| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/refractory diffuse large B-cell lymphoma (DLBL) |
| linfoma diffuso a grandi cellule B (Diffuse Large B Cell Lymphoma, DLBCL) recidivante o refrattario |
|
| E.1.1.1 | Medical condition in easily understood language |
| DLBL is a cancer of B cells, a type of white blood cell responsible for producing antibodies, it is the most common type of non-Hodgkin lymphoma |
| DLBL è un tumore delle cellule B, un tipo di globuli bianchi responsabili della produzione di anticorpi, è il tipo più comune di linfoma non Hodgkin |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012857 |
| E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) refractory |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012856 |
| E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012855 |
| E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) |
| 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 |
Stage 1
• To evaluate the safety and tolerability of Polatuzumab vedotin (Pola) -R-GemOx as a combination therapy on basis of incidence, nature and severity of physical findings and adverse events (AEs)), with a specific focus on peripheral neuropathy, according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0)
Stage 2
• To evaluate the efficacy of Pola-R-GemOx compared with R-GemOx alone on basis of overall survival (OS)
|
Stage 1
-Valutare la sicurezza e la tollerabilità di Pola-R-GemOx come terapia di associazione in relazione a incidenza, natura e severità dei riscontri fisici e degli eventi avversi (Adverse Event, AE), con particolare attenzione alla neuropatia periferica, utilizzando i criteri comuni di terminologia per gli eventi avversi del National Cancer Institute (NCI Common Terminology Criteria for Adverse Events), versione 5.0 (NCI CTCAE v5.0)
-Valutare l’efficacia di Pola-R-GemOx ion relazione alla sopravvivenza globale (Overall Survival, OS) |
|
| E.2.2 | Secondary objectives of the trial |
To Evaluate:
• Safety, tolerability of Pola-R-GemOx as a combination therapy, Pola-R-GemOx compared to R-GemOx, basis of incidence, assessment of peripheral neuropathy, tolerability, prevalence of anti-drug antibodies (ADA), incidence/nature/severity of AEs (Stage 1, 2)
• Efficacy of Pola-R-GemOx, Pola-R-GemOx compared to R-GemOx alone on basis of complete response (CR), objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), OS (Pola-R-GemOx)-Stage 1, event-free survival (EFS), duration of OR (DOR) (Stage 1, 2)
• Immunogenicity of pola, basis of prevalence of ADAs (Stage 1, 2)
• Impact of treatment, disease on aspects of health-related quality of life (Stage 2) |
Valutare:
-la sicurezza e la tollerabilità di Pola-R-GemOx rispetto a R GemOx e valutare l’immunogenicità di polatuzumab vedotin in relazione a incidenza, valutazione della neuropatia periferica, tollerabilità, prevalenza di anticorpi anti-farmaco (ADA), incidenza/natura/gravità degli eventi avversi (Stadio 1, 2)
-Valutare l’efficacia di Pola-R-GemOx rispetto alla sola R-GemOx in relazione a risposta completa (CR),tasso di risposta obiettiva (ORR), migliore risposta complessiva (BOR), sopravvivenza libera da progressione (PFS), sopravvivenza globale OS (Pola-R-GemOx)-Stage 1, sopravvivenza libera da eventi (EFS), durata della risposta obiettiva (DoR) (Stage 1, 2)
-l'immunogenicità di pola, sulla base della prevalenza degli ADA (Stage 1, 2)
-l’impatto del trattamento e della malattia sugli aspetti inerenti la qualità della vita correlata alla salute |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age >= 18 years
- Ability to comply with the study protocol, in the investigator’s judgment
- Histologically-confirmed DLBCL, not otherwise specified or history of transformation of indolent disease to DLBCL
- Relapsed or refractory disease
- At least one (>= 1) line of prior systemic therapy
- At least one bi-dimensionally measurable lesion
- Eastern Cooperative Oncology Group performance status of 0, 1 or 2
- Adequate hematological function
- For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, women must remain abstinent or use contraceptive methods with a failure rate of <1% per year during the treatment period and for 12 months after the final dose of pola or rituximab
- For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm, with a female partner of childbearing potential who is not pregnant, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the final dose of oxand/or gem |
• Età > = 18 anni
• Capacità di rispettare il protocollo dello studio, a giudizio dello sperimentatore.
• DLBCL confermato da esame istologico, non altrimenti specificato (NAS) OPPURE positività anamnestica per trasformazione da malattia indolente a DLBCL
• Malattia recidivante o refrattaria
• Almeno una (>= 1) linea precedente di terapia sistemica.
• Almeno una lesione misurabile bidimensionalmente
• Performance status secondo l’Eastern Cooperative Oncology Group (ECOG) di 0,1 o 2.
• Adeguata funzionalità ematologica
• Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o a fare uso di metodi contraccettivi, nonché consenso ad astenersi dalla donazione degli ovociti, Le donne dovranno praticare l’astinenza dai rapporti eterosessuali o fare uso di metodi contraccettivi con tasso di insuccesso <1% l’anno durante il Periodo di trattamento e per 12 mesi dopo l’ultima dose di polatuzumab vedotin o rituximab.
• Per gli uomini: consenso a praticare l’astinenza dai rapporti eterosessuali o a fare uso di metodi contraccettivi, nonché consenso ad astenersi dalla donazione del seme. Gli uomini con partner di sesso femminile in età fertile e non in gravidanza, che non si sono sottoposti a vasectomia, dovranno praticare l’astinenza dai rapporti eterosessuali o usare il preservativo insieme a un altro metodo contraccettivo che, in associazione al profilattico, garantisca un tasso di insuccesso < 1% l’anno durante il Periodo di trattamento e per 6 mesi dopo l’ultima dose di oxaliplatino e/o gemcitabina. |
|
| E.4 | Principal exclusion criteria |
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products
- Contraindication to R, gem or ox
- Peripheral neuropathy assessed to be > Grade 1 according to NCI CTCAE v5.0 at enrollment
- Prior use of pola or a gem + platinum-based agent combination
- Enrollment in any previous or ongoing pola trial
- Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to Cycle 1 Day 1
- Planned autologous or allogeneic stem cell transplantation at time of recruitment
- Primary or secondary central nervous system lymphoma at the time of recruitment
- Richter’s transformation or prior chronic lymphocytic leukemia
- Any of the following abnormal laboratory values, unless abnormal laboratory values are due to underlying lymphoma per the investigator:
o Creatinine > 1.5 x upper limit of normal (ULN) or a measured creatinine clearance < 30 mL/min
o Aspartate aminotransferase or alanine aminotransferase > 2.5 x ULN
o Total bilirubin >= 1.5 x ULN. Patients with documented Gilbert disease may be enrolled if total bilirubin is <= 3 x ULN
o International normalized ratio or prothrombin time > 1.5 x ULN in the absence of therapeutic anticoagulation
o Partial thromboplastin time or activated partial thromboplastin time > 1.5 x ULN in the absence of a lupus anticoagulant
- History of other malignancy that could affect compliance with the protocol or interpretation of results
- Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or significant pulmonary disease
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment or any major episode of infection within 4 weeks prior to Cycle 1 Day 1
- Patients with suspected or latent tuberculosis
- Positive test results for chronic hepatitis B virus infection and hepatitis C virus antibody
- Known history of human immunodeficiency virus seropositive status
- Vaccination with a live vaccine within 4 weeks prior to treatment
- Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 12 months after the last dose of study drug |
• Positività nota per gravi reazioni allergiche o anafilattiche agli anticorpi monoclonali umanizzati o murini oppure nota sensibilità o allergia ai prodotti murini
• Controindicazione per rituximab, gemcitabina, oxaliplatino
• Neuropatia periferica grado >1 in base a NCI CTCAE v5.0
• Precedente uso di pola vedotin o terapia di associazione a base di platino+gemcitabina
• Arruolamento in speriment. su pola vedotin condotta in precedenza/in corso
• Radio, chemio, immunoterapia, terapia immunosoppressiva o uso di farmaco speriment. per tratt. del tumore nelle 2 wk precedenti C1G1
• Trapianto autologo o allogenico di cellule staminali programmato all’arruolamento
• Linfoma primario/secondario del SNC all’arruolamento
• Trasformazione di Richter o precedente LLC.
• anomalie nei valori di lab, salvo se dovute al linfoma sottostante:creatinina >1,5 volte l’ULN o clearance misurata della creatinina < 30 ml/min,livelli di AST o ALT >2,5 volte l’ULN,bilirubina tot >=1,5 volte l’ULN. I paz con sindrome di Gilbert documentata potranno essere arruolati se la bilirubina tot sarà <= 3 volte l’ULN,INR o PT >1,5 volte l’ULN in assenza di terapia,PTT o aPTT >1,5 volte l’ULN in assenza di lupus anticoagulante
• Positività nota per altra neoplasia maligna
• Malattie concomitanti significative/non controllate es. patologia cardiovascolare o patologia polmonare significative
• Infezione batterica, virale, fungina, micobatterica, parassitaria o di altro tipo nota e attiva o episodio importante di infezione nelle 4 wk precedenti C1G1
• Tubercolosi sospetta o latente
• Risultato positivo per HBV, HCV., HIV
• Somministrazione di vaccino vivo nelle 4 wk precedenti il tratt.
• Procedura chirurgica maggiore recente
• Qualsiasi altra malattia, disfunzione metabolica, obiettività o referto clinico di laboratorio che susciti il ragionevole sospetto della presenza di una patologia o condizione di controindicazione
• Gravidanza/allattamento o intenzione di iniziare una gravidanza durante lo studio o nei 12 mesi successivi all’ultima dose del tratt. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Stage 1
1. Incidence, nature and severity of physical findings and adverse events (AEs), with a specific focus on peripheral neuropathy, according to the NCI CTCAE v5.0
Stage 2
2. OS
|
Stadio 1
1. Incidenza, natura e severità dei riscontri fisici e degli eventi avversi (Adverse Event, AE), con particolare attenzione alla neuropatia periferica, utilizzando i criteri comuni di terminologia per gli eventi avversi del National Cancer Institute (NCI Common Terminology Criteria for Adverse Events), versione 5.0 (NCI CTCAE v5.0)
Stadio 2
2. Sopravvivenza globale (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to 90 days or the initiation of non-protocol-specified anti-lymphoma treatment after the last dose of study drug
2. Up to 25 months
|
1. Fino a 90 giorni o inizio di un trattamento antilinfoma non specificato dal protocollo dopo l'ultima dose del farmaco in studio
2. Fino a 25 mesi |
|
| E.5.2 | Secondary end point(s) |
1. Incidence and assessment of peripheral neuropathy, as measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale (FACT-GOG/Ntx12) (Stage 1)
2. Incidence, nature and severity of AEs (including peripheral neuropathy) according to NCI CTCAE v5.0 and physical findings (Stage 2)
3. Tolerability, as measured by dose interruptions, dose reductions and dose intensity (Stage 1 and 2)
4. Prevalence of ADAs to pola at baseline and incidence of ADAs during the study (Stage 1 and 2)
5. CR as determined by an independent review committee (IRC) (Stage 2)
6. CR as determined by investigator (Stage 1 and 2)
7. ORR as determined by an IRC (Stage 2)
8. ORR as determined by investigator (Stage 1 and 2)
9. BOR as determined by investigator (Stage 1 and 2)
10. PFS as determined by investigator (Stage 1 and 2)
11. OS (Stage 1)
12. EFSeff (Stage 1 and 2)
13. DOR as determined by investigator (Stage 2)
14. Time to deterioration in physical functioning and fatigue as measured by the European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire, Core 30 (Stage 2)
15. Time to progression in lymphoma symptoms as measured by the Functional Assessment of Cancer Therapy-Lymphoma subscale (Stage 2)
16. Change from baseline in peripheral neuropathy as measured by the FACT/GOG-NTX-12 subscale score (Stage 2) |
1. Incidenza e valutazione della neuropatia periferica utilizzando la scala FACT-GOG/Ntx12 (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity a 12 item) (Stadio 1)
2. Incidenza,natura e severità degli Aes (inclusa nuropatia perifierica) in accordo a NCI CTCAE v5.0 e risultati fisici ( Stadio 2)
3. Tollerabilità, determinata in funzione delle interruzioni, delle riduzioni e dell’intensità della dose (Stadio 1,2)
4. Prevalenza degli ADA rispetto al pola al basale e incidenza degli ADA durante lo studio (stadio 1,2)
5. Risposta completa (CR) in base al giudizio dell’IRC (Stadio 2)
6.Risposta completa (CR) in base al giudizio dello sperimentatore (Stadio 1 e 2)
7. Risposta obbiettiva (ORR) in base al giudizio dell’IRC (Stadio 2)
8. Risposta obbiettiva (ORR) in base al giudizio dello sperimentatore (Stadio 1 e 2)
9. Risposta complessiva (OBR) in base al giudizio dello sperimentatore (Stadio 1 e 2)
10. Sopravvivenza libera da progressione in base al giudizio dello sperimentatore (Stadio 1 e 2)
11. Sopravvivenza globale (OS) (Stadio 1)
12. Sopravvivenza libera da eventi (Event-Free Survival, EFSeff) (Stadio 1 e 2)
13. Durata della risposta obiettiva (DoR) in base al giudizio dello sperimentatore (Stadio 1 e 2)
14. Tempo al peggioramento della funzionalità fisica e della fatigue, misurato mediante il questionario EORTC QLQ C30 (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire, Core 30) (Stadio 2)
15. Tempo alla progressione dei sintomi del linfoma, misurato mediante la sottoscala FACT Lym (Stadio 2)
16. Variazione, rispetto al basale, della neuropatia periferica, determinata mediante punteggio alla scala FACT-GOG/Ntx12 ( Stadio 2) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Day 1 of Cycle 1-8 and at end of treatment/discontinuation and long term follow-up
2. Up to 90 days or the initiation of non-protocol-specified anti-lymphoma treatment after the last dose of study drug
3. Up to 25 months
4. At baseline (Day -28 to -1), Day 1 of Cycle 1, 2, 4; treatment completion/early termination, post-treatment follow-up
5-13. Up to 25 Months
14-15. Day 1 of Cycle 1-8, end of treatment/discontinuation and long-term follow-up
16. Baseline, Day 1 of Cycle 1-8, end of treatment/discontinuation and long-term follow-up
|
1. Giorno 1 del Ciclo 1-8 e alla fine del trattamento/interruzione e follow-up a lungo termine
2. Fino a 90 giorni o inizio di un trattamento antilinfoma non specificato dal protocollo dopo l'ultima dose del farmaco in studio
3. Fino a 25 mesi
4. Al basale (Giorno da -28 a -1), Giorno 1 del Ciclo 1, 2, 4; trattamento completamento/interruzione anticipata, follow-up post-trattamento
5-13. Fino a 25 mesi
14-15. Giorno 1 del ciclo 1-8, fine del trattamento/interruzione e follow-up a lungo termine
16. Valore basale, giorno 1 del ciclo 1-8, fine del trattamento/interruzione e follow-up a lungo termine |
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| immunogenicity |
| immunogeneticità |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Pola-RGemOx vs RGemOx alone |
| Pola-RGemOx vs RGemOx alone |
|
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| 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 |
| Brazil |
| Canada |
| China |
| India |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Turkey |
| United States |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Spain |
| Sweden |
| United Kingdom |
| Greece |
|
| 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
|
| This is an event-driven trial. The clinical cut-off date for the final OS analysis will be confirmed when the targeted number of mortality events (121 deaths) have occurred |
| La sperimentazione clinica in oggetto è di tipo event-driven (guidata dagli eventi). La data di cut-off clinico per l’analisi finale dell’OS sarà confermata quando si sarà registrato il numero target di eventi di mortalità (121 decessi) |
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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