| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal carcinoma (mCRC) |
| Carcinoma metastatico del colon-retto |
|
| E.1.1.1 | Medical condition in easily understood language |
| Intestinal tumor |
| Tumore dell'intestino |
|
| 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 | 14.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10010023 |
| E.1.2 | Term | Colorectal neoplasms malignant |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| Define the antitumor activity of the anti-HER2 combinations of lapatinib + trastuzumab and pertuzumab + trastuzumab given to two separate, sequential cohorts of patients with chemo-refractory advanced disease and HER2 amplified tumours. |
| Definire l’attività antitumorale delle combinazioni anti-HER2. lapatinib + trastuzumab e pertuzumab + trastuzumab in due coorti separate e sequenziali di pazienti con malattia metastatica refrattaria e amplificazione di HER 2. |
|
| E.2.2 | Secondary objectives of the trial |
| 1. Define the safety profile of the two combinations 2. Define the Progression Free Survival (PFS) |
| 1. Definire il profilo di tollerabilità delle due combinazioni. 2. Definire il tempo di sopravvivenza senza progressione di malattia (PFS). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Subjects must meet all the following inclusion criteria to be eligible for enrolment into the study: 1. Histological/confirmed adenocarcinoma of the colon or rectum with metastatic disease not amenable to salvage surgery 2. Pathology mandatory requirements: a. the original tumour specimen must be KRAS WT and HER2 IHC 3+ positive, with ≥ 50% positive cells. This criterium is pending confirmation from the ongoing HERACLES DGX validation study. b. the original paraffin block or a minimum of 15 polarized unstained slides from the original paraffin block must be made available to the Pathology Core within 15 days from registration. 3. Age ≥18 4. ECOG PS 0-1 5. Measurable disease as defined by RECIST 1.1 criteria 6. Progression (PD) while on treatment, or within 6 months from therapy with approved standard drugs 7. Unless otherwise contraindicated patients should have received and failed the following previous therapies for mCRC: fluoropirimidines, oxaliplatin, irinotecan, cetuximab or panitumumab containing regimens. Bevacizumab is allowed 8. Adequate haematological function as defined by: ANC 1.5 x 109/L, platelet count 100 x 109/L, haemoglobin 10 g/dL. 9. Adequate renal function, as defined by: creatinine 1.5 x UNL 10. Adequate hepatobiliary function, as defined by the following baseline liver function tests: o total serum bilirubin 1.5 upper normal limit (UNL) o alanine aminotransferase (ALT), aspartate aminotransferase (AST) 2.5xUNL o alkaline phosphatase (AP) 2.5xUNL; if total alkaline phosphatase (AP) > 2.5xUNL, alkaline phosphatase liver fraction must be 2.5xUNL 11. Adequate contraception for all fertile patients 12. Negative pregnancy test. |
| I soggetti devono rispondere a tutti i seguenti criteri d’inclusione per poter essere considerati eleggibili per lo studio: 1. Conferma istologica di adenocarcinoma of the colon - retto con malattia metastatica non trattabile chirurgicamente 2. Requisiti patologici obbligatori : a. Il reperto tumorale originale deve essere KRAS WT e HER2 IHC 3+ positivo, con ≥50% cellule positive. La conferma di questo criterio dipende dai risultati dello studio di validazione Heracles DGX in corso. b. Il blocchetto originale di araffina o in alterantiva un minimo di 15 vetrini polarizzati non colorati devono essere resi disponibili al Pathology Core entro 15 giorni dalla registrazione 3. Età ≥18 4. ECOG PS 0-1 5. Malattia misurale secondo i criteri RECIST 1.1 6. Progressione (PD) durante il trattamento o entro 6 mesi da una terapia standard 7. Se non diversamente specificato i pazienti dovrebbero aver ricevuto, senza successo terapeutico, precedenti regimi contenenti i seguenti farmaci per il carcinoma colon retto metastatico: fluoropirimidine, oxaliplatino, irinotecan, cetuximab o panitumumab. L’uso di Bevacizumab è consentito 8. Adeguata funzionalità ematologica così definita: ANC 1.5 x 109/L, piastrine 100 x 109/L, emoglobina 10 g/dL. 9. Adeguata funzionalità renale, così defrinita: creatinina 1.5 x UNL 10. Adequate funzionalità epatobiliare, così definite dai seguenti tests di funzionalità epatica al basale: o bilirubina serica totale 1.5 limite superiore (UNL) o alanina aminotransferasi (ALT), aspartato aminotransferasi (AST) 2.5xUNL o fosfatasi alkalina (AP) 2.5xUNL; se la fosfatasi alkalina totale (AP) > 2.5xUNL, la frazione epatica della fosfatasi alkalina deve essere 2.5xUNL 11. Adeguate misure contraccettive per tutte le pazienti fertili 12. Test di gravidanza negativo . |
|
| E.4 | Principal exclusion criteria |
| Subjects meeting any of the following criteria must not be enrolled in the study: 1. Radiotherapy ≤ 4 weeks prior to enrolment 2. Other chemotherapy or biological therapy treatment ≤ 4 weeks prior to enrolment 3. Symptomatic brain metastases 4. Active infection 5. Gastro-intestinal abnormalities, inability to take oral medication, any condition affecting absorption 6. Impaired cardiac function including any of the following: uncontrolled hypertension (systolic >150 mmHg and/or diastolic > 100 mmHg) or clinically significant (ie active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication; unstable angina; chronic heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher; or serious cardiac arrhythmia requiring medication, baseline Left Ventricular Ejection Fraction (LVEF) ≤ 55% measured by echocardiography (ECHO) 7. Major surgery in the two weeks prior to entering the clinical trial 8. Concurrent treatment with any other anti-cancer therapy 9. History of another neoplastic disease (except basal cell carcinoma of the skin or uterine cervix carcinoma in situ adequately treated), unless in remission for ≥ 5 years 10. Patient unable to comply with the study protocol owing to psychological, social or geographical reasons 11. Pregnant and lactating women 12. Patients with history of hypersensitivity to either IMPs or excipients 13. Men and women of childbearing potential who are not using an effective method of contraception 14. Participation in another clinical trial or treatment with any investigational product within 4 weeks prior to inclusion in this study. 15. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) |
| I soggetti che rispondono a qualunque dei seguenti criteri non possono essere arruolati nello studio: 1. Radioterapia ≤ 4 settimane prima dell’arruolamento 2. Altre chemioterapie o trattamenti con terapie biologiche ≤ 4 settimane prima dell’arruolamento 3. Metastasi cerebrali sintomatiche 4. Infezioni attive 5. Presenza di patologie gastrointestinali, incapacità ad assumere farmaci orali e qualunque condizione che possa compromettere l’assorbimento. 6. Presenza di gravi patologie cardiache che includano: ipertensione non controllata (sistolica >150 mmHg e/o diastolica > 100 mmHg) o malattie cardiovascolari (ie active): ictus o stroke cerebrovascolare, infarto del miocardio entro 6 mesi dal trattamento; angina instabile; insufficienza cardiaca cronica (CHF) di Grado II o più alto secondo la scala della “New York Heart Association” (NYHA); o aritmia grave che richieda l’uso di farmaci, frazione di eiezione al basale (LVEF) ≤ 55% misurata mediante echocardiografia 7. Interventi chirurgici importanti nelle due settimane precedenti al trattamento 8. Trattamenti concomitanti con altri farmaci antitumorali 9. Precedenti malattie neoplastiche (ad eccezione del basalioma e del carcinoma in situ della cervice uterina adeguatamente trattato), se non in remissione da almeno 5 anni 10. Pazienti incapaci di aderire al protocollo di studio per ragioni psicologiche sociali o geografiche 11. Donne in gravidanza o allattamento 12. Pazienti con una storia di ipersensibilità ai farmaci in studio o ai loro eccipienti 13. Uomini e donne potenzialmente fertili che non usano efficaci sistemi contraccettivi 14. Partecipazione ad un altro studio clinico o trattamento con un farmaco sperimentale entro 4 settimane dall’inclusione in questo studio. 15. Soggetti che hanno malattie epatiche o biliari attive (ad eccezione della sindrome di Gilbert, calcolosi biliare asintomatica, metastasi epatiche o malattia epatica cronica stabile a giudizio dell’investigatore) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate according to RECIST 1.1 criteria |
| Percentuale di risposte obiettive secondo i criteri RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor response will be assessed starting on week 8 and every 8 weeks thereafter. Tumor response MUST be confirmed 4 + 1week from first assessment of response. |
| La risposta tumorale sarà valutata a partire da 8 settimane dopo l’inizio del trattamento e successivamente ogni 8 settimane . La risposta tumorale DEVE essere confermata 4 + 1 settimana dalla prima valutazione di risposta. |
|
| E.5.2 | Secondary end point(s) |
| 1. Description of the frequency and severity of Adverse Events based on the NCI –CTCAE V4.0 2. PFS 3. Correlation between selected tumor biomarkers evaluated in tumor specimens (including but not limited to mutations of effectors downstream of HER-family receptors - such as KRAS, BRAF, and PIK3CA, or related tyrosine kinase receptors), and tumor response/resistance to experimental treatment 2. Comparison of tumor biomarkers status in blood samples collected before start of treatment, with that collected during treatment and after progression |
| 1. Descrizione della frequenza e della severità degli eventi avversi basata su gli NCI –CTCAE V4.0 2. PFS 3. Correlazione tra bio-marcatori tumorali selezionati, valutati nei campioni tumorali (non limitati alle mutazioni degli effettori a valle della famiglia dei recettori HER, come KRAS, BRAF e PIK3CA, o dei correlati recettori tirosina chinasi) e la risposta/resistenza al trattamento sperimentale. 4 Confronto dello status dei bio-marcatori tumorali nei campioni di sangue raccolti prima dell’inizio del trattamento, con quelli raccolti durante il trattamento e dopo la progressione |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study |
| per tutta la durata dello studio |
|
| 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 | 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) | 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Due gruppi sequenziali: i primi 27 pazienti eleggibili inseriti nel gruppo A, i successivi 27 nel B |
| It is a 2-sequential cohorts trial: 27 pts in cohort A, other 27 in B |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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
| 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 | 5 |
| 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
|
| Data base lock |
| Chiusura del database |
|
| 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 | 24 |
| E.8.9.1 | In the Member State concerned days | 0 |
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