| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| METASTATIC COLORECTAL CANCER |
| Carcinoma colorettale metastatico (mCRC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic tumor of colon-rectum |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 main objective of this trial is to compare the efficacy of the two proposed treatment strategies in terms of duration of Progression Free Survival 2 (PFS2). |
| Confrontare le due strategie proposte in termini di sopravvivenza libera da seconda progressione (PFS2) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study are to compare the two proposed treatment strategies in terms of:
-Duration of Progression Free Survival (PFS);
-Duration of 2nd-Progression Free Survival (2nd-PFS);
-Duration of Time to Failure of Strategy (TFS);
-Duration of Overall Survival (OS);
-Distribution of Objective Response Rate (ORR) during first- and second-line treatment;
-Distribution of Early Objective Response (EOR) during first-line treatment;
-Distribution of the rate of secondary R0 resection of metastases;
-Safety profile;
-Translational analyses. |
Confrontare le due strategie proposte in termini di:
prima sopravvivenza libera da progressione (PFS), seconda sopravvivenza libera da progressione (2nd-PFS), tempo al fallimento della strategia (TFS), sopravvivenza globale (OS), tasso di risposta in 1 ° e 2 ° linea, tasso di risposta precoce, tasso di resezione R0, profilo di tollerabilità, analisi traslazionali.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Histologically proven diagnosis of colorectal cancer
-Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease
-At least one measurable lesion according to RECIST1.1 criteria
-Availability of a tumoral sample
-Male or female of 18-75 years of age
-ECOG PS < or = 2 if aged < 71 years, ECOG PS = 0 if aged 71-75 years
-Life expectancy of at least 12 weeks
-Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy and more than 6 months elapsed between the end of adjuvant and first relapse
-Neutrophils >1.5 x 109/L, Platelets >100 x 109/L, Hgb >9 g/dl
-Total bilirubin 1.5 time the upper-normal limits (UNL) of the normal values and ASAT (SGOT) and/or ALAT (SGPT) <2.5 x UNL (or <5 x UNL in case of liver metastases) alkaline phosphatase <2.5 x UNL (or <5 x UNL in case of liver metastases)
-Creatinine clearance >50 mL/min or serum creatinine 1.5 x UNL
-Urine dipstick of proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate <1 g of protein/24 hr
-Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive.
-Subjects and their partners must be willing to avoid pregnancy during the trial and until 6 months after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore,
be willing to use adequate contraception as approved by the investigator (barriere contraceptive measure or oral contraception)
-Will and ability to comply with the protocol
-Written informed consent to study procedures and to molecular analyses. |
Diagnosi confermata istologicamente di adenocarcinoma del colon-retto
Malattia metastatica inizialmente non resecabile e non precedentemente trattata con
chemioterapia
Almeno una lesione misurabile secondo i criteri RECIST 1.1
Disponibilità di campione tissutale di tumore primitivo e/o metastasi
Uomo o donna di età compresa tra 18-75 anni
ECOG PS < o = 2 se età < 71 anni, ECOG PS = 0 se età 71-75 anni
Aspettativa di vita di almeno 12 settimane
Una precedente chemioterapia adiuvante con fluoropirimidine in monoterapia è permessa se sono trascorsi almeno 6 mesi tra la fine dell’adiuvante e la prima recidiva;
Neutrofili 1.5 x 109/L, Piastrine 100 x 109/L, Emoglobina >9 g/dl;
Bilirubina totale 1.5 x limite superiore del valore normale (UNL) e AST (SGOT) e/o ALT (SGPT) 2.5 x UNL (o 5 x UNL in caso di metastasi epatiche), fosfatasi alcalina 2.5 x UNL (o 5 x UNL in caso di metastasi epatiche)
Clearance della creatinina >50 mL/min o creatinina sierica 1.5 x UNL; Proteinuria <2+. Pazienti che presentano basalmente proteinuria 2+ allo stick delle urine, devono eseguire una raccolta delle urine nelle 24 ore e avere una proteinuria/24h <1 g;
Le donne fertili devono avere test di gravidanza negativo eseguito alla visita basale su
campione di sangue. Per questo studio si intendono fertili tutte le donne dopo la
pubertà eccetto quelle in menopausa da almeno 12 mesi, quelle chirurgicamente
sterili o sessualmente inattive; pazienti e i loro partner devono evitare la gravidanza durante il trattamento e fino a 6 mesi dopo l’ultima somministrazione. I soggetti maschili con partner fertili e i soggetti femminili fertili devono quindi accettare l’uso di un adeguato metodo contraccettivo approvato dallo sperimentatore (es. barriera contraccettiva contraccettivo orale); Volontà e capacità di aderire il protocollo; Consenso informato scritto alle procedure dello studio e alle analisi molecolari. |
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| E.4 | Principal exclusion criteria |
Radiotherapy to any site within 4 weeks before the study
-Previous adjuvant oxaliplatin-containing chemotherapy
-Previous treatment with bevacizumab
-Untreated brain metastases or spinal cord compression or primary brain tumours
-History or evidence upon physical examination of CNS disease unless adequately treated
-Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria
-Serious, non-healing wound, ulcer, or bone fracture
-Evidence of bleeding diathesis or coagulopathy
-Uncontrolled hypertension and prior histor of hypertensive crisis or hypertensive encephalopathy
-Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication
-Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
-Any previous venous thromboembolism > NCI CTCAE Grade 3.
-History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment.
-Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes
Chronic, daily treatment with high-dose aspirin (>325 mg/day)
-Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer)
-Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ
-Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study
-Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication
-Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barriere contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment. |
Trattamento radioterapico in qualunque sede nelle 4 settimane precedenti lo studio, Precedente chemioterapia adiuvante con oxaliplatino, Precedente trattamento con bev, Metastasi cerebrali non trattate o compressione midollare o tumori cerebrali primitivi, Storia o evidenza obiettiva di malattia a carico del SNC a meno che adeguatamente trattata; Neuropatia periferica sintomatica di grado > 2 secondo i criteri NCI-CTC; Ferite gravi, non consolidate, ulcere, o fratture ossee; Evidenza di diatesi emorragica o coagulopatie; Ipertensione non controllata e anamnesi positiva per crisi ipertensive o encefalopatia ipertensiva; Malattie cardiovascolari clinicamente significative (in atto) per esempio eventi cerebrovascolari (≤6 mesi), infarto del miocardio (≤6 mesi), angina instabile, scompenso cardiaco grado NYHA > II, gravi aritmie che necessitano di terapia medica; Malattia vascolare significativa (ad esempio, aneurisma aortico che richiede la riparazione chirurgica o trombosi arteriosa recente) nei 6 mesi precedenti all’arruolamento nello studio;Qualsiasi precedente tromboembolismo venoso di grado >3 secondo i criteri NCI CTC; Storia di fistola addominale, perforazione gastrointestinale, ascesso intra-addominale o sanguinamento gastrointestinale attivo nei 6 mesi precedenti l’arruolamento nello studio; Trattamento con anticoagulanti a scopo terapeutico in atto o recente (nei 10 giorni precedenti l’inizio del trattamento in studio); Trattamento cronico, giornaliero con aspirina ad alte dosi (>325 mg/die); Trattamento con qualsiasi farmaco sperimentale nei 30 giorni precedenti l’arruolamento
oppure entro la durata di due emivite del farmaco sperimentale (quale dei due periodi sia più lungo); Altri tumori maligni coesistenti o diagnosticati nei 5 anni precedenti, fatta eccezione per il basalioma, il carcinoma squamocellulare della cute e il carcinoma in situ della cervice uterina; Chirurgia maggiore, biopsia aperta o gravi traumi nei 28 giorni precedenti l’inizio del trattamento in studio, o prevista necessità di una procedura chirurgica maggiore durante il corso dello studio; Mancanza di integrità fisica del tratto gastrointestinale superiore, sindrome da malassorbimento o impossibilità ad assumere una terapia orale; Donne in gravidanza o in allattamento. Le donne in età fertile con un test positivo di gravidanza o che non hanno effettuato un test di gravidanza alla visita basale. Uomini e donne (in età fertile) sessualmente attivi che rifiutano di utilizzare metodi contraccettivi (metodi di barriera o contraccettivi orali) durante lo studio e fino a 6 mesi dopo l’ultima
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is Progression Free Survival 2 (PFS2).
PFS2 will be defined as beginning with randomization and ending with the first of the following events: a) death; b) disease progression on any treatment given after 1st progression. For patients that will not receive any treatment within 3 months after 1st progression, PFS2 will be equal to PFS. The determination of disease progression will be based on investigator-reported measurements. Disease status will be evaluated according to RECIST 1.1 criteria.
Censoring rules for PFS2 will be: end of study without PD, loss at follow-up. Curative surgery for metastasis will not result in censoring for PFS2.
PFS2 will be analyzed both in the intention-to-treat population (primary analysis) and in the per-protocol population. |
| sopravvivenza libera da seconda progressione (PFS2) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| every 8 weeks |
| ogni 8 settimane |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints of this study are the following:
Progression free survival (PFS) is defined as the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis. Alive patients having no tumor assessments after baseline will have time to event censored on the date of randomization.2nd-Progression free survival (2nd-PFS) is defined as the time from the beginning of the second-line treatment to the documentation of objective disease progression or death due to any cause, whichever occurs first. 2nd-PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive, on study and 2nd-progression free at the time of the analysis. 2nd-PFS will be analyzed both in the intention-to-treat population (whichever 2nd-line treatment will be adopted) and in the per-protocol population.
Time to failure of strategy (TFS) is defined as the time time from randomization to the first of the following events: death; patient requires the addition of a new therapeutic agent (i.e. an agent not included in the original strategy); patient experiences disease progression while being treated with all agents that are components of the initial treatment strategy (except for agents which cannot be used because of persistent toxicity or contraindications); or patient experiences disease progression during a partial or complete treatment holiday from initial treatment strategy and receives no further therapy within 3 months. Subjects who did not have an event as stated above while on study will be censored at the last evaluable radiographic assessment date. TFS will be analyzed both in the intention-to-treat population (primary analysis) and in the per-protocol population.
Overall survival (OS) is defined as the time from randomization to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.
Objective Response Rate is defined as the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria, during the induction and the maintenance phases of treatment. The determination of clinical response will be based on investigator reported measurements. Responses will be evaluated every 8 weeks.Early Objective Response Rate is defined as the percentage of patients, relative to the total of the enrolled subjects, achieving a 20% decrease in the sum of diameters of RECIST target lesions at week 8 compared to baseline.
R0 Resection Rate is defined as the percentage of patients, relative to the total of enrolled subjects, undergoing secondary R0 resection of metastases. Secondary R0 surgery is defined as microscopically margin free complete surgical removal of all residual disease, performed during treatment or after its completion, allowed by tumoral shrinkage and/or disappearance of one or more lesions.
Overall Toxicity Rate is defined as the percentage of patients, relative to the total of enrolled subjects, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 4.0), during the induction and the maintenance phases of treatment.
Toxicity Rate is defined as the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 4.0), during the induction and the maintenance phases of treatment. |
Il TFS è definito come il tempo dalla randomizzazione al primo dei seguenti eventi: decesso, introduzione di un nuovo farmaco (ovvero un farmaco non previsto nella strategia originale), endpoint misurato al primo dei seguenti eventi: tempo alla progressione o tempo all’introduzione del nuovo farmaco), evidenza di progressione di malattia durante il trattamento con tutti i farmaci della strategia iniziale, tranne per i farmaci che non possono essere utilizzati a causa di tossicità persistente o controindicazioni, evidenza di progressione di malattia in corso di interruzione parziale o totale del trattamento previsto dalla strategia iniziale in pazienti che non ricevono ulteriore terapia entro 3 mesi. I soggetti in cui non si sia verificato alcun evento, tra quelli sopracitati, in corso di trattamento in studio, saranno censorizzati all'ultima valutazione radiologica.
L’OS è definita come il tempo dalla randomizzazione alla data di morte per qualsiasi causa. Il tasso di risposta obiettiva è definito come la percentuale di pazienti, rispetto al totale dei soggetti arruolati, che raggiungono una completa (CR) o parziale (PR) risposta, secondo i criteri RECIST 1.1.
Il tasso di resezione R0 è definito come la percentuale di pazienti, rispetto al totale dei soggetti arruolati, sottoposti a resezione secondaria R0 delle metastasi.
Il tasso di tossicità complessiva è definito come la percentuale di pazienti, rispetto al totale dei soggetti arruolati, in cui si verifica qualsiasi evento avverso, secondo i criteri del National Cancer Institute Common Toxicity (versione 4.0), durante l'induzione e le fasi di trattamento di mantenimento.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| every 8 weeks |
| ogni 8 settimane |
|
| 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 | Yes |
| 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 | Yes |
| 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 | 60 |
| 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 | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 54 |
| E.8.9.1 | In the Member State concerned days | |
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