E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
chronic lymphocytic leukemia |
Leucemia linfatica cronica |
|
E.1.1.1 | Medical condition in easily understood language |
chronic lymphocytic leukemia |
Leucemia linfatica cronica |
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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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008956 |
E.1.2 | Term | Chronic lymphatic leukaemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine efficacy by investigator-assessed PFS of a combined regimen of obinutuzumab and GDC 0199 compared with GClb in previously untreated patients with CLL who have coexisting medical conditions. |
Determinare l’efficacia in base alla PFS valutata dallo sperimentatore di un regime combinato di obinutuzumab + GDC 0199 rispetto a GClb in pazienti affetti da CLL non trattata in precedenza che presentano condizioni mediche coesistenti. |
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E.2.2 | Secondary objectives of the trial |
To determine efficacy as assessed by additional outcome measures, including Independent Review Committee [IRC]-assessed PFS, overall response and MRD response rate as measured by allele-specific oligonucleotide polymerase chain reaction [ASO-PCR]
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Determinare l’efficacia valutata dalle misure aggiuntive degli outcome (specificate nella sezione 3.4.2, che includono la PFS valutata dal Comitato di revisione indipendente (IRC), il tasso di risposta globale e di risposta della MRD, misurati mediante reazione a catena della polimerasi con oligonucleotide allele-specifico (ASO-PCR) (vedere l’obiettivo secondario di sicurezza nella sezione 2.2.) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Documented previously untreated CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
- CLL requiring treatment according to IWCLL criteria
- Total Cumulative Illness Rating Scale (CIRS score) > 6
- Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as per protocol, unless cytopenia is due to marrow involvement of CLL
- Adequate liver function
- Life expectancy > 6 months
- Agreement to use highly effective contraceptive methods per protocol |
CLL non trattata in precedenza, documentata in base ai criteri dell’International Workshop on Chronic Lymphocytic Leukemia (IWCLL)
- CLL che necessita di trattamento secondo i criteri IWCLL
- Punteggio totale della scala CIRS >6
- Funzionalità midollare adeguata indipendentemente dai fattori di crescita o dal supporto della trasfusione nelle 2 settimane precedenti lo screening, tranne qualora la citopenia sia dovuta a interessamento del midollo per CLL
- Funzionalità epatica adeguata
- Aspettativa di vita >6 mesi
- accettare di usare metodi contraccettivi ad alta efficacia come da protocollo
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E.4 | Principal exclusion criteria |
Transformation of CLL to aggressive Non-Hodgkin's lymphoma (Richters transformation or pro-lymphocytic leukemia)
- Known central nervous system involvement
- Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML)
- An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system
- Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
- Inadequate renal function
- History of prior malignancy, except for conditions as listed in the protocol if patients have recovered from the acute side effects incurred as a result of previous therapy
- Patients with active bacterial, viral, or fungal infection requiring systemic treatment within the last two months prior to registration
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
- Hypersensitivity to chlorambucil, obinutuzumab, or GDC-0199 or to any of the excipients
- Pregnant women and nursing mothers
- Positive test results for chronic HBV infection (defined as positive HBsAg serology) or positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
- Patients with known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus-1 (HTLV-1)
- Requires the use of warfarin, marcumar, or phenprocoumon
- Received agents known to be strong CYP3A4 inhibitors or inducers within 7 days prior to the first dose of study drug |
Trasformazione di CLL in NHL (sindrome di Richter o leucemia prolinfocitica) in forma aggressiva
- Interessamento noto del sistema nervoso centrale
Pazienti con un’anamnesi di leucoencefalopatia multifocale progressiva (PML) confermata
- Un punteggio di compromissione di un singolo sistema/organo pari a 4 secondo la definizione della scala CIRS, che limita la capacità di ricevere il regime di trattamento di questo studio, con l’eccezione di occhi, orecchie, naso, gola
- Pazienti con anemia emolitica autoimmune o trombocitopenia autoimmune non controllata
- Funzione renale inadeguata
- Anamnesi di precedente malignità, eccetto che per le condizioni elencate di seguito, se i pazienti si sono ripresi dagli effetti collaterali acuti manifestatisi a causa della terapia precedente
- Pazienti con infezione attiva di natura batterica, virale o fungina che richiede il trattamento sistemico nei 2 mesi precedenti la registrazione
Anamnesi di gravi reazioni allergiche o anafilattiche agli anticorpi monoclonali murini o umanizzati oppure sensibilità o allergia conclamata a prodotti murini
- Ipersensibilità a clorambucile, obinutuzumab o GDC-0199 o a qualsiasi eccipiente (ad
- Donne in gravidanza e che allattano
- Risultati positivi del test dell’infezione cronica da HBV (definita come sierologia positiva per HBsAg) o risultati positivi del test dell’infezione da epatite C [test sierologico degli anticorpi anti virus dell’epatite C (HCV)]
- Pazienti con infezione nota causata dal virus dell’immunodeficienza umana (HIV) o dal virus della leucemia a cellule T di tipo 1 dell’uomo (HTLV-1)
- Condizione che richiede l’uso di warfarin, marcumar o phenprocoumone
- Trattamento con agenti che sono noti essere forti inibitori o induttori di CYP3A4 nei 7 giorni che precedono la prima dose del farmaco in studio
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS), defined as the time from randomization to the first occurrence of progression, relapse or death from any cause as assessed by the investigator using IWCLL criteria |
PFS, definita come il tempo dalla randomizzazione alla prima comparsa di progressione della malattia, recidiva o decesso per qualsiasi causa, come determinato dallo sperimentatore. La progressione della malattia sarà valutata dallo sperimentatore usando i criteri IWCLL |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At baseline, day 1 of cycle 7 and 9, day 1 of cycle 4, day 28 after treatment completion or early termination, during follow up i.e. 3 months after treatment completion or early termination and then regularly until 5 years from last patient enrolled.
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Al basale, al giorno 1 dei cicli 7 e 9, al giorno 1 del ciclo 4, al giorno 28 dopo la fine del trattamento o la “early termination”, durante il follow-up (es.: 3 mesi dopo la fine del trattamento |
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E.5.2 | Secondary end point(s) |
- PFS based on Institutional Review Committee (IRC)-assessments, defined as the time from randomization to the first occurrence of progression or relapse or death from any cause
- Objective response rate ([ORR] defined as rate of a clinical response of complete response [CR], CR with incomplete bone marrow recovery [CRi] or partial response [PR]) as determined by the investigator, according to the IWCLL criteria
- Minimal residual disease (MRD) response rate, as measured by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR)
- ORR at completion of combination treatment response assessment
- MRD response rate, as measured by ASO-PCR at completion of combination treatment response assessment
- Overall survival
- Duration of objective response
- Best response achieved (CR, CRi, PR, stable disease, or progressive disease)
- Event-free survival
- Time to next anti-leukemic treatment
- Incidence of adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0
- Incidence of severe adverse events
- Incidence of adverse events of special interest |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to 5 years from last patient enrolled.
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PFS basata sulla valutazione dell’IRC, definita come il tempo dalla randomizzazione alla prima comparsa di progressione della malattia, recidiva o decesso per qualsiasi causa. - ORR (definito come tasso di risposta clinica di CR, CRi o PR) al completamento della valutazione del trattamento, determinato dallo sperimentatore in base alle linee guida IWCLL - Tasso di risposta della MRD, misurato con allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). ORR al completamento della valutazione della risposta al trattamento combinato - |
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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 | Yes |
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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient reported Outcomes (PRO) |
Patient reported Outcomes (PRO)
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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 | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 160 |
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 |
Argentina |
Australia |
Austria |
Brazil |
Bulgaria |
Canada |
Croatia |
Czech Republic |
Denmark |
Egypt |
Estonia |
France |
Germany |
Italy |
Mexico |
New Zealand |
Romania |
Russian Federation |
Slovakia |
Spain |
Switzerland |
United Kingdom |
United States |
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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
|
The end of this study is defined as 5 years from last patient enrolled (unless all patients have died). |
La fine dello studio è definita come 5 anni dall’ultimo paziente arruolato (tranne nel caso in cui tutti i pazienti siano deceduti). |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | |
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 | 8 |