| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| colorectal cancer |
| tumore del colon-retto |
|
| E.1.1.1 | Medical condition in easily understood language |
| colorectal cancer |
| tumore 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 | 17.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10008442 |
| E.1.2 | Term | Chemotherapies |
| E.1.2 | System Organ Class | 100000004865 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10069759 |
| E.1.2 | Term | KRAS mutation |
| E.1.2 | System Organ Class | 100000004867 |
|
| 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 |
| Progression free survival |
| sopravvivenza libera da malattia |
|
| E.2.2 | Secondary objectives of the trial |
| Overall survival |
| Sopravvivenza globale |
|
| 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 |
| Tissue and blood biomarkers |
| analisi dei biomarcatori tissutali e plasmatici |
|
| E.3 | Principal inclusion criteria |
• Signed Informed Consent Form
• Histologically or cytologically confirmed adenocarcinoma of the colon and/or rectum, with MGMT promoter methylation and RAS mutation.
• Progressive disease on or after a first-line oxaliplatin-containing chemotherapy regimen for mCRC with or without bevacizumab or other anti-angiogenic drugs. Patients with documented disease relapsed within 6 months from the completion of adjuvant oxaliplatin-based chemotherapy are considered eligible.
• Patients must have received oxaliplatin-containing chemotherapy for ≥ 3 months. No more than one prior chemotherapy regimen for metastatic disease is allowed.
• Disease that is measurable per RECIST v1.1
• Age ≥ 18 years and ≤ 75 years
• Life expectancy ≥ 12 weeks
• ECOG Performance Status of 0 or 1
• Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to first administration of study treatment: ANC ≥ 1500/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 9.0 g/dL Albumin ≥ 2.5 g/dL
• Total bilirubin ≤ 1.5 × the upper limit of normal (ULN)
• AST, ALT, and/or alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions: Patients with documented hepatic metastases are eligible with AST, ALT, and/or alkaline phosphatase ≤ 5 × ULN. Patients with documented bone metastases are eligible with alkaline phosphatase ≤ 5 × ULN.
• Serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 − age) × (weight in kg) × (0.85 if female) 72 × (serum creatinine in mg/dL)
• INR and aPTT ≤ 1.5 × ULN
• For female patients of childbearing potential and male patients with partners of childbearing potential, documented agreement (by patient and/or partner) to use an effective means of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants) and to continue its use for the duration of the study and for 60 days for female patients or 150 days for male patients with partners of childbearing potential after the last infusion of study treatment.
• Consent to provide mandatory archival tumor tissue for biomarker testing
|
I pazienti devono soddisfare i seguenti criteri per poter essere inclusi nello studio:
• Firmare consenso informato scritto.
• Essere affetti da adenocarcinoma del colon, con metilazione del promotore di MGMT. La determinazione dello stato di RAS è richiesta prima dell’arruolamento.
• Malattia in progressione dopo una I linea con regime contenente oxaliplatino con o senza anticorpi monoclonali (bevacizumab, cetuximab, panitumumab).
I pazienti devono essere stati trattati con schemi chemioterapici contenenti oxaliplatino per almeno 3 mesi. Non più di un trattamento precedente per malattia metastatica è permesso.
• malattia misurabile in accordo con i criteri RECIST v1.1
• Età ≥ 18 anni
• Aspettativa di vita ≥ 12 settimane
• ECOG Performance Status di 0 o 1
• Adeguati valori emometrici e funzionalità epatica e renale, definiti dai seguenti risultati di laboratorio ottenuti entro 14 giorni prima della prima somministrazione del trattamento in studio: leucociti neutrofili ≥ 1500/μL conta piastrinica ≥ 100,000/μL, emoglobina ≥ 9.0 g/dL, albumina ≥ 2.5 g/dL
bilirubina totale ≤ 1.5 rispetto al limite normale superiore (ULN)
I pazienti con nota malattia di Gilbert con valori di bilirubina sierica ≤ 3 × ULN possono essere arruolati.
AST, ALT, e/o fosfatasi alcalina ≤ 2.5 × ULN, con le seguenti eccezioni:
-pazienti con documentate metastasi epatiche sono eleggibili con AST, ALT, e/o fosfatasi alcalina ≤ 5 × ULN.
-pazienti con documentate metastasi epatiche sono eleggibili con valori di fosfatsi alcalina ≤ 5 × ULN.
-valori di creatinina sierica ≤ 1.5 × ULN, o creatinina clearance ≥ 50 mL/min al basale , valutata con la formula di Cockcroft-Gault:
(140 − age) × (peso in kg) × (0.85 se donna)
72 × (creatinina sierica in mg/dL)
-INR e aPTT ≤ 1.5 × ULN
• per pazienti donne in età fertile o pazienti maschi con partner in età fertile, è necessario documentare il consenso all’uso di metodi contraccettivi (per esempio sterilizzazione chirurgica, metodi contraccettivi di barriera, pillola contraccettiva, o impianti ormonali contraccettivi) e raccomandarne l’utilizzo per tutta la durata dello studio e per 60 giorni per pazienti donne o 150 giorni per pazienti maschi con partner in età fertile, dopo l’ultima somministrazione del trattamento
|
|
| E.4 | Principal exclusion criteria |
• Prior treatment with irinotecan and temozolomide
• Major surgical procedure within 4 weeks and radiotherapy within 2 weeks prior to Day 1 Cycle 1
• Symptomatic hypercalcemia requiring continued use of bisphosphonate therapy. Patients who are receiving bisphosphonate therapy specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.
• Known clinically significant dihydropyrimidine dehydrogenase deficiency
• Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing disorders; ulcers or bone fractures), active infection requiring IV antibiotics
• History of heart failure of any New York Heart Association criteria or serious cardiac arrhythmia requiring treatment (except for atrial fibrillation and paroxysmal supraventricular tachycardia)
• History of myocardial infarction within 6 months prior to Cycle 1, Day 1, or history of unstable angina
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; or current alcohol abuse
• History of bleeding diathesis or coagulopathy other than that due to anticoagulation therapy
• Patients receiving oral coumarin-derived anticoagulants
• Active haemoptysis (defined as bright red blood of ½ teaspoon or more) within 30 days prior to Cycle 1, Day 1
• Known HIV infection
• Untreated/active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible provided they meet all of the following criteria:
Measurable disease outside the CNS as defined by RECIST v1.1.Radiotherapy completed ≥ 4 weeks prior to Cycle, 1 Day 1
• Pregnancy (positive pregnancy test) or lactation. Women of childbearing potential (including those who have had a tubal ligation) must have a documented negative serum pregnancy test within 14 days prior to Cycle 1, Day 1.
• Inability to take oral medications.
• Malignancies other than CRC within 3 years prior to randomization, with the exception of adequately treated basal or squamous cell skin cancer and carcinoma in situ of the cervix
|
• precedente trattamento con irinotecan o temozolomide
• intervento di chirurgia maggiore entro 4 settimane dal primo giorno del primo ciclo
• malattia leptomeningea come unica localizzazione di malattia
• Infezioni attive che richiedano antibiotici ev
• malattia autoimmune attiva e non controllata da anti-infiammatori non steroidei
• ipercalcemia sintomatica che richieda uso continuo di bifosfonati. Pazienti che hanno ricevuto trattamenti con bifosfonati come prevenzione per eventi scheletrici e che non hanno una storia di ipercalcemia possono essere arruolati.
• Deficit noto di diidropirimidina deidrogenasi.
• Malattia sistemica grave (es. Malattia cardiovascolare, polmonare clinicamente significative, malattia metabolica, ulcere; fratture d’osso)
• Storia di cardiopatie di qualunque grado rispetto ai criteri della New
York Heart Association o seria aritmia cardiaca che richieda trattamento (tranne che per fibrillazione atriale e tachicardia parossistica sopraventricolare)
• Storia di infarto del miocardio entro 6 mesi prima del giorno 1 del primo ciclo, o storia di angina instabile
• Nota malattia epatica clinicamente significativa, incluse epatiti virali in fase acuta, epatiti alcoliche o di altra natura; cirrosi epatica; o corrente abuso di alcool
• Storia di diatesi emorragica o di coagulopatie diverse da quelle causate da terapia anti-coagulante
• Emottisi attiva (definite come defined as bright red blood of ½ teaspoon or more) within 30 days prior to Cycle 1, Day 1
• Sanguinamento gastroenterico clinicamente significativo (sanguinamento che richieda procedure chirurgiche come bendaggio di varici esofagee, shunt porto-sistemico intraepatico, embolizzazione arteriosa, coagulazione topica) entro 6 giorni prima dal giorni 1 del primo ciclo
• Storia di ILD
• Storia di reazione allergia o iper-sensibilizzaizone severa (Grado 3 o 4) a terapia antibiotica che richieda discontinuazione di tale trattamento
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • To evaluate the efficacy, measured by progression-free survival, of FOLFIRI (administered every 2 weeks) versus CAPTEM (administered four-weekly) |
| Valutare l’efficacia, misurata come sopravvivenza libera da malattia (PFS), di FOLFIRI (somministrato ogni 2 settimane) versus CAPTEM; (somministrato ogni 4 settimane) in pazienti con mCRC |
|
| 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) |
To evaluate the activity of the two regimens, as measured by response rate; secondary efficacy endpoints also include duration of response and overall survival of FOLFIRI (administered every 2 weeks) versus CAPTEM (administered four-weekly)
• To evaluate the safety and tolerability of FOLFIRI versus CAPTEM
• To assess the quality of life as measured by EORTC QLQ – CR29 QLQ-C30
|
Valutare l’attività dei due regimi misurata come tasso di risposta (response rate, RR); un endpoint secondario riguarda invece l’ efficacia, misurata come durata di risposta e sopravvivenza (overall survival, OS) del FOLFIRI (somministrato ogni due settimane) versus CAPTEM (somministrato ogni quattro settimane) nei pazienti con mCRC
• Valutare la sicurezza e la tollerabilità dello schema FOLFIRI versus CAPTEM
• Monitorare la qualità di vita come valutato EORTC QLQ – CR29 QLQ-C30
|
|
| 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 | 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 | 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 | 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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