E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed indolent B-cell non-Hodgkin's lymphoma |
linfoma non-Hodgkin indolente a cellule B recidivato (iNHL) |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed indolent B-cell non-Hodgkin's lymphoma |
linfoma non-Hodgkin indolente a cellule B recidivato |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029600 |
E.1.2 | Term | Non-Hodgkin's lymphoma recurrent |
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 |
The primary objective of this study is: - To evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab, and who either had a treatment-free interval of =12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity. |
L'obiettivo primario di questo studio è quello di valutare se copanlisib in associazione con rituxlmab sia superiore al placebo in associazione con rituximab nel prolungare la sopravvivenza libera da progressione (PFS) in pazienti affetti da iNHL recidivato, che abbiano ricevuto una o più linee di trattamento, incluso rituximab, e che hanno un intervallo libero da trattamento superiore o uguale a 12 mesi dopo il completamento di un trattamento con rituximab, o i quali rifiutano il trattamento chemioterapico /per i quali è controindicata la chemioterapia per motivi di età, comorbidità, e/o tossicità residua. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate:¿ The following characteristics of disease-related symptoms: "time to deterioration" and "time to improvement" ¿ Other radiological and clinical indicators of treatment efficacy¿ Safety and tolerability of copanlisibThe other objectives of this study are to evaluate:- Pharmacokinetics- Biomarkers- Quality of life |
Gli obiettivi secondari di questo studio sono valutare: ¿ ¿ il tempo al miglioramento e al peggioramento dei sintomi correlati alla malattia ¿ Altri indicatore clinici o radiologici dell¿efficacia del trattamento ¿ la sicurezza e tollerabilit¿ di copanlisib Gli altri obiettivi di questo studio sono valutare: ¿ La farmacocinetica ¿ I biomarcatori ¿ La qualit¿ di vita
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Ability to understand and willingness to sign written ICF. Signed ICF must be obtained before any study specific procedure. 2. Histologically confirmed diagnosis of iNHL in CD20 positive patients, with histological subtype limited to: -Follicular lymphoma (FL) grade 1- 2-3a, -Small lymphocytic lymphoma (SLL) with absolute monoclonal XML File Identifier: /KmHxAMofFIzISiHnmvUdPQkY/4= Page 15/35 lymphocyte count <5x109/L at study entry, -Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), -Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal) 3. Patients must have relapsed (recurrence after complete response or presented progression after partial response) after the last rituximab, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab) containing therapy (other previous treatment lines after rituximab are allowed). A previous regimen is defined as one of following: at least 2 mths of single-agent therapy (less than 2 mths of therapy is allowed for patients who responded to single-agent rituximab, rituximab biosimilars, or anti-CD20 monoclonal antibody); at least 2 consecutive cycles of polychemotherapy; acceptable provided there is no resistance. Patients with prior intolerance to PI3K inhibitors other than copanlisib are eligible. 4. Non-WM patients must have at least one bi-dimensionally measurable lesion (not been previously irradiated) according to Lugano Classification. For patients with splenic MZL this requirement may be restricted to splenomegaly alone since that is usually the only manifestation of measurable disease. 5. Patients affected by WM who do not have at least one bidimensionally measurable lesion in baseline radiologic assessment must have measurable disease, defined as presence of IgM paraprotein with a minimum IgM level =2 x upper limit of normal and positive immunofixation test 6. Male/female patients =18 yrs of age 7. ECOG performance status =2 8. Life expectancy at least 3 mths 9. Availability of fresh tissue and/or archival tumor tissue for central pathology (obtained within 5 yrs of the consent date) at Screening 10. Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for time period between signing of ICF and 12 mths (for WOCBP) and 5 mths (for men) after last administration of study treatment. A high FSH level in postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator/a designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate of less than 1%), e.g. IUD, IUS, bilateral tubal occlusion, vasectomized partner and sexual abstinence. Use of condoms by male patients required unless female partner permanently sterile 11. Adequate baseline laboratory values collected no more than 7 days before starting study treatment: -Total bilirubin =1.5 x ULN (<3 x ULN for patients with Gilbert-Meulengracht syndrome or for patients with cholestasis due to compressive adenopathies of the hepatic hilum), -ALT and AST =2.5 x ULN (=umm5 x ULN for patients with liver involvement by lymphoma), -Lipase =1.5 x ULN, -GFR =30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula, -International normalized ratio (INR) =1.5 and partial thromboplastin time (PTT) =1.5 x ULN. PT can be used instead of INR if =1.5 x ULN, - Platelet count =75,000/mm3. For patients with confirmed lymphomatous bone marrow infiltration, platelet count =50,000/mm3. Platelet transfusion should not be given less than 7 days before exam collection, -Hb =8g/dL, Packed red blood cell transfusion or erythropoietin should not be given less than 7 days before exam collection, -ANC =1,000/mm3, For patients with confirmed lymphomatous bone marrow infiltration, ... TEXT EXCEEDS THE LIMITS (FOR THE COMPLETE LIST SEE MAIN PROTOCOL) |
Diagnosi istologicamente confermata di iNHL in pazientiCD20-positivo con sottotipo istologico limitato a: • Linfoma follicolare (FL) G1-2-3a • Linfoma linfocitico (SLL) con conta linfocitaria monoclonale assoluta <5x109/L all’ingresso nello studio • Linfoma linfoplasmocitoide / macroglobulinemia di Waldenström (LPL/WM) • Linfoma marginale (MZL) (splenico, nodale od extra-nodale) I pazienti devono essere recidivati (ricaduti dopo risposta completa o in progressione dopo risposta parziale) dopo l’ultima terapia contenente rituximab, farmaci biosimilari di rituximab o anticorpi monoclonali anti-CD20 (ad esempio obinutuzumab) (sono permesse ulteriori precedenti linee terapeutiche dopo rituximab). Una precedente linea terapeutica è definita come uno dei seguenti regimi: almeno 2 mesi consecutivi di monoterapia (sono permessi meno di 2 mesi di terapia per quei pazienti che hanno risposto alla monoterapia con rituximab, farmaci biosimilari di rituximab o anticorpi monoclonali anti-CD20); almeno 2 cicli consecutivi di polichemioterapia; trapianto autologo; radioimmunoterapia.
Una precedente esposizione ad altri inibitori della PI3K è accettabile (eccetto copanlisib), se c'è evidenza che non sia stata sviluppata resistenza. I pazienti con pregressa intolleranza ad altri inibitori della PI3K diversi da copanlisib sono eleggibili. I pazienti non affetti da WM devono avere almeno una lesione misurabile bi-dimensionalmente (che non sia stata precedentemente irradiata) secondo le raccomandazioni del "Revised Recommendations for lnitial Evaluation, Staging, and Response Criteria for Malignant Assessment of Hodgkin and Non-Hodgkln Lymphoma: The Lugano Classification. Per i pazienti con MZL splenico questo requisito può essere limitato alla sola splenomegalia dal momento che solitamente questa è l’unica manifestazione della malattia misurabile. I pazienti affetti da WM, che non presentano almeno una lesione misurabile bidimenslonalmente alla valutazione basale, devono avere una malattia misurabile definita come la presenza di una componente monoclonale M (lgM) con un livello minimo di lgM =2 volte oltre il limite superiore della norma (ULN) e con risultato positivo al test dell'immunofissazione. Pazienti di sesso maschile o femminile =18 anni d' età Performance Status secondo l' Eastern Cooperative Oncology Group (ECOG) = 2 Aspettativa di vita di almeno 3 mesi Disponibilità di tessuto tumorale fresco e/o di tessuto tumorale archiviato allo screening da inviare al laboratorio centrale di patologia, (ottenuto entro 5 anni dalla data di firma del consenso informato) Parametri di laboratorio al basale adeguati valutati entro 7 giorni prima di iniziare il trattamento dello studio […] Frazione di elezione ventricolare =45% Pazienti devono: •avere un Intervallo libero da progressione di malattia e da trattamento superiore o uguale a 12 mesi dopo il completamento di un trattamento con rituximab OPPURE • presentare una controindicazione per la chemioterapia per motivi di età, comorbidità e/o tossicità residua di trattamenti precedenti, o rifiutare il trattamento chemioterapico. Questi pazienti devono anche aver avuto un intervallo libero da progressione di malattia e da trattamento = a 6 mesi dopo il completamento di un trattamento con rituximab. I pazienti per i quali la chemioterapia è controindicata sono definiti dalle seguenti caratteristiche: - Età =80 anni - Età <80 anni e almeno una delle seguenti caratteristiche: almeno 3 commorbidità di grado 3 CIRS·G oppure almeno 1 commorbidità di grado 4 CIRS·G (se compatibile con la partecipazione allo studio) |
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E.4 | Principal exclusion criteria |
1. Previous assignment to treatment during this study 2. Close affiliation with site 3. FL grade 3b or transformed disease, or CLL 4. Progression free interval or treatment free interval of less than 12 mths since the last rituximab, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab) containing treatment (including maintenance with these drugs). For patients considered unwilling/unfit to receive chemotherapy: progression free interval or treatment free interval of less than 6 mths since the last rituximab, rituximab biosimilars-, or anti-CD20 monoclonal antibody containing treatment (including maintenance with these drugs), as assessed by the investigator 5. Previous/concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL (as described in Inc. criteria 2)within 5 yrs prior to treatm start except for curatively treated cervical carcinoma in situ, non-melanoma skin cancer, superficial bladder cancer (Ta, Tis & T1), and asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for =1 yr prior to randomization 6. Known lymphomatous involvement of central nervous system 7. Congestive heart failure > NYHA class 2 8. Unstable angina, new-onset angina. Myocardial infarction less than 6 mths before start of test drug 9. Uncontrolled arterial Hypertension despite optimal medical management 10. Patients with HbA1c >8.5% at Screening 11. Arterial or venous thrombotic or embolic events such as cerebrovascular accident, DVT or pulmonary embolism within 3 mths before start of study treatment 12. Non-healing wound, ulcer, or bone fracture 13. Active, clinically serious infections >CTCAE Grade 2 14. Known history of HIV infection 15. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start. Patients positive for HBsAg or HBcAb will be eligible if negative for HBV-DNA, these patients should receive prophylactic antiviral therapy; patients positive for anti-HCV antibody will be eligible if negative for HCV-RNA 16. seizure disorder requiring medication 17. evidence or history of bleeding diathesis. Any hemorrhage or bleeding event =CTCAE Grade 3 within 4 wks prior to start of study treatm 19. Proteinuria of CTCAE Grade 3 20. History/concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function 21. Concurrent diagnosis of pheochromocytoma 22. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a max of 7 days before start of treatm and negative result must be documented before start of treatm 23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow parameters 24. Known hypersensitivity to any of test drugs, test drug classes, or excipients in formulation 25. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of study results 26. Any illness or medical conditions that are unstable or could jeopardize safety of patients and compliance in study 28. Treatment with investigational drugs other than PI3K inhibitors less than 28 days before start of treatment, unless evidence of progression since last treatm. 29. Ongoing immunosuppressive therapy 30. Radiotherapy or immuno-/chemotherapy less than 4 wks before start of treatment, unless evidence of progression since last treatm. 31. Radioimmunotherapy or autologous transplant less than 3 mths before start of treatm, unless evidence of progression since last treatm 32. Myeloid growth factors less than 7 days before start of treatm ...
TEXT EXCEEDS THE LIMITS (FOR THE COMPLETE LIST SEE MAIN PROTOCOL) |
E.5.1 End point primario (ripetere se necessario): Sopravvivenza libera da progressione di malattia (PFS) E.5.1.1 Tempo/i di rilevazione di questo end point: La variabile di efficacia primaria è la PFS, valutata mediante revisione centralizzata. I pazienti vivi senza progressione di malattia documentata al momento dell'analisi verranno censiti alla data della loro ultima rivalutazione del tumore E.5.2 End point secondario (ripetere se necessario): - Objective tumor response rate (ORR) - Duratlon of response (DOR) - Complete response rate (CRR) - Time to progression (TIP) - Overall survival (OS) - Time lo deterioration In DRS-P - Time to improvement in DRS.P E.5.2.1 Tempo/i di rilevazione di questo end point: L'OS, il TTP, il DOR ed il tempo al peggioramento e di miglioramento di DRSP di almeno = 3 punti verranno analizzati utilizzando un test di rango logaritmico stratificato simile a quello dell'end point primario, la PFS. L'ORR ed il CRR verranno analizzati mediante il test di Cochran-Mantel-Haenszel. I test verranno aggiustali per gli stessi fattori di stratificazione impiegali per la PFS. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival (PFS)
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Sopravvivenza liera da progressione di malattia (PFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time (in days) from randomization to PD or death from any cause (if no progression is documented). The actual date of tumor assessments will be used for this calculation. PFS for patients without PD or death at the time of analysis will be censored at the date of their last tumor evaluation. PFS for patients who have neither tumor assessments nor death after baseline will be censored at Day 1. |
La variabile di efficacia primaria è la PFS, valutata mediante revisione centralizzata. I pazienti vivi senza progressione di malattia documentata al momento dell’analisi verranno censorizzati alla data della loro ultima rivalutazione del tumore. |
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E.5.2 | Secondary end point(s) |
- Objective tumor response rate (ORR) - Duration of response (DOR)- Complete response rate (CRR)- Time to progression (TTP)- Overall survival (OS)- Time to deterioration in DRS-P - Time to improvement in DRS-P |
- Objective tumor response rate (ORR) - Duration of response (DOR) - Complete response rate (CRR) - Time to progression (TTP) - Overall survival (OS) - Time to deterioration in DRS-P - Time to improvement in DRS-P |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- ORR - assessed in all patients up to the time of analysis of PFS. - DOR: time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until PD or death from any cause, whichever is earlier- CRR: assessed in all patients up to the time of analysis of PFS.- TTP: time from randomization to PD or death related to PD, whichever is earlier- OS: time (in days) from randomization until death from any cause. - Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire. - Time to improvement in DRS-P of at least 3 points, as measured by theFLymSI-18 questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less. |
L¿OS, il TTP, il DOR ed il tempo al peggioramento e di miglioramento di DRS-P di almeno = 3 punti verranno analizzati utilizzando un test di rango logaritmico stratificato simile a quello dell¿end point primario, la PFS. L¿ORR ed il CRR verranno analizzati mediante il test d¿ Cochran-Mantel-Haenszel. I test verranno aggiustati per gli stessi fattori di stratificazione impiegati per la PFS.
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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 | Yes |
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 | Yes |
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 |
Biomarkers and Quality of Life |
Biomarcatori e Quality of Life |
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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 | No |
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 | Yes |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Chile |
China |
Colombia |
Hong Kong |
Korea, Republic of |
Mexico |
Philippines |
Russian Federation |
Singapore |
South Africa |
Taiwan |
Thailand |
Turkey |
Ukraine |
United States |
Vietnam |
Austria |
Belgium |
Bulgaria |
Denmark |
France |
Germany |
Hungary |
Ireland |
Italy |
Lithuania |
Poland |
Portugal |
Spain |
Sweden |
Czechia |
Argentina |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |