| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Colorectal carcinoma |
| carcinoma del colon-retto |
|
| E.1.1.1 | Medical condition in easily understood language |
| Intestinal cancer |
| carcinoma del colon-retto |
|
| 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 | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| 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 |
| The primary objective of this study is to determine the anti-tumor activity, as measured by overall response rate (ORR) of atezolizumab in combination with bevacizumab in patients with chemotherapy resistant CRC and positivity for MSI-like molecular signature. |
| L¿obiettivo primario di questo studio ¿ determinare l¿attivit¿ antitumorale, misurata in base al tasso di risposta complessiva (ORR), di atezolizumab in combinazione con bevacizumab in pazienti con carcinoma del colon-retto (CRC) resistente alla chemioterapia e presenza di caratteristiche molecolari indicative di instabilit¿ dei microsatelliti (MSI). |
|
| E.2.2 | Secondary objectives of the trial |
¿ To assess anti-tumor activity of atezolizumab combined with bevacizumab as measured by duration of response and time to response, immune-related tumor response, progression free survival (PFS) and overall survival (OS).
¿ To determine the anti-tumor activity, as measured by ORR of atezolizumab in combination with bevacizumab in the subgroup of patients with chemotherapy resistant CRC and positive for both MSI-like signature and ¿real MSI¿ by standard testing ¿ immunohistochemistry (IHC) or PCR.
¿ To determine the anti-tumor activity, as measured by ORR of atezolizumab in combination with bevacizumab in the subgroup of patients with chemotherapy resistant CRC and positive for MSI-like signature but ¿MSS¿ by standard testing.
¿ To characterize the safety and tolerability of atezolizumab plus bevacizumab as assessed by the incidence and severity of adverse events. |
¿ To evaluate anti-tumor activity of atzolizumab combined with bevacizumab as measured by duration of response and time to response, immune-related tumor response, progression free survival (PFS) and overall survival (OS).
¿ To determine the anti-tumor activity, as measured by ORR of atezolizumab in combination with bevacizumab in the subgroup of patients with chemotherapy resistant CRC and positive for both MSI-like signature and "real MSI" by standard testing - immunohistochemistry (IHC) or PCR.
¿ To determine the anti-tumor activity, as measured by ORR of atezolizumab in combination with bevacizumab in the subgroup of patients with chemotherapy resistant CRC and positive for MSI-like signature but "MSS" by standard testing.
¿ To characterize the safety and tolerability of atezolizumab plus bevacizumab as assessed by the incidence and severity of adverse events. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
· Written informed consent must be given according to ICH/GCP and national/local regulations.
· Histological or cytological proof of metastatic CRC.
· Disease progression or relapse after at least one line of treatment for advanced CRC with a fluoropyrimidine containing chemotherapy as single agent or in combination (combinations with oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab are allowed).
· Written documentation of positivity for MSI-like gene signature as determined by Agendia test.
· Unresectable disease, with at least one measurable lesion according to RECIST 1.1.
· Age = 18 years.
· WHO performance status of 0-1.
· Ability and capacity to comply with study and follow-up procedures.
· Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 28 calendar days prior to the first study treatment:
- ANC > 1.5 x 109/L (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
- WBC counts > 2500/µL
- Platelet count > 100,000/ µL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
- Hemoglobin > 9.0 g/dL
- AST, ALT, and alkaline phosphatase < 2.5 x ULN, with the following exceptions:
i Patients with documented liver metastases: AST and ALT < 5 x ULN
ii Patients with documented liver or bone metastases: alkaline phosphatase < 5 x ULN
- Bilirubin <1.5 x ULN. Patients with known Gilbert disease who have serum bilirubin level < 3 x ULN may be enrolled.
- PT and PTT <1.5 x ULN, unless on a stable dose of warfarin
- Serum albumin > 2.5 g/dL
- Creatinine clearance > 30 mL/min (Cockcroft-Gault formula or based on 24-hour urine collection)
- Protein < 2+ on dipstick urinalysis or = 1.0 g in a 24-hour urine collection. All patients with =2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein.
· Women of child bearing potential (WOCBP) must have a negative serum pregnancy test before registration.
· Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last bevacizumab treatment (for women and men) and 5 months
after the last atezolizumab treatment (for women) . A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
· Female subjects who are breast feeding should discontinue nursing before trial registration and until 6 months after the last bevacizumab treatment and 5 months after the last atezolizumab treatment. |
· Il consenso informato scritto deve essere fornito secondo le norme ICH / GCP e nazionali / locali.
· Prova istologica o citologica del CRC metastatico.
· La progressione o la ricaduta di malattia dopo almeno una linea di trattamento per CRC avanzato con una chemioterapia contenente fluoropirimidina come agente singolo o in combinazione (sono consentite combinazioni con oxaliplatina, irinotecan, bevacizumab e cetuximab o panitumumab).
· Documentazione scritta della positività per la firma del gene simile a MSI come determinato dal test Agendia.
· Malattia non resecabile, con almeno una lesione misurabile secondo RECIST 1.1.
· Età = 18 anni.
· Stato di prestazioni OMS di 0-1.
· Capacità e capacità di conformarsi alle procedure di studio e follow-up.
· Funzione ematologica e end-organica adeguata, definita dai seguenti risultati di laboratorio ottenuti entro 28 giorni di calendario prima del primo studio:
- ANC> 1,5 x 109 / L (senza granulocyte fattore stimolante della colonia entro 2 settimane prima del ciclo 1, giorno 1)
- WBC conta> 2500 / µL
- conta piastrinica> 100.000 / µL (senza trasfusione entro 2 settimane prima del ciclo 1, giorno 1)
- emoglobina> 9,0 g / dL
- AST, ALT e fosfatasi alcalina <2,5 x ULN, con le seguenti eccezioni:
I pazienti con metastasi epatiche documentate: AST e ALT <5 x ULN
Ii Pazienti con metastasi documentate di fegato o ossa: fosfatasi alcalina <5 x ULN
Bilirubina <1,5 x ULN. Possono essere iscritti pazienti con malattia nota di Gilbert che hanno livelli di bilirubina nel siero <3 x ULN.
- PT e PTT <1,5 x ULN, a meno di una dose stabile di warfarin
- albumina di siero> 2,5 g / dL
- Liberazione della creatinina> 30 mL / min (formula Cockcroft-Gault o basata su una raccolta di urine di 24 ore)
- Proteina <2+ sulla analisi urinaria di livello o = 1,0 g in una raccolta di urina di 24 ore. Tutti i pazienti con proteina =2 + su analisi urinaria a livello di base devono essere sottoposti a una raccolta di urine di 24 ore per proteine.
· Le donne che hanno un potenziale portante dei bambini (WOCBP) devono essere sottoposte a test di gravidanza del siero negativo prima della registrazione.
· I pazienti in età fertile / riproduttiva dovrebbero utilizzare adeguate misure di controllo delle nascite, come definite dagli investigatori, durante il periodo di trattamento e per almeno 6 mesi dopo l'ultimo trattamento bevacizumab (per donne e uomini) e 5 mesi
Dopo l'ultimo trattamento con atezolizumab (per le donne). Un metodo altamente efficace per il controllo delle nascite è definito come quello che determina un basso tasso di guasto (cioè meno dell'1% all'anno) quando viene utilizzato in modo coerente e corretto.
· Gli allievi femminili che allattano devono interrompere l'infermiera prima della registrazione del trial e fino a 6 mesi dopo l'ultimo trattamento con bevacizumab e 5 mesi dopo l'ultimo trattamento con attezolizumab.
|
|
| E.4 | Principal exclusion criteria |
· Any treatment with investigational drugs within 28 d prior to Cycle 1, Day 1.
· Previous cytotoxic agent within 14 d of planed treatment initiation.
· Active or untreated CNS metastases as determined by computed CT or MRI
· Radiotherapy within 14 d prior to Cycle 1, Day 1.
· Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
· Previous (within the last 5 y) or concurrent malignancies, with the exception of those treated with expected curative outcome as cone-biopsied in situ carcinoma of the cervix, basal cell carcinoma of the skin, localized prostate cancer or ductal carcinoma in situ of the
breast.
· Life expectancy of < 12 w.
· History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
· Positive test for HIV.
· Active hepatitis B or hepatitis C.
· Active tuberculosis.
· Severe infections within 4 w prior to Cycle 1, Day 1.
· Infection within 2 w prior to Cycle 1, Day 1.
· Received therapeutic oral or IV antibiotics within 2 w prior to Cycle 1, Day 1.
· Significant cardiovascular or cerebrovascular disease
· Major surgical procedure within 28 d prior to cycle 1, day 1, or planned procedure or surgery during the study.
· Prior allogeneic stem cell or solid organ transplant.
· Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
· Prior treatment with CD137 agonists, anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapeutic antibody or immune-related pathway-targeting agents.
· Current or recent use of dipyridamole, ticlopidine, clopidogrel, or cilostazol .
· Unstable dose in the last 2 w prior to the first study treatment of prophylactic or therapeutic low molecular-weight heparin, direct thrombin inhibitors, or warfarin. Stable dose is permitted where appropriate anticoagulation indices are stable.
· Inadequately controlled hypertension.
· Prior history of hypertensive crisis or hypertensive encephalopathy.
· Significant vascular disease within 6 m prior to Cycle 1, Day 1.
· Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the bevacizumab or atezolizumab formulation.
· Evidence of bleeding diathesis or clinically significant coagulopathy.
· Patients with history of pulmonary hemorrhage/hemoptysis within 6 m prior to Cycle 1, Day 1.
· Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 calendar days prior to the first dose of bevacizumab.
· History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 m prior to Cycle 1, Day 1.
· Clinical signs or symptoms of gastrointestinal 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.
· 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:
· Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
· History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
· Administration of a live, attenuated vaccine within 4 w before Cycle 1, day 1
· Treatment with systemic immunostimulatory agents within 4 w or five half-lives of the drug, whichever is longer, prior to study treatment.
· Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 w prior to start of study maintenance treatment, or requirement for systemic immunosuppressive medications during the trial. The use of inhaled corticosteroids and mineralocorticoids is allowed.
· If receiving a RANKL inhibitor, unwilling to adopt alternative
treatment such as bisphosphonates, while receiving atezolizumab. |
· Qualsiasi trattamento con farmaci di ricerca entro 28 giorni prima del ciclo 1, giorno 1.
· Agente citotossico precedente entro 14 giorni dall'avvio del trattamento pianificato.
· Metastasi CNS attive o non trattate come determinato da CT o MRI calcolato
· Radioterapia entro 14 giorni prima del ciclo 1, giorno 1.
· Effusione pleurica non controllata, effusione pericardica o ascite che richiedono procedure di drenaggio ricorrenti.
· Malattie precedenti (entro gli ultimi 5 anni) o malattie concorrenti, ad eccezione di quelli trattati con l'esito curativo previsto, come carcinoma cono-biopsiato in situ della cervice, carcinoma delle cellule basali della pelle, tumore della prostata localizzata o carcinoma ductale in situ di il
Seno.
· Aspettativa di vita di <12 w.
· Storia di reazioni allergiche gravi, anafilattiche o di altre ipersensibilità agli anticorpi chimici o umanizzati o alle proteine ¿¿di fusione.
· Test positivo per l'HIV.
· Epatite B attiva o epatite C
· Tubercolosi attiva.
· Infezioni gravi entro 4 settimane prima del ciclo 1, giorno 1.
· Infezione entro 2 settimane prima del ciclo 1, giorno 1.
· Ricevuto antibiotici terapeutici orali o anti-IV entro 2 settimane prima del ciclo 1, giorno 1.
· Significativa malattia cardiovascolare o cerebrovascolare
· Maggiore procedura chirurgica entro 28 d prima del ciclo 1, primo giorno, o procedura programmata o intervento chirurgico durante lo studio.
Prima cellula staminale allogenica o trapianto di organi solidi.
· Qualsiasi altra malattia, disfunzione metabolica, esame di esame fisico o ricerca di laboratorio clinico che fornisca ragionevole sospetto di una malattia o di una condizione che controindichi l'uso di un farmaco in esame o che possa influenzare l'interpretazione dei risultati o rendere il paziente ad alto rischio dal trattamento complicazioni.
· Trattamento precedente con agonisti CD137, anticorpi terapeutici anti-CTLA-4, anti-PD-1 o anti-PD-L1 o agenti di targeting legati all'immunizzazione.
· Uso corrente o recente di dipiridamolo, ticlopidina, clopidogrel o cilostazolo.
· Dose instabile nell'ultima 2 settimane prima del primo studio di trattamento con eparina a basso peso molecolare profilattico o terapeutico, inibitori diretti di trombina o warfarin. La dose stabile è consentita laddove gli indici anticoagulanti siano stabili.
· Ipertensione insufficiente.
· Storia precedente di crisi ipertensiva o encefalopatia ipertensiva.
· Malattia vascolare significativa entro 6 m prima del ciclo 1, giorno 1.
· Ipersensibilità o allergia nota ai biofarmaceutici prodotti in cellule ovariche di criceto cinese o qualsiasi componente della formulazione bevacizumab o atezolizumab.
· Evidenza di diatesi emorragica o coagulopatia clinicamente significativa.
· Pazienti con storia di emorragia polmonare / hemoptysis entro 6 m prima del ciclo 1, giorno 1.
· La biopsia di base o un'altra procedura chirurgica minore, escluso il posizionamento di un dispositivo di accesso vascolare, entro 7 giorni di calendario prima della prima dose di bevacizumab.
· Storia della fistola addominale o tracheoesofagea o perforazione gastrointestinale entro 6 m prima del ciclo 1, giorno 1.
· Segni o sintomi clinici di ostruzione gastrointestinale o necessità di idratazione parenterale, nutrizione parenterale o alimentazione di tubi.
· Evidenza di aria libera addominale non spiegata con paracentesi o recente procedura chirurgica.
· Ferite gravi, non guarigione o dehiscing, ulcera attiva o frattura ossea non trattata.
· Storia della malattia autoimmune, inclusa ma non limitata a myasthenia gravis, miosite, epatite autoimmune, lupus eritematoso sistemico, artrite reumatoide, malattia infiammatoria intestinale, trombosi vascolare associata alla sindrome antifosfolipida,
La granulomatosi di Wegener, la sindrome di Sjögren, la sindrome di Guillain-Barré, la sclerosi multipla, la vasculite o la glomerulonefrite:
· Prelievo del trapianto di midollo osseo allogenico o del trapianto di organi solidi precedenti.
· Storia della fibrosi polmonare idiopatica, organizzazione della polmonite, polmonite indotta dalla droga, pneumonite idiopatica o prova di pneumonite attiva sulla scansione CT del torace.
· Amministrazione di un vaccino vivo e attenuato entro 4 settimane prima del ciclo 1, giorno 1
· Trattamento con agenti immunostimolanti sistemici entro 4 o 5 mesi di vita del farmaco, a seconda di quale sia più lungo, prima del trattamento dello studio.
· Trattamento con corticosteroidi sistemici o altri farmaci immunosoppressivi sistemici entro 2 settimane prima dell'inizio del trattamento di mantenimento dello studio o requisito di farmaci immunosoppressivi sistemici durante il processo. È consentito l'uso di corticosteroidi inalati e mineralogorticoidi.
· Se riceve un inibitore RANKL, non desideroso di adottare alternative
Trattamento come i bisfosfonati, mentre riceve l'atezolizumab. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is overall response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| every 9 weeks after C1D1 date |
|
| E.5.2 | Secondary end point(s) |
1. Duration of RECIST response.
2. Time to RECIST response.
3. Immune-related (ir) response rate as measured by irRC with the use of unidimensional measurement.
4. Progression free survival (PFS), defined as time from treatment initiation to progressive disease or death.
5. Overall survival (OS), defined as time from treatment initiation to death. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4. every 9 weeks after C1D1 date
5. at each visit |
|
| 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) | 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 | 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 | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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
|
End of study occurs when all of the following criteria have been satisfied:
¿ Thirty days after the last patient has stopped protocol treatment
¿ The trial is mature (i.e. reached the required number of events) for the analysis of the primary endpoint as defined in the protocol.
¿ The database has been fully cleaned and frozen for this analysis. |
Fine dello studio si verifica quando tutti i seguenti criteri sono stati soddisfatti:
¿ Trenta giorni dopo che l'ultimo paziente ha interrotto il trattamento del protocollo
¿ Il processo ¿ maturo (cio¿ ha raggiunto il numero di eventi richiesto) per l'analisi dell'endpoint primario come definito nel protocollo.
¿ Il database ¿ stato completamente pulito e congelato per questa analisi.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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