlato al tumore•Versamento pleurico, versamento pericardico o ascite non controllato che necessita di ricorrenti procedure di drenaggio .•Insufficienza epatica da moderata a severa •Ipercalcemia non controllata o sintomatica o ipercalcemia sintomatica che necessita dell’utilizzo continuativo di una terapia a base di bifosfonati o denosumab•Anamnesi positiva per neoplasia maligna diversa dal carcinoma renale nei 5 anni precedenti lo screening, eccetto per quelle neoplasie caratterizzate da un rischio trascurabile di metastasi o decesso, quali forme adeguatamente trattate di carcinoma in situ della cervice, carcinoma cutaneo non melanomatoso, tumore localizzato della prostata, carcinoma duttale in situ o tumore uterino in stadio I.•Radioterapia per l’RCC nei 14 g precedenti il Giorno 1 del Ciclo 1.•Tubercolosi attiva.•Procedure di chirurgia maggiore, per ragioni diverse dalla diagnosi, nelle 4 sett precedenti l’inizio del tratt in studio o necessità prevista di una procedura di chirurgia maggiore durante lo studio•Gravidanza o allattamento o intenzione di iniziare una gravidanza durante il tratt in •Infezione severa nelle 4 sett precedenti l’inizio del tratt in studio.•Tratt con un vaccino vivo attenuato nelle 4 sett precedenti l’inizio del tratt in studio o necessità prevista di ricevere un vaccino vivo attenuato durante il trattamento con atezolizumab o nei 5 mesi successivi l’ultima dose di atezolizumab.•Tratt con immunostimolanti sistemici precedenti l’inizio del tratt in studio.•Tratt con immunosoppressori sistemici nelle 2 sett precedenti l’inizio del tratt in studio o necessità prevista di immunosoppressori sistemici durante il tratt in studio•Tratt con antibiotici terapeutici orali o e.v. nelle 2 sett precedenti l’inizio del tratt in studio•Precedente trapianto allogenico di cellule staminali o di organi solidi.•Qualsiasi altra malattia, disfunzione metabolica, obiettività o referto di laboratorio che rappresenti una controindicazione all’uso di un farmaco sperimentale, che possa interferire con l’interpretazione dei risultati o che possa esporre il paziente ad alto rischio di complicanze associate al tratt.•Tratt in corso con una terapia antivirale per l’HBV o l’HCV.•Malattia autoimmune o immunodeficienza attiva o pregressa•Anamnesi positiva per fibrosi polmonare idiopatica, polmonite in organizzazione,polmonite indotta da farmaci o polmonite idiopatica, oppure evidenza di polmonite attiva alla TAC del torace allo screening•Pz con rari problemi ereditari di intolleranza al galattosio, deficit di Lapp lattasi o malassorbimento di glucosio-galattosio•Ipertensione non controllata•Ictus•Cardiovasculopatia significativa •Anamnesi positiva per disaritmie ventricolari •Anamnesi positiva per sindrome del QT congenita•Anamnesi positiva per o presenza di anomalie all’elettrocardiogramma•Intervallo QT corretto secondo la formula di Fridericia•Vasculopatia significativa •Evidenza di diatesi emorragica o coagulopatia significativa•Anamnesi positiva per fistola addominale o tracheoesofagea o perforazione gastrointestinale •Tratt anticoagulante concomitante con agenti cumarinici •Segni o sintomi clinici di occlusione GI •Evidenze di aria libera a livello addominale •Ferita grave•Anamnesi positiva per crisi o encefalopatia ipertensiva •Pazienti non in grado di deglutire una compressa |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free survival as assessed by Independent Review Facility (IRF)
2. Overall survival |
1. Sopravvivenza libera da progressione valutata dall'Independent Review Facility (IRF)
2. Sopravvivenza globale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Approximately 55 months |
| 1. Circa 55 mesi |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free survival as assessed by investigators
2. Investigator- and IRF-assessed objective response rate
3. Investigator- and IRF-assessed duration of objective response
4. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0
5. Change from baseline in targeted vital signs
6. Change from baseline in targeted clinical laboratory test results
7. Atezolizumab concentrations at specified timepoints (for atezolizumab+ cabozantinib arm)
8. Cabozantinib concentrations at specified timepoints
9. Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and incidence of ADAs to atezolizumab during the study (for atezolizumab+ cabozantinib arm)
|
1. Sopravvivenza libera da progressione valutata dagli investigatori
2. Tasso di risposta obiettiva valutato dall'investigatore e dall'IRF
3. Durata della risposta obiettiva valutata dall'investigatore e dall'IRF
4. Incidenza e gravità degli eventi avversi, con gravità determinata in base ai criteri terminologici comuni del National Cancer Institute per gli eventi avversi Versione 5.0
5. Cambiamento dalla linea di base in segni vitali mirati
6. Variazione rispetto al basale nei risultati di test clinici di laboratorio mirati
7. Concentrazioni di Atezolizumab a punti temporali specifici (per braccio atezolizumab + cabozantinib)
8. Concentrazioni di cabozantinib a punti temporali specifici
9. Prevalenza di anticorpi anti-farmaco (ADA) ad atezolizumab al basale e incidenza di ADA ad atezolizumab durante lo studio (per braccio atezolizumab + cabozantinib) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4. Approximately 55 months
5-6. From baseline (Day-28 to -1) to 55 months
7. Day 1 of Cycle 1-4, 8, 12, 16 and at treatment discontinuation visit (for atezolizumab+ cabozantinib arm)
8. Day 1 of Cycle 2-4, and at treatment discontinuation visit
9. Day 1 of Cycle 1-4, 8, 12, 16 and at treatment discontinuation visit (for atezolizumab+ cabozantinib arm)
|
1-4. 55 mesi circa
5-6. Dal basale (giorno 28 a -1) a 55 mesi
7. Giorno 1 del ciclo 1-4, 8, 12, 16 e alla visita di sospensione del trattamento (per braccio atezolizumab + cabozantinib)
8. Giorno 1 del ciclo 2-4 e alla visita di sospensione del trattamento
9. Giorno 1 del ciclo 1-4, 8, 12, 16 e alla visita di sospensione del trattamento (per braccio atezolizumab + cabozantinib) |
|
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United States |
| Denmark |
| France |
| Germany |
| Greece |
| Italy |
| Poland |
| Spain |
| United Kingdom |
| Argentina |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
The end of this study is defined as the date when the required numbers of events for the final analysis of OS in the ITT population has occurred.
In addition, the Sponsor may decide to terminate the study at any time. |
| La fine di questo studio è definita come la data in cui i numeri richiesti di eventi per l'analisi finale del sistema operativo nella popolazione ITT. Inoltre, lo sponsor può decidere di interrompere lo studio in qualsiasi momento. |
|
| 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 | 55 |
| 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 | 55 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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