E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed/refractory follicular lymphoma |
Linfoma follicolare recidivante o refrattario |
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E.1.1.1 | Medical condition in easily understood language |
Follicular lymphoma is a cancer that affects white blood cells called lymphocytes. The term relapsed or refractory indicates disease that grows again or does not respond to the treatment. |
Il linfoma follicolare è un tumore che colpisce i globuli bianchi chiamati linfociti. Il termine recidiva o refrattaria indica una malattia che ricresce o non risponde al trattamento. |
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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 | 10016906 |
E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 evaluate the efficacy of mosunetuzumab in combination with lenalidomide (M+Len) compared with rituximab in combination with lenalidomide (R+Len) based on progression-free survival as determined by the independent review committee (IRC)
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valutare l’efficacia di mosunetuzumab in associazione a lenalidomide (M + Len) rispetto a rituximab in associazione a lenalidomide (R + Len) basata sulla sopravvivenza libera da progressione determinato dal comitato di revisione indipendente (IRC) |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of M+Len compared with R+Len based on progression-free survival as determined by the investigator, complete response rate as determined by the IRC and investigator, objective response rate as determined by the IRC and investigator, overall survival, duration of objective response, duration of complete response (CR), time to deterioration in physical functioning and fatigue and time to deterioration in lymphoma symptoms To evaluate the safety of M+Len compared with R+Len To characterize the pharmacokinetic (PK) profile of M+Len and R+Len To evaluate the immune response to mosunetuzumab and rituximab
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-valutare l’efficacia di M+Len rispetto a R+Len basata sulla sopravvivenza libera da progressione determinato dallo sperimentatore -tasso di risosta completa determinata da IRC e sperimentatore -tasso di risposta obiettiva determinata da IRC e sperimentatore - sopravvivenza globale - durata della risposta obiettiva - durata della risposta completa (CR) - tempo al deterioramento del funzionamento fisico e affaticamento e tempo al deterioramento dei sintomi del linfoma - valutare la sicurezza di M+Len rispetto a R+Len - caratterizzare il profilo PK di di M+Len e R+Len - valutare la risosta immunitaria di mosunetuzumab e rituximab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age >=18 years at the time of signing Informed Consent Form Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 Histologically documented CD20 + follicular lymphoma (FL) (Grades 1-3a) Requiring systemic therapy assessed by investigator based on tumor size and/or Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria Received at least one prior systemic lymphoma therapy, which included prior immunotherapy or chemoimmunotherapy Availability of a representative tumor specimen and the corresponding pathology report at the time of relapse/persistence for confirmation of the diagnosis of FL Adequate hematologic function (unless due to underlying lymphoma, per the investigator) Normal laboratory values Agreement to comply with all local requirements of the lenalidomide risk minimization plan, which includes the global pregnancy prevention program Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use 2 adequate methods of contraception during the treatment period (including periods of treatment interruption), and for at least 28 days after the final dose of lenalidomide, 3 months after the final dose of tocilizumab (if applicable), mosunetuzumab, and 12 months after the final dose of rituximab Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm during the treatment period and for at least 28 days after the final dose of lenalidomide, 3 months after the final dose of tocilizumab (if applicable), mosunetuzumab and 12 months after the final dose of rituximab For patients enrolled in the extended China enrollment phase at National Medical Products Administration (NMPA)-recognized sites: current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry
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• Età >= 18 anni • ECOG pari a 0, 1 o 2. • LF CD20+ (di grado 1-3a) documentato dall’esame istologico: • Necessaria valutazione da parte dell’Investigatore basata sulle dimensioni tumorali o soddisfacimento dei criteri GELF, per la somministrazione di terapia sistemica • Tratt. con almeno 1 precedente terapia sistemica per il linfoma, che comprende immunoterapia o chemioimmunoterapia. • Disponibilità di un campione tumorale rappresentativo e del referto patologico corrispondente al momento della recidiva/persistenza per la conferma della diagnosi di LF. • Adeguata funzionalità ematologica (tranne se dovuta al linfoma sottostante secondo il parere dello sperimentatore) • Valori di laboratorio nella norma • Consenso a rispettare tutti i requisiti locali del piano di minimizzazione del rischio di lenalidomide, comprendente il programma globale di prevenzione della gravidanza. • Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o ad adottare 2 metodi contraccettivi adeguati, tra cui almeno 1 metodo con tasso di insuccesso < 1% all’anno, per almeno 28 gg prima del G1C1, durante il trattamento (compresi i periodi di sospensione del trattamento) e per almeno 28 gg dopo l’ultima dose di lenalidomide, 3 mesi dopo l’ultima dose di toci (se applicabile) e mosu, e 12 mesi dopo l’ultima dose di rituximab.e astenersi dalla donazione degli ovuli. • Per gli uomini: consenso a praticare l’astinenza dai rapporti eterosessuali, adottare metodi contraccettivi, consenso ad astenersi dalla donazione del seme, durante il periodo di trattamento e per almeno 28 gg dopo l’ultima dose di lenalidomide, 3 mesi dopo l’ultima dose di toci (se applicabile) e mosu, e 12 mesi dopo l’ultima dose di rituximab. • Per i pazienti arruolati nella fase estesa di arruolamento cinese presso centri riconosciuti dalla NMPA: attuale residenza nella Cina continentale, a Hong Kong o Taiwan e origine cinese. |
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E.4 | Principal exclusion criteria |
Grade 3b FL History of transformation of indolent disease to diffuse large B-cell lymphoma (DLBCL) Documented refractoriness to lenalidomide, defined as no response (partial response or complete response) or relapse within 6 months of therapy Active or history of central nervous system (CNS) lymphoma or leptomeningeal infiltration Prior standard or investigational anti-cancer therapy Clinically significant toxicity (other than alopecia) from prior treatment that has not resolved to Grade <=1 (per National Cancer Institute Common Toxicity Criteria for Adverse Events Version 5.0 [NCI CTCAE, v5.0]) prior to Day 1 of Cycle 1 Treatment with systemic immunosuppressive medications within 2 weeks prior to Day 1 of Cycle 1 History of solid organ transplantation History of severe allergic or anaphylactic reaction to humanized, chimeric or murine MAbs Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells or any component of the mosunetuzumab, lenalidomide, or thalidomide formulation, including mannitol History of erythema multiforme, Grade >=3 rash, or blistering following prior treatment with immunomodulatory derivatives History of interstitial lung disease (ILD), drug-induced pneumonitis, and autoimmune pneumonitis Known active bacterial, viral, fungal, or other infection, or any major episode of infection requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1 Known or suspected chronic active Epstein-Barr virus (EBV) infection Known or suspected history of hemophagocytic lymphohistiocytosis (HLH) Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis Active Hepatitis B or C infection Known history of human immunodeficiency virus (HIV) positive status History of progressive multifocal leukoencephalopathy (PML) Administration of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study Other malignancy that could affect compliance with the protocol or interpretation of results Active autoimmune disease requiring treatment History of autoimmune disease Prior allogeneic stem cell transplant (SCT) Evidence of any significant, uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including, but not limited to, significant cardiovascular disease or significant pulmonary disease Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1 Day 1 or anticipation of a major surgical procedure during the course of the study Pregnant or lactating or intending to become pregnant during the study Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment
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• LF di grado 3b • Anamnesi pos. per trasformazione da linfoma indolente a diffuso a grandi cellule B • Refrattarietà a lenalidomide • SNC o infiltrazione leptomeningea attiva o pregress. • Prec. terapia antitumorale standard o sperimentale • Tossicità significativa (no alopecia) per tratt. prec. che non sia regredita a = 1 (CTCAE v.5.0) prima del G1C1 • Tratt. con immunosoppressori sistemici 2 wk precedenti G1C1 • Anamnesi pos. per trapianto organi solidi e reazione allergica/anafilattica severa agli anticorpi monoclonali umanizzati chimerici o murini • Sensibilità o allergia ai prodotti murini • Ipersensibilità nota a biofarmaci prodotti in cellule ovariche di criceto cinese o a qualsiasi dei componenti di mosu, rituxi, toci, lenalidomide o talidomide, mannitolo • Anamnesi pos. per eritema multiforme, rash grado = 3 o bolle dopo un precedente tratt. con derivati immunomodulanti. • Storia malatt. interstiziale polmonare, polmonite farmaco-indotta/autoimmune • Infezione attiva nota o episodio magg. di infezione tratt. con antibiotici e.v. entro 4 wk dal G1C1 • Infezione cronica att. EBV nota o sospetta. • Linfoistiocitosi emofagocitica pregressa nota o sospetta. • Epatopatia pregressa significativa • Infezione att. HBV, HCV, HIV • Anamnesi positiva per PML • Somministrazione di vaccino vivo attenuato nelle 4 wk precedenti la prima dose o necessità prevista di un vaccino vivo attenuato durante lo studio. • Altra neoplasia maligna che potrebbe interferire col protocollo o l’interpretazione dei risultati, • Malattia autoimmune attiva necessitante di trattamento. • Anamnesi positiva per malattia autoimmune, • Precedente trapianto allogenico di cellule staminali. • Controindicazione a tratt. per profilassi antitromboembolica. • Evidenza di malattia conc. significativa non controllata • Procedura chirurgia maggiore, no diagnosi, nei 28 gg prec. G1C1 o previsione • Gravidanza/allattamento/intenzione di iniziare gravidanza • condizione medica o anomalia negli esami clinici di laboratorio grave |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival as determined by the IRC with use of the 2014 Lugano Response Criteria or death from any cause in the intent-to-treat (ITT) population |
-Sopravvivenza libera da progressione valutata da IRC in base ai criteri di Lugano 2014 o il decesso per qualsiasi causa nella popolazione intent-to-treat |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to approximately 8 years |
Fino a circa 8 anni |
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E.5.2 | Secondary end point(s) |
• Progression-free survival as determined by the investigator in the ITT population • Complete response rate in the ITT population as determined by the IRC and investigator • Objective response rate in the ITT population as determined by the IRC and investigator • Overall survival in the ITT population • Duration of objective response (DOR) • Duration of CR • Time to deterioration in physical functioning and fatigue, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) • Time to deterioration in lymphoma symptoms, as measured by the Functional Assessment of Cancer Therapy-Lymphoma Subscale (FACT-LymS) • Incidence and severity of adverse events, with severity determined according to the NCI CTCAE, v5.0, including cytokine release syndrome (CRS), with severity determined according to the American Society for Transplantation and Cellular Therapy (ASTCT) CRS grading criteria • Change from baseline in targeted vital signs • Change from baseline in targeted clinical laboratory test results • Tolerability, as assessed by dose interruptions, dose reductions, and dose intensity, and study treatment discontinuation because of adverse events • Minimum observed concentration (Cmin) of Mosunetuzumab • Cmin of Lenalidomide • Maximum observed concentration (Cmax) of Mosunetuzumab • Cmax of Lenalidomide • Area under the concentration-time curve (AUC) of Mosunetuzumab • AUC of Lenalidomide • Prevalence of anti-drug antibodies (ADAs) against mosunetuzumab at baseline • Prevalence of ADAs against rituximab at baseline • Incidence of ADAs against mosunetuzumab during the study • Incidence of ADAs against rituximab during the study • Cmin of Rituximab • Cmax of Rituximab • AUC of Rituximab
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1. Sopravvivenza libera da progressione valutata dallo sperimentatore nella popolazione intent-to-treat 2. Tasso di risposta completa valutata da IRC e dallo sperimentatore nella popolazione intent-to-treat 3. Tasso di risposta obbiettiva valutata da IRC e dallo sperimentatore nella popolazione intent-to-treat 4. Sopravvivenza globale nella popolazione intent-to-treat 5. Durata della risposta obiettiva 6. Durata risposta completa 7. Tempo al peggioramento della funzionalità fisica e della fatigue, misurato mediante il questionario EORTC QLQ-C30 8. Tempo alla progressione dei sintomi del linfoma, misurato mediante la sottoscala FACT-LymS 9. Incidenza, natura e severità degli AE in base ai criteri NCI CTCAE v5.0, inclusa la sindrome da rilascio delle citochine con severità valutata in base ai criteri CRS 10. Variazione rispetto al basale dei parametri vitali mirati 11. Variazione rispetto al basale nei risultati dei test di laboratorio clinici mirati 12. Tollerabilità, determinata in funzione delle interruzioni, delle riduzioni e dell’intensità della dose e l'interruzione del trattamento in studio a causa di eventi avversi 13. Concentrazione minima osservata di Mosunetuzumab 14. Concentrazione minima di Lenalidomide 15. Concentrazione massima osservata di Mosunetuzumab 16. Concentrazione massima di Lenalidomide 17. Area sottesa alla curva concentrazione-tempo di Mosunetuzumab 18. Curva concentrazione-tempo di Lenalidomide 19. Prevalenza degli anticorpi anti-farmaco (ADA) contro Mosunetuzumab al basale 20. Prevalenza degli anticorpi anti-farmaco (ADA) contro rituximab al basale 21. Incidenza degli anticorpi anti-farmaco (ADA) contro Mosunetuzumab durante lo studio 22. Incidenza degli anticorpi anti-farmaco (ADA) contro rituximab durane lo studio 23. Concentrazione massima di rituximab 24. Concentrazione minima di rituximab 25. Curva concentrazione-tempo di rituximab |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-9. Up to approximately 8 years 10-11. Baseline to 8 years 12. Up to approximately 8 years 13. Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2 to 12 14. Day 1 of Cycles 2 to 11 15. Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2 to 12 16. Day 1 of Cycles 2 to 11 17. Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2 to 12 18. Day 1 of Cycles 2 to 11 19-20. At Baseline 21-22. Up to approximately 8 years 23-25. Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2 to 11
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1-9. Fino a circa 8 anni 10-11. Baseline a 8 anni 12. Fino a circa 8 anni 13. Giorni 1, 8 e 15 del Ciclo 1, Giorno 1 dei Cicli da 2 a 12 14. Giorno 1 dei cicli da 2 a 11 15. Giorni 1, 8 e 15 del Ciclo 1, Giorno 1 dei Cicli da 2 a 12 16. Giorno 1 dei cicli da 2 a 11 17. Giorni 1, 8 e 15 del Ciclo 1, Giorno 1 dei Cicli da 2 a 12 18. Giorno 1 dei cicli da 2 a 11 19-20. Alla base 21-22. Fino a circa 8 anni 23-25. Giorni 1, 8 e 15 del Ciclo 1, Giorno 1 dei Cicli da 2 a 11 |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
randomizzato , in aperto |
randomized, open |
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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.8.2.4 | 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 | 64 |
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 | Information not present in EudraCT |
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 |
Australia |
Brazil |
China |
Japan |
Korea, Republic of |
Russian Federation |
Taiwan |
Turkey |
Ukraine |
United States |
France |
Germany |
Italy |
Poland |
Spain |
United Kingdom |
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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
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The end of this study is defined as the date when the last patient, last visit, occurs (i.e., last patient in the global and extended China enrollment phases combined) or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient (global and extended China enrollment phases combined), whichever occurs later. In addition, the Sponsor may decide to terminate the study at any time. |
La fine dello studio coinciderà con la data dell’ultima visita dell’ultimo paziente (da intendersi come l’ultimo paziente della fase di arruolamento globale e della fase estesa di arruolamento cinese combinate) o con la data di ricezione dell’ultima osservazione relativa all’ultimo paziente necessaria per l’analisi statistica o il follow-up di sicurezza (fase di arruolamento globale e fase estesa di arruolamento cinese combinate), a seconda della circostanza che si verifichi per ultima. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
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 |