| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma |
| leucemia linfatica cronica / linfoma linfocitico a piccole cellule |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma |
| leucemia linfatica cronica / linfoma linfocitico a piccole cellule |
|
| 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 | 10041152 |
| E.1.2 | Term | Small lymphocytic lymphoma, consistent with CLL (Working Formulation) |
| 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 | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| 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 efficacy of zanubrutinib versus ibrutinib as measured by overall response rate determined by investigator assessment |
| Confrontare l'efficacia di zanubrutinib (noto anche come BGB-3111) rispetto a ibrutinib, misurata in base al tasso di risposta globale stabilito dalla valutazione dello sperimentatore |
|
| E.2.2 | Secondary objectives of the trial |
To compare the efficacy of zanubrutinib versus ibrutinib as measured by:
o Progression-free survival determined by investigator assessment
o Overall response rate determined by independent central review
o Progression-free survival determined by investigator assessment
o Duration of response as determined by independent central review
o Duration of response as determined by investigator assessment
o Time to treatment failure
o Rate of partial response with lymphocytosis or higher determined by
independent
central review
o Overall survival
o Patient-reported outcomes
¿ To compare the safety of zanubrutinib versus ibrutinib |
Confrontare l'efficacia di zanubrutinib rispetto a ibrutinib, misurata mediante:
o Sopravvivenza libera da progressione stabilita dalla valutazione dello sperimentatore
o Tasso di risposta globale stabilitoda revisione centrale indipendente
o Sopravvivenza libera da progressione stabilita dalla valutazione dello sperimentatore
o Durata della risposta stabilita da revisione centrale indipendente
o Durata della risposta stabilita dalla valutazione dello sperimentatore
o Tempo all'insuccesso del trattamento
o Tasso di risposta parziale con linfocitosi o superiore stabilito da revisione centrale indipendente
o Sopravvivenza globale
o Esiti riferiti dai pazienti
• Confrontare la sicurezza di zanubrutinib rispetto a ibrutinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age 18 years or older
2.Confirmed diagnosis of CLL or SLL that meets the IWCLL criteria
3.CLL/SLL requiring treatment as defined by at least 1 of the following criteria:
a.Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
b.Massive (= 6 cm below left costal margin), progressive, or symptomatic splenomegaly
c.Massive nodes (= 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy
d.Progressive lymphocytosis with an increase of > 50% over a 2 month period or lymphocyte doubling time of < 6 months. Lymphocyte doubling time may be obtained by linear regression extrapolation of
absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of < 30 x 10 9/L (30,000/µL), lymphocyte doubling
time should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (eg, infection) should be excluded.
e.Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs:
i.Unintentional weight loss of = 10% within the previous 6 months
ii Significant fatigue (ie, inability to work or perform usual activities)
iii.Fevers > 100.5ºF or 38ºC for = 2 weeks without other evidence of
infection
iv.Night sweats for > 1 month without evidence of infection
4.Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. A line of therapy is defined as completing at least 2 cycles of treatment of standard regimen according to current NCCN or ESMO guidelines or of an investigational regimen on a clinical trial
5.Measurable disease by CT/magnetic resonance imaging (MRI). Measurable disease is defined as = 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular diametersor an extranodal
lesion must measure > 10 mm in longest perpendicular diameter (LPD).
6.Eastern Cooperative Oncology Group (ECOG) performance status of 0,1, or 2
7.Life expectancy = 6 months
8.Adequate bone marrow function as defined by:
a.Absolute neutrophil count (ANC) = 1000/mm3 (growth factor use is allowed), except for patients with bone marrow involvement in which case ANC must be = 750/mm3
- the screening hematology values confirming patient meets the ANC requirement must be dated at least 14 days following the most recent administration of pegfilgrastim and at least 7 days following the most recent administration of other myeloid growth factors (eg, G-CSF, GM-CSF)
b.Platelet = 75,000/mm3 (may be post-transfusion), except for patients with bone marrow involvement by CLL in which case the platelet count must be = 30,000/mm 3
c.Hemoglobin = 7.5 g/dL (may be post-transfusion)
9.Patient must have adequate organ function defined as:
a.Creatinine clearance = 30 mL/min (as estimated by the Cockcroft- Gault equation or the Modification of Diet in Renal Disease [MDRD] equation, or as measured by nuclear medicine scan or 24 hour urine
collection)
b.Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase = 2.5 × upper limit of normal unless due to CLL/SLL
c.Serum total bilirubin < 3.0 × upper limit of normal (unless documented Gilbert's syndrome)
10.Female patients of childbearing potential must practice highly effective methods (Section 5.1.2) of contraception initiated prior to first dose of study drug, for the duration of the study, and for = 90 days after
the last dose of zanubrutinib or ibrutinib
11.Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other highly effective methods described in Section 5.1.2 during the study treatment period and for = 90 days after
the last dose of zanubrutinib or ibrutinib
12.Ability to provide written informed consent,can understand and comply with the requirements of the study. |
Principali criteri di eleggibilità come da sinossi:
I pazienti da includere in questa sperimentazione presenteranno una diagnosi confermata di LLC o SLL che soddisfa i criteri del Workshop internazionale sulla leucemia linfatica cronica e richiede trattamento come definito da almeno 1 dei seguenti eventi: insufficienza progressiva del midollo; splenomegalia massiva, progressiva o sintomatica; linfoadenopatia massiva, progressiva o sintomatica; linfocitosi progressiva con rapido tempo di raddoppiamento; o sintomi costituzionali. I pazienti devono avere un’età pari o superiore a 18 anni, aver manifestato recidiva o refrattarietà ad almeno 1 precedente terapia sistemica per LLC/SLL, con somministrazione dell'ultima dose di terapia precedente per LLC/SLL > 14 giorni prima della randomizzazione, e presentare una malattia misurabile (definita come = 1 linfonodo > 1,5 cm nel diametro più lungo e misurabile in 2 diametri perpendicolari o una lesione extranodale deve misurare > 10 mm nel diametro perpendicolare più lungo). Nota: Una linea di terapia è definita come il completamento di almeno 2 cicli di trattamento di regime standard secondo le linee guida più recenti o di un regime sperimentale durante una sperimentazione clinica. I pazienti non presenteranno anamnesi di leucemia prolinfocitica o trasformazione di Richter, attuale malattia cardiovascolare attiva clinicamente significativa, infezione da HIV o infezione attiva da virus dell'epatite B o C. |
|
| E.4 | Principal exclusion criteria |
FOR THE ENTIRE LIST PLEASE REFER TO PARAGRAPH 4.2 OF PROTOCOL
1. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s transformation (biopsy based on clinical suspicion may be needed to rule out transformation)2. Clinically significant cardiovascular disease including the following: a. Myocardial infarction within 6 months before screening b. Unstable angina within 3 months before screening c. New York Heart Association class III or IV congestive heart failure (Appendix 4) d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes) e. QTcF > 480 milliseconds based on Fridericia’s formula f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening 3. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, non-muscle-invasive or carcinoma in situ of the cervix or breast 4. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention 5. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug 6. Severe or debilitating pulmonary disease 7. Unable to swallow study drug or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery
procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction 8. Active fungal, bacterial, and/or viral infection requiring systemic therapy 9. Known central nervous system involvement by leukemia or lymphoma 10. Underlying medical conditions that, in the investigator’s opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs 11. Known infection with HIV or serologic status reflecting active viral hepatitis B or C infection as follows: a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20 IU), and if they are willing to undergo monitoring for HBV reactivation b. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable 12. Moderate or severe hepatic impairment, ie, Child-Pugh class B or C 13. Major surgery within 4 weeks of the first dose of study drug 14. Prior treatment with a BTK inhibitor 15. Last dose of prior therapy for CLL/SLL = 14 days before randomization, with the following additional exclusion requirements: a. Treatment with monoclonal antibody-based therapy within 28 days of first dose of study drug b. Treatment with chimeric antigen receptor T-cell therapy within 180 days of first dose of study drug c. Treatment with Chinese herbal medicine with anticancer intent within 28 days of first dose of study drug d. Chemotherapy or radiation treatment within 21 days of first dose of study drug or hematopoietic stem cell transplantation within 90 days of first dose of study drug 16. Prior steroid use ¿ For prior corticosteroid use of 10mg/day or less, regardless of reason or duration o treatment, must stop steroid no later than day prior to first dose. ¿ For prior corticosteroid use of 10mg/day or more, regardless of reason or duration of treatment, must stop steroid 4 weeks prior to date of randomization. 17. Toxicity from prior anticancer therapy that has not recovered to = Grade 1 (except for alopecia, ANC, and platelet count; for ANC and platelet count, see inclusion criterion 8) |
| Per l'intera lista dei criteri di esclusione si prega di far riferimento alla sezione 4.2 del protocollo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is ORR determined by investigator assessment using the "modified" 2008 IWCLL guidelines with modification for treatment-related lymphocytosis for patients with CLL and per Lugano
Classification for non-Hodgkin lymphoma (NHL) for patients with SLL.
While the primary efficacy endpoint is per investigator assessment, ORR per independent central review will also be analyzed to support the primary analysis. In the United States, ORR assessed by independent central review will be the basis for regulatory decisions. |
L'endpoint di efficacia primario è il tasso di risposta globale ORR stabilito dallo sperimentatore secondo le linee guida “modificate” del Workshop internazionale del 2008 sulla leucemia linfatica cronica (con modifica sulla linfocitosi correlata al trattamento per i pazienti affetti da LLC e in base alla Classificazione di Lugano relativa al linfoma non Hodgkin per i pazienti affetti da SLL.
Mentre l’endpoint di efficacia primario si basa sulla valutazione dello sperimentatore, verrà analizzato anche l’ORR sulla base della revisione centrale indipendente a supporto dell’analisi primaria. Negli Stati Uniti, l’ORR valutato mediante revisione centrale indipendente sarà alla base delle decisioni regolatorie. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The final analysis will occur approximately 12 months after 600 patients have been randomized. |
| L’analisi finale avverrà circa 12 mesi dopo la randomizzazione di 600 pazienti |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint:
- The key secondary endpoint is PFS, defined as the time from randomization to the date of first documentation of disease
progression or death, whichever occurs first, determined by investigator assessment, PFS
per independent central review will also be analyzed to support the key
secondary endpoint analysis. In the United States, PFS assessed by
independent central review will be used to support regulatory decisions.
Other Secondary Endpoints:
- ORR determined by investigator assessment
- PFS determined by investigator assessment
- Duration of response, defined as the time from the date that response
criteria are first met to
the date that disease progression is objectively documented or death,
whichever occurs first,
determined by independent central review
- Duration of response by investigator assessment
- Time to treatment failure, defined as time from randomization to
discontinuation of study
drug due to any reason
- Rate of PR-L or higher, defined as the proportion of patients who
achieve a CR/CRi + PR + nodular PR + PR-L determined by independent
central review
- Overall survival, defined as the time from randomization to the date of
death due to any cause
- PROs measured by the EQ-5D-5L and EORTC QLQ-C30 questionnaires
- Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, and vital signs |
Key Secondary Endpoint:
- The key secondary endpoint is PFS, defined as the time from randomization to the date of first documentation of disease
progression or death, whichever occurs first, determined by investigator assessment, PFS
per independent central review will also be analyzed to support the key
secondary endpoint analysis. In the United States, PFS assessed by
independent central review will be used to support regulatory decisions.
Other Secondary Endpoints:
- ORR determined by investigator assessment
- PFS determined by investigator assessment
- Duration of response, defined as the time from the date that response
criteria are first met to
the date that disease progression is objectively documented or death,
whichever occurs first,
determined by independent central review
- Duration of response by investigator assessment
- Time to treatment failure, defined as time from randomization to
discontinuation of study
drug due to any reason
- Rate of PR-L or higher, defined as the proportion of patients who
achieve a CR/CRi + PR + nodular PR + PR-L determined by independent
central review
- Overall survival, defined as the time from randomization to the date of
death due to any cause
- PROs measured by the EQ-5D-5L and EORTC QLQ-C30 questionnaires
- Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, and vital signs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final analysis will occur approximately 12 months after 600 patients have been randomized. |
| L’analisi finale avverrà circa 12 mesi dopo la randomizzazione di 600 pazienti |
|
| 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 | 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 | 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) | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 83 |
| 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 |
| China |
| New Zealand |
| Turkey |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Sweden |
| United Kingdom |
|
| 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 | 51 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 51 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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