E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed, progressive and/or refractory mature B-cell lymphoma Patients with: - Diffuse large B-cell lymphoma – de novo or transformed - High-grade B-cell lymphoma - Primary mediastinal large B-cell lymphoma - Follicular lymphoma - Mantle cell lymphoma - Small lymphocytic lymphoma - Marginal zone lymphoma (nodal, extranodal or mucosa associated) |
linfoma a cellule B recidivante, progressivo o refrattario. Pazienti con: o Linfoma diffuso a grandi cellule B (DLBCL) o Linfoma a cellule B ad alto grado di malignità (HGBCL) o Linfoma a cellule B primitivo del mediastino (PMBCL) o Linfoma follicolare (FL) o Linfoma mantellare (MCL) o Piccolo linfoma linfocitico (SLL) o Linfoma della zona marginale (MZL) |
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E.1.1.1 | Medical condition in easily understood language |
Lymphoma of B-cell origin |
linfoma a cellule B |
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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 | 10003903 |
E.1.2 | Term | B-cell lymphoma 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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Escalation Phase:
- Determine maximum tolerated dose and recommended phase 2 dose
Expansion Phase:
- To evaluate clinical efficacy as determined by Lugano criteria |
Fase di aumento progressivo della dose - Determinare la dose massima tollerata (MTD) e la RP2D
Fase di espansine - Valutare l’efficacia clinica determinata in base ai criteri di Lugano |
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E.2.2 | Secondary objectives of the trial |
Escalation Phase: - Establish tolerability of GEN3013 - Establish PK profile after single and multiple doses - Evaluate immunogenicity - Evaluate anti-lymphoma activity
Expansion Part: - To further evaluate clinical efficacy as determined by Lugano criteria - To evaluate clinical efficacy as determined by Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) - To further evaluate clinical efficacy - To evaluate MRD status as a clinical efficacy endpoint - To evaluate safety and tolerability of GEN3013 - To evaluate the PK and immunogenicity of GEN3013 - To evaluate patient-reported outcomes (PROs) related to lymphoma symptoms |
Fase di aumento progressivo della dose - Stabilire la tollerabilità di GEN3013 - Stabilire il profilo farmacocinetico (PK) dopo dosi singole e multiple - Valutare l’immunogenicità - Valutare l’attività anti-linfoma
Fase di espansine - Valutare ulteriormente l’efficacia clinica determinata in base ai criteri di Lugano - Valutare l’efficacia clinica determinata in base a LYRIC - Valutare ulteriormente l’efficacia clinica - Valutare lo stato MRD come endpoint di efficacia clinica - Valutare la sicurezza e la tollerabilità di GEN3013 - Valutare la PK e l’immunogenicità di GEN3013 - Valutare i risultati riportati dai pazienti (PRO) relativi ai sintomi del linfoma |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient must be 18 years of age or older 2. Documented CD20+ mature non-Hodgkin B-cell lymphoma according to WHO classification 3. Relapsed, progressive and/or refractory disease (Cheson et al., 2007) following treatment with an anti-CD20 monoclonal antibody 4. Patients must have received at least 2 prior lines of therapy 5. Patients must have measurable disease by imaging 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (2 for escalation) |
Per entrambe le parti dello studio, i pazienti devono avere almeno 18 anni di età, essere affetti da una neoplasia a cellule B CD20+ matura documentata secondo la classificazione OMS 2008 o 2016 sulla base di un referto patologico rappresentativo, e presentare almeno 1 sito misurabile della malattia basato su TAC/RMN.
Per la parte di aumento progressivo della dose, i pazienti devono presentare DLBCL, HGBCL, PMBCL, FL, MCL, SLL o MZL. I pazienti devono essere affetti da malattia recidivante, progressiva e/o refrattaria.
Per la parte di espansione, i pazienti devono presentare aNHL R/R (DLBCL, PMBCL, HGBCL, FL grado 3B) o iNHL R/R (FL grado 1-3A, MZL, SLL). I pazienti devono essere stati sottoposti ad almeno 2 precedenti linee di terapia.
[Per l'elenco completo si veda il protocollo.] |
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E.4 | Principal exclusion criteria |
1. Primary central nervous system (CNS) lymphoma or known CNS involvement by lymphoma 2. AST, and/or ALT > 3 x upper limit of normal 3. Total bilirubin > 1.5 x upper limit of normal 4. Creatinine clearance < 45 mL/min 5. Known clinically significant cardiac disease, including: a. Onset of unstable angina pectoris within 6 months of signing ICF b. Acute myocardial infarction within 6 months of signing ICF c. Congestive heart failure (grade III or IV as classified by the New York Heart Association and/or known decrease ejection fraction of < 45% 6. Chronic ongoing infectious diseases (except hepatitis B or hepatitis C) requiring treatment (excluding prophylactic treatment) at the time of enrolment or within the previous 2 weeks prior to the first dose of GEN3013 7. Eligible for curative salvage therapy with high dose therapy followed by stem cell rescue 8. Active hepatitis B or ongoing hepatitis C infacrion that has not been cured. If laboratory evidence for a chronic infection with hepatitis B close monitoring and prophylactic therapy is required 9. Known human immunodeficiency virus (HIV) infection 10. Exposed to live or live attenuated vaccine within 4 weeks prior to signing ICF 11. Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 30 days prior to first GEN3013 administration 12. Autologous HSCT within 100 days prior to first GEN3013 administration, or any prior allogeneic HSCT or solid organ transplantation 13. Contraindication to all uric acid lowering agents |
I pazienti sono esclusi dalla partecipazione a qualsiasi parte dello studio se presentano linfoma primitivo a carico del sistema nervoso centrale (SNC) o coinvolgimento noto dell’SNC, neoplasia passata o attuale (eccetto quelle indicate nel protocollo), AST o ALT >3x ULN, bilirubina totale > 1,5x ULN, clearance della creatinina < 45 ml/min, malattie cardiache clinicamente significative, malattie infettive croniche in corso, malattie o trattamenti che provocano immunosoppressione o disturbi convulsivi che richiedono terapia.
[Per l'elenco completo si veda il protocollo.] |
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E.5 End points |
E.5.1 | Primary end point(s) |
Escalation End Points:
- Dose limiting toxicity
- Adverse events
Expansion End Points:
- Overall response rate (ORR) determined by Lugano criteria as assessed by independent review committee (IRC) |
Endpoint della fase di aumento progressivo della dose: ¿ Tossicità dose-limitante (DLT) ¿ Eventi avversi (AE)
Endpoint della fase di espansione: ¿ Tasso di risposta globale (ORR) determinato in base ai criteri di Lugano e valutato da un comitato di revisione indipendente (IRC) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- DLT evaluation period is defined as the first 4 weeks, i.e. 28 days after the first administration of GEN3013.
- AE evaluation will be done at each visit during the entire study |
- DLT evaluation period is defined as the first 4 weeks, i.e. 28 days after the first administration of GEN3013. - AE evaluation will be done at each visit during the entire study |
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E.5.2 | Secondary end point(s) |
Escalation End Points:
- Cytokine measures
- Laboratory parameters (biochemistry, hematology including immunophenotyping for absolute T-cell and B-cell counts as well as T-cell activation and exhaustion markers)
- PK parameters (clearance, volume of distribution and area-under-the concentration- time curve (AUC0-Clast and AUC0-8), maximum concentration (Cmax), time of Cmax (Tmax), pre dose values, and half-life)
- Immunogenicity of GEN3013
- Anti-lymphoma activity, i.e. resolution of constitutional symptoms, reduction in tumor size, objective and best response
- Duration of response
- Progression free survival
- Time to next anti-lymphoma therapy
- Overall survival
Expansion End Points:
- Duration of response (DOR) determined by Lugano criteria as assessed by IRC
- Complete response (CR) rate determined by Lugano criteria as assessed by IRC
- Progression-free survival (PFS) determined by Lugano criteria as assessed by IRC
- Time to response (TTR) determined by Lugano criteria as assessed by IRC
- Objective and best response rate determined by Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) as assessed by IRC
- PFS determined by LYRIC as assessed by IRC
- DOR determined by LYRIC as assessed by IRC
- TTR determined by LYRIC as assessed by IRC
- Overall survival (OS)
- Time to next (anti-lymphoma) therapy (TTNT)
- MRD status by detection of cancer cell gene sequences
- Safety (i.e., adverse events, laboratory parameters [biochemistry, hematology including immunophenotyping for absolute T-cell and B-cell counts as well as T-cell activation and exhaustion markers], hospitalizations, and cytokine measures)
- PK parameters (clearance, volume of distribution, Cmax, Tmax, trough concentrations, and half-life) and incidence of ADAs to GEN3013
- Changes in lymphoma symptoms as measured by the Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym)
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Endpoint della fase di aumento progressivo della dose ¿ Valori delle citochine ¿ Parametri di laboratorio (biochimica, ematologia con immunofenotipizzazione per le conte assolute delle cellule T e delle cellule B, nonché dei marcatori di attivazione e di esaurimento delle cellule T) cellule B, nonché dei marcatori di attivazione e di esaurimento delle cellule T) ¿ Parametri PK [clearance, volume di distribuzione e area sotto la curva concentrazione-tempo (AUC0-Clast e AUC0-8), concentrazione massima (Cmax), tempo di Cmax (Tmax), valori pre-dose e emivita] ¿ Immunogenicità di GEN3013 ¿ Attività anti-linfoma, ossia risoluzione dei sintomi costituzionali, riduzione delle dimensioni del tumore, risposta obiettiva e ottimale (ORR, CR e PR) ¿ Durata della risposta (DOR) ¿ Sopravvivenza libera da progressione (PFS) ¿ Tempo fino alla prossima terapia anti-linfoma (TTNT) ¿ Sopravvivenza globale (OS)
Endpoint della fase di espansione ¿ DOR determinata in base ai criteri di Lugano secondo la valutazione dell’IRC ¿ Risposta completa (CR) determinata in base ai criteri di Lugano secondo la valutazione dell’IRC ¿ PFS determinata in base ai criteri di Lugano secondo la valutazione dell’IRC ¿ Tempo alla risposta (TTR) determinata in base ai criteri di Lugano secondo la valutazione dell’IRC ¿ Tasso di risposta obiettiva e ottimale determinato dalla risposta del linfoma ai criteri della terapia immunomodulante (LYRIC) valutata dall’IRC ¿ PFS determinata in base a LYRIC secondo la valutazione dell’IRC ¿ DOR determinata in base a LYRIC secondo la valutazione dell’IRC ¿ TTR determinata in base a LYRIC secondo la valutazione dell’IRC ¿ OS ¿ TTNT ¿ Stato MRD mediante rilevazione delle sequenze geniche delle cellule tumorali ¿ Sicurezza [ossia eventi avversi, parametri di laboratorio (biochimica, ematologia con immunofenotipizzazione per le conte assolute delle cellule T e delle cellule B, nonché dei marcatori di attivazione e di esaurimento delle cellule T), ricoveri in ospedale e valori delle citochine] ¿ Parametri PK (clearance, volume di distribuzione, Cmax, Tmax, concentrazioni minime e emivita) e incidenza degli ADA verso GEN3013 ¿ Variazioni nei sintomi del linfoma misurati dalla valutazione funzionale della terapia antitumorale-linfoma (Functional Assessment of Cancer Therapy-Lymphoma, FACT-Lym) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the study. |
Durante tutto lo studio |
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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 | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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 | 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 |
E.8.1.2 -In aperto: la risposta corretta è SI |
E.8.1.2- Open : should be YES |
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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 | 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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
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 |
Canada |
Denmark |
France |
Germany |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Singapore |
Spain |
United Kingdom |
United States |
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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 trial is considered completed with the last safety follow-up visit (4 weeks after last dose) for the last patient participating in the trial. The trial will run for a maximum of 5 years after the last patient’s first treatment. |
Lo studio sarà ritenuto concluso con l'ultimo follow-up di sicurezza (4 settimane dopo l'ultima dose) per l'ultimo soggetto partecipante nello studio. Lo studio durerà per un massimo di 5 anni dopo il primo trattamento dell'ultimo soggetto. |
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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 | 3 |
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 | 3 |
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 |