| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| relapsed or refractory CLL/SLL |
| leucemia linfocitica cronica (CLL)/linfoma linfocitico a piccole cellule (SLL) recidivi o refrattari |
|
| E.1.1.1 | Medical condition in easily understood language |
| relapsed or refractory CLL/SLL |
| leucemia linfocitica cronica (CLL)/linfoma linfocitico a piccole cellule (SLL) recidivi o refrattari |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060671 |
| E.1.2 | Term | B-cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 ibrutinib compared to ofatumumab based on the independent review committee (IRC) of PFS in patients with relapsed or refractory CLL/SLL |
| Valutare l'efficacia di ibrutinib rispetto a ofatumumab in termini di sopravvivenza senza progressione stabilita da un comitato di revisione indipendente (IRC) secondo i criteri International Workshop on Chronic Lymphocytic Leukemia Criteria (IWCLL, Hallek 2008) (di seguito citati come criteri IWCLL 2008) in pazienti con CLL/SLL recidivi o refrattari |
|
| E.2.2 | Secondary objectives of the trial |
| To compare between the two treatment groups in terms of: Efficacy • To evaluate Investigator-assessed PFS per IWCLL 2008 criteria • To determine IRC-assessed ORR per IWCLL2008 criteria • To evaluate Investigator-assessed ORR per IWCLL 2008 criteria • To evaluate OS • To evaluate hematological improvement • To evaluate improvement and/or resolution of disease-related symptoms Safety • To evaluate the safety and tolerability of ibrutinib compared to of Ofatumumab |
Confrontare l'efficacia tra i due gruppi di trattamento in termini di:
• valutazione della sopravvivenza senza progressione valutata dallo sperimentatore secondo i criteri IWCLL 2008;
• determinazione del tasso di risposta globale valutato dall'ICR secondo i criteri IWCLL 2008;
• determinazione del tasso di risposta globale valutato dallo sperimentatore secondo i criteri IWCLL 2008;
• valutazione della sopravvivenza globale;
• valutazione del miglioramento ematologico;
• valutazione del miglioramento e/o risoluzione dei sintomi correlati alla malattia.
Sicurezza
• Valutare la sicurezza e la tollerabilità di ibrutinib rispetto a ofatumumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Men and women ≥ 18 years of age 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 3. Life expectancy of > 4 months from the 1st dose of study medication 4. Diagnosis of CLL/SLL that meets published diagnostic criteria (Hallek 2008): a) Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co expressing at least one B-cell marker (CD19, CD20, or CD23) and CD5, b) The diagnosis of CLL requires a history of lymphocytosis with a B-lymphocyte count ≥5,000/µl while SLL patients are characterized by the same criteria with a circulating B lymphocyte count <5,000/µl. Prolymphocytes may comprise no more than 55% of blood lymphocytes 5. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment: a) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (Hgb < 11 g/dL) and/or thrombocytopenia (platelets < 100,000/L), b) Massive, progressive, or symptomatic splenomegaly, c) Massive nodes, progressive, or symptomatic lymphadenopathy, d) Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) 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 109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL should be excluded, e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, f) Constitutional symptoms, defined as one or more of the following disease-related symptoms or signs, i) Unintentional weight loss > 10% within the previous 6 months prior to Screening ii) Significant fatigue; iii) Fevers higher than 100.5° F or 38 .0° C for 2 or more weeks prior to Screening without evidence of infection or iv) Night sweats for more than 1 month prior to Screening without evidence of infection 6. Must have received at least one prior therapy for CLL/SLL and not be appropriate for treatment or retreatment with purine analog based therapy, defined by at least one of the following criteria: a) Failure to respond (stable disease [SD] or disease progression on treatment), or a progression-free interval of less than 3 years from treatment with a purine analog based therapy and anti-CD20 containing chemoimmunotherapy regimen after at least two cycles, b) Age ≥ 70 years, or age ≥ 65 and the presence of co-morbidities (Cumulative Illness Rating Scale [CIRS] ≥ 6 or CrCl < 70 mL/min) that might place the patient at an unacceptable risk for treatment-related toxicity with purine analog based therapy, provided they have received >1 prior treatment including at least two cycles of an alkylating-agent based (or purine analog based) anti-CD20 antibody containing chemoimmunotherapy regimen. CIRS score can be determined utilizing a web-based tool. c) History of purine analog-associated autoimmune anemia or autoimmune thrombocytopenia, d) FISH showing 17p del in ≥ 20% of cells (either at diagnosis or any time before study entry) either alone or in combination with other cytogenetic abnormalities, provided they have received at least one prior therapy 7. Measurable nodal disease by CT. 8. Meet the following laboratory parameters: a) Absolute neutrophil count (ANC) ≥ 750 cells/μL (0.75 x 109/L), independent of growth factor support within 7 days of the first dose with study drug, b) Platelet count ≥ 30,000 cells/μL (30 x 109/L) without transfusion support within 7 days of the first dose with study drug. Patients with transfusion-dependent thrombocytopenia are excluded, c) Serum aspartate transaminase (AST) or alanin |
• Stato di validità dell'ECOG (Eastern Cooperative Oncology Group) di 0-1
• Aspettativa di vita superiore a 4 mesi
• Diagnosi di CLL o SLL che soddisfa i criteri IWCLL 2008
• Malattia attiva che soddisfa almeno uno dei criteri IWCLL 2008 per la necessità di trattamento
• I pazienti devono aver ricevuto almeno una precedente terapia per CLL/SLL
• I pazienti non devono essere idonei al trattamento o alla ripetizione del trattamento con terapia basata sugli analoghi delle purine
• Malattia nodale misurabile mediante TAC
• Per l'inclusione, i pazienti devono soddisfare i seguenti parametri di laboratorio:
Conta assoluta dei neutrofili (ANC) 750 cellule/μL (senza assumere fattori di crescita)
Conta piastrinica 30.000 cellule/μL (30 x 109/L) senza trasfusione
Aspartato transaminasi (AST/SGOT) o alanina transaminasi (ALT/SGPT) nel siero < 2,5 volte rispetto al limite superiore dell’intervallo normale di riferimento
Bilirubina totale ≤ 1,5 volte rispetto al limite superiore dell’intervallo normale di riferimento
Creatinina ≤ 2 volte rispetto a limite superiore dell’intervallo normale di riferimento e velocità di filtrazione glomerulare (GFR [Cockcroft-Gault]) stimata ≥ 30 mL/min.
• I pazienti devono potersi sottoporre al trattamento in regime ambulatoriale e al monitoraggio di laboratorio presso l'istituto che somministra il farmaco sperimentale per l'intera durata dello studio |
|
| E.4 | Principal exclusion criteria |
| Patients will be ineligible for this study if they meet any of the following criteria: 1. Known central nervous system (CNS) lymphoma or leukemia 2. Any history of Richter’s transformation or prolymphocytic leukemia 3. No documentation of cytogenetic and/or FISH results reflecting 17p del status in records prior to first dose of study drug 4. Uncontrolled Autoimmune Hemolytic Anemia (AIHA) or ideopathic thrombocytopenia purpura (ITP), such as those patients with a declining hemoglobin (Hgb) level or platelet count secondary to autoimmune destruction within the 4 weeks prior to first dose of study drug or the need for daily corticosteroids >20 mg daily 5. Prior exposure to ofatumumab or to ibrutinib 6. Previous randomization in a PCI-32765/ibrutinib study 7. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days prior to first dose of study drug 8. Corticosteroid use within 1 week prior to first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. Patients requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count lowering are excluded 9. Radio- or toxin-conjugated antibody therapy within 10 weeks prior to first dose of study drug 10. Prior autologous transplant within 6 months prior to first dose of study drug 11. Prior allogeneic stem cell transplant within 6 months prior to first dose of study drug 12. Major surgery within 4 weeks prior to first dose of study drug 13. History of prior malignancy, with the exception of the following: a) Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to Screening and felt to be at low risk for recurrence by treating physician b) Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease c) Adequately treated cervical carcinoma in situ without current evidence of disease 14. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months prior to first dose with study drug 15. Unable to swallow capsules or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption such as; malabsorption syndrome, resection of the small bowel, or poorly controlled inflammatory bowel disease affecting the small intestine 16. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) 17. Known history of infection with human immunodeficiency virus (HIV) 18. Serologic status reflecting active hepatitis B or C infection. Patients with hepatitis B core antibody positive who are antigen negative will need to have a negative polymerase chain reaction (PCR) result prior to enrollment. Those who are hepatitis B antigen positive or PCR positive will be excluded 19. History of stroke or intracranial hemorrhage within 6 months prior to enrollment 20. Pregnant or lactating women 21. Current life-threatening illness, medical condition, or organ system dysfunction 22. Requires anticoagulation with warfarin 23. Requires treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor |
• Linfoma del sistema nervoso centrale o leucemia noti
• Anamnesi di trasformazione di Richter o leucemia prolinfocitica
• Nessuna documentazione di risultati citogenetici e/o FISH che riflettano lo stato 17p del nei dati del paziente prima della dose iniziale del farmaco sperimentale
• Anemia emolitica autoimmune non controllata (AIHA) o porpora trombocitopenica idiopatica (ITP)
• Precedente esposizione a ofatumumab o a ibrutinib
• Il paziente si è sottoposto a chemioterapia o a radioterapia con fascio esterno, ha assunto anticorpi anticancro o un farmaco sperimentale entro 30 giorni prima della dose iniziale del farmaco sperimentale
• Utilizzo di corticosteroidi > 20 mg entro una settimana prima della dose iniziale del farmaco sperimentale
• Utilizzo di terapia anticorpale associata a radioterapia o assunzione di tossine entro 10 giorni prima della dose iniziale del farmaco sperimentale
• Precedente trapianto autologo entro sei mesi prima della dose iniziale del farmaco sperimentale
• Precedente trapianto allogenico di cellule staminali entro sei mesi prima della dose iniziale del farmaco sperimentale
• Intervento chirurgico importante entro quattro settimane prima della dose iniziale del farmaco sperimentale
• Anamnesi di neoplasia pregressa, ad eccezione di determinati cancri e neoplasie della cute trattati con intento curativo e con nessuna evidenza di malattia attiva da più di tre anni
• Malattia cardiovascolare significativa dal punto di vista clinico e attualmente attiva o anamnesi di infarto miocardico entro sei mesi prima della dose iniziale del farmaco sperimentale
• Anamnesi nota di infezione da virus dell'immunodeficienza umana (HIV)
• Stato sierologico che riflette infezione da epatite B o C attiva
• Incapacità di ingoiare capsule o malattia che compromette significativamente la funzione gastrointestinale
• Infezione micotica, batterica, virale o di altra natura sistemica attiva non controllata
• Anamnesi di ictus o emorragia intracranica entro sei mesi prima della dose iniziale del farmaco sperimentale
• Necessità di anticoagulazione con warfarin
• Necessità di trattamento con un forte inibitore del CYP 3A4/5 e/o del CYP2D6 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is PFS, as assessed by IRC review per IWCLL 2008 criteria |
| L'endpoint primario di questo studio è la sopravvivenza senza progressione della malattia, in base alla valutazione da parte dell'IRC secondo i criteri IWCLL 2008 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| secondary endpoints are : Efficacy To compare between the two treatment groups in terms of: • Investigator-assessed PFS per IWCLL 2008 criteria. • Overall response rate (ORR) is defined as the proportion of patients who achieve complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR), or partial response (PR) per IWCLL 2008 criteria over the course of the study as evaluated by an IRC • Investigator-assessed ORR per IWCLL 2008 criteria • OS • Hematological improvement in the subset of patients with cytopenia(s) at baseline assessed by time to improvement and percentage of patients with improvement • Improvement of disease-related symptoms (fatigue, night sweats, and splenomegaly) Safety • To compare the safety and tolerability between the two treatment |
Efficacia
Confrontare l'efficacia tra i due gruppi di trattamento in termini di:
• sopravvivenza senza progressione valutata dallo sperimentatore secondo i criteri IWCLL 2008;
• tasso di risposta globale (ORR) definito come la proporzione di pazienti che raggiungono una risposta (in base alla valutazione da parte dell'IRC secondo i criteri IWCLL 2008)
• tasso di risposta globale valutato dallo sperimentatore secondo i criteri IWCLL 2008;
• sopravvivenza globale;
• miglioramento ematologico nel sottoinsieme di pazienti con citopenia(e) al basale valutata(e) in base alla percentuale di pazienti con un miglioramento nelle conte ematiche e al tempo di raggiungimento di tale miglioramento
• miglioramento dei sintomi correlati alla malattia (stanchezza, sudorazioni notturne e splenomegalia)
Sicurezza
• Confrontare la sicurezza e la tollerabilità tra i due gruppi di trattamento |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 |
| tolerability |
| tollerabilità |
|
| 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 | 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 47 |
| 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 | No |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 40 |
| 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 | 40 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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