| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma |
Studio in pazienti treatment-naive con
leucemia linfatica cronica o linfoma linfocitico a piccole cellule |
|
| E.1.1.1 | Medical condition in easily understood language |
| Leukemia or Lymphoma |
| Leucemia o linfoma |
|
| 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 | 15.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060669 |
| E.1.2 | Term | B-cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma |
| 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 evaluate the efficacy of PCI-32765 compared with chlorambucil
based on the Independent Review Committee (IRC) assessment of
progression-free survival (PFS) in patients 65 years of age or older
with treatment-naive chronic lymphocytic leukemia (CLL) or small
lymphocytic lymphoma (SLL) |
Valutare l'efficacia di PCI-32765 rispetto al clorambucile sulla
base della valutazione del Comitato di revisione indipendente (IRC, independent review
committee) della sopravvivenza libera da progressione (PFS) in pazienti di 65 anni o più
affetti da leucemia linfatica cronica naive al trattamento (CLL) o linfoma linfocitico a piccole
cellule (SLL). |
|
| E.2.2 | Secondary objectives of the trial |
To compare the treatment groups in terms of the following:
Efficacy
• Overall response rate (ORR) according to International Workshop
on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria, as assessed by the IRC
• Rate of minimal residual disease (MRD)-negative complete responses (CRs)
• Overall survival (OS)
• Fatigue measured by Functional Assessment of Chronic Illness
Therapy-Fatigue (FACIT-F)
• Hematological improvement measured by hemoglobin and platelet
counts
Safety
• To evaluate the safety and tolerability of PCI-32765 compared with chlorambucil |
Confrontare i gruppi di trattamento in termini di: Efficacia •
Tasso di risposta globale (ORR) secondo i criteri del gruppo di lavoro internazionale sulla
leucemia linaftica cronica (International Workshop on Chronic Lymphocytic Leukemia -
IWCLL) del 2008, come valutati dall'IRC • Tasso di malattia minima residua
(MRD)-risposte complete negative (CR) • Sopravvivenza globale (OS) • Affaticamento
misurato in base al punteggio di Valutazione funzionale della terapia per patologie croniche
– Affaticamento (FACIT-Fatigue) • Miglioramento ematologico misurato in base
all'emoglobina e alle conte piastriniche Sicurezza • Valutare la sicurezza e la tollerabilità di
PCI-32765 rispetto al clorambucile |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females of 65 years of age or greater. Patients between
the ages of 65 and 70 years of age must have 1 or more of the following comorbidities that may preclude the use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide or rituximab:
• Creatinine clearance < 70 mL/min using the Cockcroft-Gault equation
• Platelet count < 100,000/μLor hemoglobin < 10 g/dL
• Clinically apparent autoimmune cytopenia (autoimmune hemolytic
anemia or immune thrombocytopenia): Autoimmune hemolytic anemia is defined by at least one marker of hemolysis indirect bilirubin above the upper limit of normal (ULN) not due to liver disease, increased lactate dehydrogenase (above ULN) without alternative etiology, or increased absolute reticulocytosis (above ULN) or bone marrow erythropoiesis in the absence of bleeding) AND at least one marker of direct or indirect autoimmune mechanism (positive direct antiglobulin for IgG or C3d, cold agglutinins) (Ding 2007).; Immune thrombocytopenia is defined by
platelets ≤ 100,000/μL and increased megakaryocytes on the bone
marrow exam.
• Eastern Cooperative Oncology Group (ECOG) performance score = 1 or 2
2. Diagnosis of CLL/SLL that meets published diagnostic criteria (Hallek 2008):
• Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally coexpressing at least 1 B-cell marker (CD19 or CD20) and CD5.
• Prolymphocytes may comprise no more than 55% of blood lymphocytes.
3. Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) for requiring treatment:
• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL)
• Massive (≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly
• Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic lymphadenopathy
• Progressive lymphocytosis with an increase of more than 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 obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of < 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 (eg, infections) should be excluded.
• Autoimmune hemolytic anemia and/or immune thrombocytopenia
(defined in Inclusion Criterion 1) that is poorly responsive to corticosteroids or other standard therapy (but see Exclusion Criterion 4).
• Constitutional symptoms, defined as one or more of the following disease-related symptoms or signs, documented in the patient’s record prior to randomization:
− unintentional weight loss > 10% within 6 months prior to screening
− significant fatigue (inability to work or perform usual activities)
− fevers > 100.5°F or 38.0°C for 2 or more weeks prior to screening without evidence of infection
− night sweats for more than 1 month prior to screening without evidence of infection
4. Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node > 1.5 cm in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.
5. ECOG performance status of 0–2.
6. Life expectancy > 4 months from randomization.
7. Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1,000/μL (independent of growth factor support for at least 7 days prior to screening) and platelet count ≥ 50,000/μL (independent of transfusion and growth factor support for at least 7 days prior to screening).
8. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine transaminase (ALT) < 2.5 x ULN, and total bilirubin ≤ 1.5 x ULN.
9. Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation.
10. Willingness to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers study drug for the entire study.
11. Willingness of male patients, if sexually active with a female of childbearing potential, to use an effective barrier method of contraception during the study and for 3 months following the last
dose of study drug.
12. Ability to provide written informed consent and to understand and comply with the requirements of the study. |
1. Uomini o donne di età pari o superiore a 65 anni. I pazienti di età compresa tra i 65 e i 70
anni devono essere affetti da una o più delle seguenti comorbidità che possono precludere
l'uso di chemio-immunoterapia in prima linea a base di fludarabina, ciclofosfamide o
rituximab: o Clearance della creatinina < 70 ml/min calcolata in base alla formula di
Cockroft-Gault o Conta piastrinica < 100,000/L o emoglobina < 10 g/dL o Citopenia
autoimmune constatabile a livello clinico (anemia emolitica autoimmune o trombocitopenia
immune) o Punteggio di performance ECOG pari a 1 o 2. 2. Diagnosi di CLL/SLL che
soddisfa i criteri diagnostici IWCLL (Hallek 2008) 3. Patologia attiva che soddisfa almeno 1
dei seguenti criteri IWCLL (Hallek 2008) per la richiesta di trattamento: o Evidenza di
insufficienza di midollo osseo progressiva manifestata dallo sviluppo o dal peggioramento di
anemia e/o trombocitopenia o Splenomegalia massiccia, progressiva o sintomatica o Nodi
massivi o linfoadenopatia progressiva o sintomatica o Linfocitosi progressiva o Anemia
emolitica autoimmune e/o trombocitopenia immune che risponde scarsamente ai
corticosteroidi o alla terapia standard o Sintomi costituzionali 4. Malattia nodale misurabile
con tomografia computerizzata (TC) 5. Stato di performance ECOG di 0-2 6. Aspettativa di
vita > 4 mesi dalla randomizzazione 7. Funzione ematologica adeguata, definita come conta
assoluta dei neutrofili (ANC) 1,000/L (indipendente dal supporto del fattore di crescita per
almeno 7 giorni prima dello screening) e conta piastrinica 50,000/L (indipendente dalla
trasfusione e dal supporto del fattore di crescita per almeno 7 giorni prima dello screening)
8. Funzione epatica adeguata, definita come aspartato transaminasi (AST) e
alanino-transaminasi (ALT) nel siero < 2.5 x limite superiore rispetto al normale (ULN) e
bilirubina totale 1.5 x ULN 9. Funzione renale adeguata, definita come clearance della
creatinina calcolata 30 ml/min secondo la formula di Cockroft e Gault 10. Intenzione di
ricevere tutto il trattamento ambulatoriale, tutti i controlli di laboratorio e gli esami
radiologici presso l'istituto che si occupa della somministrazione del farmaco per l'intera
durata dello studio 11. Per i pazienti di sesso maschile con una partner in età fertile,
intenzione di utilizzare un metodo contraccettivo a barriera efficace durante la durata dello studio e per i 3 mesi successivi alla somministrazione dell'ultima dose del farmaco dello
studio 12. Capacità di fornire un consenso informato scritto e capire, e conformarsi ai
requisiti dello studio Fare riferimento alla sezione 4 del protocollo per l'elenco completo e
dettagliato dei criteri di inclusione/esclusione. |
|
| E.4 | Principal exclusion criteria |
1. Known involvement of the central nervous system by lymphoma
or leukemia.
2. History or current evidence of Richter’s transformation or prolymphocytic leukemia.
3. Documentation of deletion of the short arm of chromosome17: del (17p13.1), as defined by del 17p in more than 20% of cells examined on any pretreatment fluorescence in situ hybridization (FISH) or cytogenetic evaluation.
4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, such as those patients with a declining
hemoglobin level or platelet count secondary to autoimmune destruction within the 4 weeks prior to first dose of study drug, or the need for daily prednisone ≥ 20 mg daily (or corticosteroid equivalent) to control the autoimmune disease.
5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies) intended specifically to treat CLL/SLL.
6. Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior to randomization.
7. Corticosteroid use within 1 week prior to first dose of study drug, with the exception of inhaled steroid for asthma, topical steroid use, or other local corticosteroid administration.
Patients requiring systemic steroids at daily doses >20 mg prednisone (or corticosteroid equivalent), or those who are administered steroids for leukemia control or white blood cell(WBC)-count-lowering are excluded.
8. Major surgery within 4 weeks prior to randomization
9. History of prior malignancy, with the exception of the following:
• 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.
• Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease.
• Adequately treated cervical carcinoma in situ without current evidence of disease.
10. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York HeartAssociation Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
11. Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (including malabsorption syndrome, resection of the small bowel, or poorly controlled inflammatory bowel disease).
12. 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), or requirement for intravenous (IV) antibiotics.
13. Known history of infection with human immunodeficiency virus (HIV).
14. Serologic status reflecting active hepatitis B or C infection. Patients who are positive for hepatitis B core antibody and negative for hepatitis B surface antigen must have a negative
polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen positive or PCR positive will be excluded.
15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
16. Current life-threatening illness, medical condition, or organ-system dysfunction that, in the investigator’s opinion, could compromise the patient’s safety or put the study at risk.
17. Requirement for anticoagulation with warfarin.
18. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor. |
1. Coinvolgimento noto del sistema nervoso centrale nel linfoma o nella leucemia 2.
Anamnesi o evidenza attuale di trasformazione Richter o leucemia prolinfocitica 3.
Documentazione della delezione del braccio corto del cromosoma 17: del(17p13.1) in più del
20% delle cellule esaminate in occasione di qualsivoglia ibridazione fluorescente in situ
pre-trattamento (FISH) o valutazione citogenetica 4. Anemia emolitica autoimmune non
controllata o porpora trombocitopenica idiopatica 5. Qualsiasi trattamento precedente
(chemioterapia, radioterapia e/o anticorpi monoclonali) indirizzato specificamente al
trattamento della CLL/SLL 6. Trattamento con immunoterapia, vaccino o agente
sperimentale nelle 4 settimane precedenti alla randomizzazione 7. Uso di corticosteroidi
entro 1 settimana antecedente alla somministrazione della prima dose del farmaco dello
studio, con l'eccezione di somministrazioni per inalazione, uso topico o locale di altra natura.
Sono esclusi i pazienti che necessitano di steroidi sistemici in dosaggi quotidiani > 20 mg,
prednisone (o equivalente corticosteroide, si veda l’Appendice N) o quelli a cui sono
somministrati steroidi per il controllo della leucemia o per ridurre la conta dei globuli
bianchi. 8. Intervento chirurgico significativo entro 4 settimane prima della randomizzazione.
9. Storia precedente di tumori maligni, con l'eccezione di quanto segue: o Tumore maligno trattato con intento curativo e senza evidenza di malattia attiva presente per più di 3 anni
prima dello screening e scarso rischio di recidiva secondo il parere del medico curante o
Tumore della pelle diverso dal melanoma adeguatamente trattato o melanoma di tipo lentigo
maligna in assenza di evidenza corrente della malattia o Carcinoma cervicale in situ
adeguatamente trattato senza evidenza corrente della malattia 10. Malattia cardiovascolare
attualmente attiva e clinicamente significativa o storia di infarto al miocardio nei 6 mesi
precedenti la randomizzazione 11. Incapacità di inghiottire capsule o compresse o malattia
che compromette significativamente la funzionalità gastrointestinale 12. Infezione attiva e
sistemica di natura micotica, batterica, virale o diversa o necessità di antibiotici
somministrati per via endovenosa 13. Storia nota di infezione da virus
dell’immunodeficienza umana (HIV). 14. Stato sierologico che riflette un'infezione da epatite
B o C attiva 15. Anamnesi di ictus o emorragia intracranica entro 6 mesi prima
dell'arruolamento 16. Patologia, condizione medica o disfunzione dei sistemi organici
potenzialmente fatale in corso che potrebbe compromettere la sicurezza del paziente o
mettere a rischio lo studio 17. Necessità di terapia anticoagulante a base di warfarina 18.
Necessità di trattamento con un forte inibitore CYP3A4/5 e/o CYP2D6. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS as assessed by IRC review according to IWCLL criteria (Hallek 2008) with modification for treatment-related lymphocytosis (Hallek 2012). |
L'endpoint primario di questo studio è la PFS così come valutata dall'IRC ai sensi dei criteri
IWCLL 2008 (Hallek 2008)con la modifica relativa alla linfocitosi correlata al trattamento
(Hallek 2012). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| (a) after all enrolled patients have received a minimum of 12 months of treatment and/or follow-up, and (b) either 81 confirmed progression or death events have occurred or 15 months have elapsed after the last patient was randomized -whichever comes first. |
L'analisi della PFS verrà eseguita (a) dopo che tutti i pazienti arruolati hanno ricevuto il
trattamento e/o il follow up per almeno 12 mesi e (b) si sono manifestati 81 eventi di
progressione o decessi confermati o sono trascorsi 15 mesi dalla randomizzazione dell'ultimo
paziente - a seconda di quale evento si verifica per primo. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
• ORR defined as the proportion of patients who achieve CR, CRi, nPR, or partial response (PR) per IWCLL 2008 criteria over the course of the study as assessed by the IRC
• Rate of MRD-negative CRs
• OS
• Change from baseline FACiT-Fatigue score
• Rate of hematological improvement in patients with baseline anemia and thrombocytopenia defined by hemoglobin > 11 g/dL or increase ≥ 50% over baseline or platelet count >100,000/mm3, respectively
Safety
• Incidence of AEs and changes in laboratory variables, vital signs, and ECG
In addition, Event-Free Survival (EFS) will be included as a secondary endpoint in response to a European Medicines Agency (EMA) recommendation, where progressive disease (PD), death and non-response at 3 months after randomization are defined as events. |
L'analisi della PFS verrà eseguita (a) dopo che tutti i pazienti arruolati hanno ricevuto il
trattamento e/o il follow up per almeno 12 mesi e (b) si sono manifestati 81 eventi di
progressione o decessi confermati o sono trascorsi 15 mesi dalla randomizzazione dell'ultimo
paziente - a seconda di quale evento si verifica per primo |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| (a) after all enrolled patients have received a minimum of 12 months of treatment and/or follow-up, and (b) either 81 confirmed progression or death events have occurred or 15 months have elapsed after the last patient was randomized—whichever comes first. |
L'analisi degli end points secondari verrà eseguita (a) dopo che tutti i pazienti arruolati
hanno ricevuto il trattamento e/o il follow up per almeno 12 mesi e (b) si sono manifestati 81
eventi di progressione o decessi confermati o sono trascorsi 15 mesi dalla randomizzazione
dell'ultimo paziente - a seconda di quale evento si verifica per primo. |
|
| 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 | Yes |
| 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 | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 |
| Australia |
| Canada |
| China |
| Israel |
| New Zealand |
| Turkey |
| Ukraine |
| United States |
|
| 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
|
| The database will be locked at the point that all enrolled patients have had the opportunity to complete at least 12 months of treatment and/or follow-up and either (a) 81 progression or death events have been observed or (b) 15 months have elapsed after the last patient is randomized— whichever occurs first. |
Il database si chiuderà quando tutti i pazienti avranno completato almeno 12 mesi di
trattamento e/o follow-up e (a) si sono manifestati 81 eventi di progressione o decessi
confermati o (b) sono trascorsi 15 mesi dalla randomizzazione... |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 |
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