| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously untreated patients with CD20-positive follicular lymphoma, Grade 1, 2 or 3a according to the WHO 2008 classification system. |
| Pazienti precedentemente non trattati con linfoma follicolare CD-20 positivo di grado 1,2 o 3a secondo la classificazione WHO 2008. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously untreated patients with CD20-positive follicular lymphoma, Grade 1, 2 or 3a according to the WHO 2008 classification system |
| Pazienti precedentemente non trattati con linfoma follicolare CD-20 positivo di grado 1,2 o 3a secondo la classificazione WHO 2008. |
|
| 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 | LLT |
| E.1.2 | Classification code | 10059432 |
| E.1.2 | Term | Follicular mixed small and large cell lymphoma |
| 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 |
| To compare the CR+CRu rate of MK-8808 plus CHOP versus MabThera plus CHOP at week 20 (+/- 1 week) after randomization. |
| Confrontare il tasso di risposte complete (CR) e risposte complete non confermate (CRu) di MK-8808 più CHOP vs MabThera più CHOP alla settimana 20 ( +/- 1 settimana) dopo la randomizzazione. |
|
| E.2.2 | Secondary objectives of the trial |
| 1. To compare MK-8808 plus CHOP versus MabThera plus CHOP with respect to: - Overall Response Rate (CR + CRu + PR at 20 weeks) - Progression Free Survival - Time-to Treatment Failure - Overall Survival 2. To compare MK-8808 plus CHOP versus MabThera plus CHOP with respect to: - Safety - Depletion of CD19-positive B cells - Immunogenicity 3. To evaluate efficacy (CR+CRu rate and secondary endpoints) and safety in patients with the 158V/V, 158V/F and 158F/F germ line genotypes of the FcγRIIIa receptor. |
| 1) Confrontare MK-8808 più CHOP vs MabThera più CHOP rispettivamente per: Tasso di risposta complessivo (CR + CRu + PR a 20 settimane); sopravvivenza libera da progressione; tempo al fallimento terapeutico; sopravvivenza globale 2) Confrontare MK-8808 più CHOP vs MabThera più CHOP rispettivamente per: sicurezza, deplezione delle cellule B CD19 positive; immunogenicità. 3) Valutare l'efficacioa ( Tasso CR + CRu ed obiettivi secondari) e sicurezza in pazienti con i genotipi del recettore FcγRIIIa 158V / V, 158V / F e 158F / F germinale |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Patient understands the study procedures, alternative treatments available, the risks involved with the study, and agrees to participate by giving informed consent. 2. Patient is male or female, and ≥18 years of age on the day of signing informed consent. 3. Patient has a life expectancy >3 months with no expected need of immediate intervention to treat life threatening complications. 4. Patient has a histological diagnosis of CD20-positive follicular lymphoma, Grade 1, 2 or 3a according to the WHO 2008 classification system (see Appendix 6.3), the biopsy must be comprised of <50% diffusearchitectural pattern (i.e., the follicular pattern component must be 50%), and areas of diffuse architecture may not show histological characteristics of diffuse large B-cell lymphoma. A surgical lymph node excision or biopsy is highly preferred as tissue source for pathological diagnosis. A core needle biopsy is acceptable if there are no palpable peripheral lymph nodes available for surgical excision or biopsy. A core needle biopsy requires a minimum needle size of 16 gauge. A bone marrow aspirate or biopsy is not acceptable for the sole diagnosis of FL in this study. 5. Patient has Ann Arbor Stage III or IV (See Appendix 6.4) and, in the opinion of the investigator, patient requires chemo immunotherapy. Common reasons for initiation of chemo-immunotherapy include (but are not exclusive to): - Rapid clinical lymphoma progression - Bulky disease (e.g., nodal or extranodal mass >6 cm in its greatest diameter) - Symptomatic enlargement of spleen or liver Vital organ compression - Ascites or pleural effusion - Cytopenia secondary to lymphoma - B symptoms (e.g. fever >38°C without infection; drenching night sweats; unexplained loss of >10% body weight within the preceding 6 months) 6. Patient has at least one bi-dimensionally measureable lesion and that lesion must not have been previously irradiated. 7. Patient has Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see Appendix 6.2). 8. Female patients of childbearing potential (defined as women who have not been surgically sterilized or have not been free from menses for > 2 years) have a negative urine pregnancy test within 72 hours prior to receiving the first dose of study medication. |
| 1.Ottenimento del consenso informato del/la paziente alla partecipazione. 2.Soggetti di entrambi i sessi di età ≥18 anni. 3.Aspettativa di vita >3 mesi senza necessità prevista di un intervento immediato per il trattamento di complicanze che mettono a rischio la vita del/la paziente. 4.Diagnosi istologicamente confermata di linfoma follicolare CD20-positivo di Grado 1, 2 o 3 in base al sistema di classificazione dell’OMS del 2008. 5.Stadio Ann Arbor III o IV e necessità, secondo il giudizio dello sperimentatore, di chemio-immunoterapia. 6.Almeno 1 lesione misurabile bidimensionalmente e non precedentemente irradiata. 7.Indice di performance ECOG (Eastern Cooperative Oncology Group) ≤2. 8.Donne in età fertile risultate negative a un test di gravidanza su urine effettuato nelle 72 ore precedenti la somministrazione della prima dose di farmaco in studio. 9.Le pazienti in età fertile devono essere disposte a utilizzare 2 metodi di contraccezione o essere chirurgicamente sterili oppure devono astenersi dall’attività eterosessuale per l’intera durata dello studio e per 12 mesi dopo l’ultima dose di farmaco in studio. I pazienti devono acconsentire a utilizzare un metodo di contraccezione adeguato a partire dalla Visita 1 fino a 90 giorni dopo l’ultima dose di farmaco in studio. 10.Funzionalità degli organi adeguata per la R-CHOP. |
|
| E.4 | Principal exclusion criteria |
| 1. Number of circulating lymphatic cells >10,000/mcL. 2. Presence or history of CNS involvement (either CNS lymphoma or lymphomatous meningitis). 3. Prior systemic therapy for FL, including but not limited to chemotherapy, anti- CD20 compounds, immunotherapy and any other type or class of anti-cancer drugs. 4. Prior therapy with an anthracycline (e.g., doxorubicin, epirubicin, liposomal doxorobucin). 5. Radiotherapy within 2 months prior to Cycle 1 Day 1, except involved field irradiation of up to two lesions that will not be used to evaluate disease progression. 6. Patient has a known hypersensitivity to any of the drugs required in this study or to any of the excipients or to murine proteins. 7. Patient with a history of a prior malignancy, with the exception of cervical intraepithelial neoplasia; basal cell carcinoma of the skin; or who has undergone therapy with curative intent with no evidence of disease recurrence for five years. 8. Patient is currently participating or has participated in a study with an investigational compound within 30 days prior to Cycle 1 Day 1. 9. Patient has any medical contra-indication for prednisone as being dosed in the CHOP chemotherapy regimen. 10. Patient is in a severely immunocompromised state. 11. Patient has poorly controlled diabetes mellitus. 12. Patient has Grade ≥2 peripheral neuropathy. 13. Patient has one of the following: a. Is HIV-positive b. Is positive for Hepatitis B surface antigen (HBsAg+) or antibodies to Hepatitis B core antigen (anti-HBcAg+) c. Has antibodies to Hepatitis C virus 14. Patient has an active infection, including but not limited to tuberculosis. 15. Patient has severe cardiovascular disease, cardiac heart failure, unstable cardiovascular conditions including recent myocardial infarction, angina, arrhythmias or uncontrolled hypertension. |
| 1.Cellule linfatiche circolanti >10.000/mcL. 2.Coinvolgimento corrente o pregresso del SNC (linfoma del SNC o meningite linfomatosa). 3.Precedente terapia sistemica per il LF inclusi, a titolo esemplificativo, chemioterapia, composti anti-CD20, immunoterapia e qualsiasi altro tipo o classe di farmaci anticancro. 4.Precedente terapia con un’antraciclina (p. es. doxorubicina, epirubicina, doxorubicina liposomiale). 5.Radioterapia nei 2 mesi precedenti il Giorno 1 del Ciclo 1, tranne irradiazione dell’area interessata fino a un massimo di 2 lesioni che non saranno utilizzate per la valutazione della progressione della malattia. 6.Precedente neoplasia maligna, fatta eccezione per la neoplasia intraepiteliale cervicale, carcinoma cutaneo basocellulare, o precedente terapia con intento curativo senza evidenze di recidiva da cinque anni. 7.Paziente gravemente immunocompromesso. 8.Paziente con Diabete mellito scarsamente controllato. 9.Neuropatia periferica di Grado ≥2. 10.Positività all’HIV o all’antigene di superficie dell’epatite B (HBsAg+) o presenza di anticorpi contro l’antigene core dell’epatite B (anti-HBcAg+) o di anticorpi anti-virus dell’epatite C. 11.Infezione attiva inclusa, a titolo puramente esemplificativo, la tubercolosi. 12.Malattia cardiovascolare grave, insufficienza cardiaca, disturbi cardiovascolari instabili inclusi recente infarto del miocardio, angina, aritmie o ipertensione non controllata. 13.Procedura di chirurgia maggiore (esclusa la biopsia dei linfonodi) nelle 4 settimane precedenti il Giorno 1 del Ciclo 1. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| CR+CRu rate: is defined as the proportion of patients who achieve a complete response or unconfirmed complete response per centrally assessed IWG 1999 criteria [25]. LIST OF SAFETY MEASUREMENTS (Refer to the Study Flow Charts in Section 1.7 of the study protocol for time points and other details regarding these measurements.): - Evaluation of adverse experiences - PE - Vital signs - ECOG Performance Status (see Appendix 6.2) - CBC & Blood Chemistry (see Appendix 6.1) - CD19-positive B-cells - Serum immunoglobulins - ECHO or MUGA |
| Tasso CR+CRu: definito come la proporzione di pazienti che raggiunge una risposta completa o una risposta completa non confermata secondo criterio IWG 1999 valutato centralmente. Elenco delle valutazioni di sicurezza: Valutazioni degli eventi avversi; Esame obiettivo, Segni vitali, Indice di performance ECOG; parametri meatochimici; Cellule B CD19 positive, immunoglobulina serica, ECHO o MUGA. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be assessed when all patients have either completed the week 20 CT scan assessment, plus or minus 1 week from randomization, or discontinued the study. |
| Questo end point sarà valutato quando tutti i pazienti avranno completato la scansione CT alla settimana 20 ( +/- 1 settimana dalla randomizzazione) oppure saranno discontinuati dallo studio. |
|
| E.5.2 | Secondary end point(s) |
| - Overall response rate (Overall RR): is defined as the proportion of patients who achieve a complete response, an unconfirmed complete response, or a partial response (CR+CRu+PR) per centrally assessed IWG 1999 criteria [25]. - Progression Free Survival (PFS): is defined as the time from randomization to documented progressive disease by centrally assessed IWG 1999 criteria [25] or death, whichever occurs first. Please see 3.5.5.1 for the definition of censoring for the endpoint. - Time-to Treatment Failure (TTF): is defined as the time from randomization to discontinuation of treatment for any reason, including disease progression (by centrally assessed IWG 1999 criteria [25], treatment toxicity, and death. - Overall Survival (OS): is defined as the time from randomization to death due to any cause. Patients without documented death at the time of analysis will be censored at the date last known to be alive. |
| Tasso di risposta complessiva: definito come come la proporzione di pazienti che raggiunge una risposta completa o una risposta completa non confermata, o una risposta parziale (CR+Cru+PR)secondo criterio IWG 1999 valutato centralmente. Sopravvivenza libera da progressione ( PFS): definita come il tempo trascorso tra la randomizzazione e la progressione documentata della malattia secondo criterio IWG 1999 valutato centralmente o morte , o l'evento che occorre prima. Si prega di fare riferimento alla sezione 3.5.5.1 per la definizione di censura per endpoint. tempo al fallimento terapeutico ( TTF) è definito come il tempo trascorso dalla randomizzazione alla interruzone del trattamento per qualsiasi ragione, compresa la progressione della malattia ( secondo criterio IWG 1999 misurato centralmente), tossicità del trattamento, morte. Sopravvivenza complessiva ( OS): definita come il tempo trascorso dalla randomizzazione alla decesso per qualsiasi causa. I pazienti senza morte documentata al momento dell'analisi saranno censurati alla data ultima in cui era noto essere ancora vivi. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints will be assessed when all patients have either completed the week 20 CT scan assessment, plus or minus 1 week from randomization, or discontinued the study. |
| L'end point secondario sarà rilevato quando tutti i pazienti avranno completato la scansione CT alla settimana 20 ( +/- 1 settimana dalla randomizzazione) oppure saranno discontinuati dallo 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Yes |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 | No |
| 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 |
| Argentina |
| Australia |
| Belarus |
| Brazil |
| Canada |
| Chile |
| China |
| Croatia |
| Egypt |
| Georgia |
| India |
| Israel |
| Korea, Republic of |
| Malaysia |
| Mexico |
| New Zealand |
| Peru |
| Philippines |
| Russian Federation |
| Singapore |
| South Africa |
| Taiwan |
| Thailand |
| Ukraine |
|
| 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
|
|
| 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 | 85 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| 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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