E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory acute myeloid leukemia (AML) |
LEUCEMIA MIELOIDE ACUTA RECIDIVATA O REFRATTARIA (LMA) |
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E.1.1.1 | Medical condition in easily understood language |
Acute myeloid leukemia (AML) is a type of cancer that starts in the blood-forming cells of the bone marrow, characterised by an overproduction of immature white blood cells. |
La Leucemia Mieloide Acuta (LMA ) ¿ un tipo di cancro che inizia nella cellule ematopoietiche del midollo osseo, caratterizzate da una sovrapproduzione di globuli bianchi immaturi. |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
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 |
Within the TP53 wild-type population: - To compare overall survival (OS) in patients with relapsed or refractory AML who have been randomized to idasanutlin in combination with cytarabine versus those who have been randomized to cytarabine and placebo. |
Nella popolazione con TP53 wild-type ¿ Confrontare la sopravvivenza globale (OS, Overall Survival) in pazienti affetti da leucemia mieloide acuta (LMA) recidivata o refrattaria che sono stati randomizzati a ricevere idasanutlin in associazione a citarabina rispetto a quelli randomizzati a ricevere citarabina e placebo. |
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E.2.2 | Secondary objectives of the trial |
Within the TP53 wild-type population - To compare the proportions of complete remission (CR) and allogeneic hematopoietic stem cell transplant (HSCT) following CR between treatment arms - To compare ORR (CR, complete remission with incomplete platelet count recovery (CRp), CR with incomplete blood count recovery (CRi)), event-free survival (EFS), and duration of remission (DoR) between treatment arms - To assess OS and CR in clinically actionable mutation-defined AML subpopulations, including FLT3, IDH1, and IDH2 - To assess the safety of idasanutlin plus cytarabine as compared with cytarabine and placebo - To compare the differences in disease and treatment-related symptoms and health related quality of life (HRQoL) between treatment arms.
Within the all-patient population - To assess the safety between treatment arms - To characterize the pharmacokinetics of both idasanutlin and cytarabine - To compare the differences in disease and treatment related symptoms and HRQoL. |
Popolazione di paz. con TP53 WT •Confrontare le % di CR (CompleteRemission) e di HSCT (HematopoieticStemCellTransplant) in seguito a CR •Confrontare ORR (OverallRemissionRate-definito come CR), CRp (CompleteRem. with incompl. platelet count recovery), Cri (Complete Rem. with incompl. blood count recovery), EFS (Event-FreeSurvival), DOR (DurationOfRem.followingCR) •Valutare OS e CR nelle sottopop. affette da LMA definita da mutazioni clinicam. azionabili, comprese mutaz. di FLT3, IDH1 e IDH2 •Valutare la sicurezza di idasanutlin+citarabina vs citarabina e placebo •Confrontare le diff. in termini di sintomi correlati alla malattia e al trattam. e in termini di qualità della vita correlata alla salute Popolazione di paz. complessiva •Valutare la sicurezza tra bracci di trattam. •Caratterizzare la farmacoc. di idasanutlin e citarabina. •Confrontare le diff. in termini di sintomi della malattia e al trattam. e in termini di qualità della vita correlata alla salute tra bracci di trattam. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >=18 years - Documented/confirmed 1st/2nd refractory/relapsed AML using World Health Organization classification, except acute promyelocytic leukemia - No more than 2 prior induction regimens (excl. prior HSCT) in their 1st line treatment and one must have included cytarabine with an anthracycline (or anthracenedione) - Eastern Cooperative Oncology Group performance status of 0 to 1 - Adequate hepatic and renal function. - WBC count at randomization of <=50,000/cubic millimeter (mm3). |
- Età ³ 18 anni. - Diagnosi documentata/confermata di LMA alla prima/seconda recidiva o refrattaria, utilizzando la classificazione dell’Organizzazione Mondiale della Sanità, eccetto leucemia promielocitica acuta - Non più di 2 precedenti regimi di induzione (escluso precedente HSCT), di cui uno deve aver incluso citarabina con un'antraciclina (o un antracenedione). - Punteggio del performance status secondo l'Eastern Cooperative Oncology Group (ECOG) compreso tra 0 e 1. - Funzione epatica adeguata - Conta totale dei globuli bianchi (WBC) al momento della randomizzazione = 50.000 / mm3 |
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E.4 | Principal exclusion criteria |
- First relapsed patients aged < 60 years with a CR1 duration of > 1 year - AML secondary to any prior chemotherapy unrelated to leukemia - Patients who are either refractory to/or relapsed within 90 days of receiving a regimen containing a cumulative dose of >=18 gram/square meter cytarabine - Patients who hace received allogeneic HSCT within 90 days prior to randomization - Patients who have received immunosoppresive therapy for graft versus host disease within 2 weeks prior to randomization - Prior tratment with a Murine Double Minute 2 (MDM2) antagonist - Patients with clinically relevant QTc prolongation (QTcF > 480 ms), a family history of long QT syndrome, or who are currently receiving treatment with medications that are known to prolong the QT interval - Patients receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy within 30 days from the first receipt of study drug with the exception of HU or leukapheresis in patients who need to continue this therapy to maintain a WBC count <=50000/mm3. HU or leukapheresis must be discontinued at least 24 hours prior to the initiation of study medication - Patients with acute toxicities from any prior anti-leukemia therapy that have not resolved to Grade <=2 per National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE), version 4.03 - Patients with a history of other malignancy within 5 years prior to screening - Patients unable to temporarily interrupt treatment with moderate to strng CYP2C8inducers and inhibitors (including gemfibrozil, which is also an inhibitor of UGT1A3), CYP2C8 or OATP1B1/3 substrates, or strong CYP3A4 inducers during the treatment phase. These agents must be discontinued 7-14 days prior to the start of study medication - Patients unable to temporarily interrupt treatment with oral or parenteral anticoagulants/anti-platelet agents (e.g., warfarin, chronic daily treatment with aspirin [>325 mg/day], clopidogrel, dabigatran, apixaban, rivaroxaban, or subcutaneous [SC] anticoagulant prophylaxis) during the tratment phase. These agents must be discontinued 7 days (or 5 half-lives) prior to the start of the study medication - Patients with a history of systemic hypersensitivity reactions >=Grade 2 attibuted to cytarabine - Patients who have any severe and/or uncontrolled medical conditions or other conditions that could impair the ability of the investigator to evaluate the patient, or impair the patient's ability to complete the study - Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the patient upon the induction of neutropenia, that is, patients who are or should be on antimicrobial agents for the treatment of active infection - Patients with extramedullary AML with no evidence of systemic involvement |
- Pazienti in prima ricaduta con CR1 di durata > 1 anno ED età < 60 anni. - LMA secondaria a qualsiasi precedente chemioterapia non correlata alla leucemia. - Pazienti refrattari a o pazienti che hanno sviluppato una recidiva entro 90 giorni da un regime contenente una dose cumulativa di citarabina >=18g/m2 - Pazienti sottoposti ad HSCT allogenico nei 90 giorni precedenti la randomizzazione - Pazienti sottoposti a terapia immunosoppressiva per malattia da trapianto contro l’ospite (graft versus host disease) nelle 2 settimane prima della randomizzazione - Precedente trattamento con un antagonista di MDM2. - Pazienti con prolungamento del QTc clinicamente rilevante (intervallo QT corretto utilizzando la formula di Fridericia [QTcF]>480ms), con anamnesi familiare di sindrome da allungamento del QT op azienti che stanno ricevendo un trattamento con farmaci noti per prolungare l'Intervallo QT. - Pazienti trattati con agenti sperimentali o commerciali o terapie somministrate con l’intento di trattare la neoplasia nei 30 giorni (o 5 emivite) precedenti la prima somministrazione del farmaco in studio, eccetto idrossiurea (HU) in pazienti che necessitano di proseguire l'assunzione di tale agente per mantenere una conta leucocitaria <= 50.000/mm3. La HU o la leucaferesi devono essere interrotte almeno 24 ore prima dellinizio del trattamento in studio. - Pazienti con tossicità acute derivanti da qualsiasi precedente terapia anti-leucemica che non siano state ricondotte ad un grado <=2 secondo i Common Terminology Criteria for Adverse Events del National Cancer Institute (NCI CTCAE), Versione 4.03. - Pazienti con anamnesi di altra neoplasia maligna nei 5 anni precedenti lo screening. - Pazienti che durante la fase di trattamento dello studio non possono temporaneamente interrompere il trattamento con moderati o forti induttori e inibitori del CYP2C8 (inclusi gemfibrozil, che è anche un inibitore UGT1A3), substrati di CYP2C8 o OATP1B1/3, oppure forti induttori del CYP3A4. Questi agenti devono essere interrotti almeno 7-14 giorni prima dell'inizio del trattamento in studio. - Pazienti che durante la fase di trattamento dello studio non possono interrompere temporaneamente la terapia orlae o parenterale con agenti anticoagulanti/antiaggreganti piastrinici (ad esempio warfarin, trattamento cronico quotidiano con aspirina [>325 mg/die], clopidogrel, dabigatran, apixaban, rivaroxaban o profilassi anticoagulante per via sottocutanea [SC]. Questi farmaci devono essere interrotti almeno 7 giorni (o 5 emivite) prima dell'inizio del trattamento in studio. - Pazienti con una storia di ipersensibilità sistemica di grado >=2 attribuite alla citarabina - Pazienti che presentano patologie gravi e/o non adeguatamente controllate, o altre condizioni che potrebbero influire sulla loro partecipazione allo studio, compromettere la possibilità da parte dello sperimentatore di valutare il paziente o compromettere la possibilità di completare lo studio |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival (OS) in TP53 wild-type population. |
La sopravvivenza globale ( OS) inella popolazione TP53 wild-type |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Interim analysis, after 120 patients enrolled - Primary analysis, approximately 4.5 years after study start. |
- Analisi ad Interim, dopo arruolamento di 120 pazienti - Analisi primaria, approssimativamente 4.5 anni dopo l'inizio dello studio |
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E.5.2 | Secondary end point(s) |
In TP53 wild-type population - CR proportions - ORR (CR, CRp and CRi) - EFS - DOR - Proportion of HSCT - OS and CR in clinically actionable mutation-defined AML subpopulations, incl. FLT3, IDH1, and IDH2 - Safety, disease and treatment related symptoms, and health related quality of life (HRQoL).
Within the all-patient population - Safety, pharmacokinetics, disease and treatment related symptoms, and HRQoL. |
Popolazione di paz. con TP53 WT • Percentuale di CR. • EFS. • ORR (CR, CRp e CRi). • DOR (durata della remissione a seguito di CR). • Percentuale di HSCT a seguito di CR. • Percentuale di CR e OS nella sottopopolazione definita da mutazioni clinicamente azionabili (FLT3, IDH1 e IDH2). • Sicuezza, sintomi correlati alla malattia e al trattam. e qualità della vita correlata alla salute Popolazione di paz. complessiva • Sicuezza, Farmacocinetica, sintomi correlati alla malattia e al trattam. e qualità della vita correlata alla salute |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Futility interim analysis, after 120 patients enrolled; Efficacy interim analysis at 80% of OS events (TP53 wild-type) - Primary analysis, approximately 5.5 years after study start. |
- Analisi ad Interim di futilità, dopo arruolamento di 120 pazienti; Analisi ad interim di efficacia all'80% degli eventi OS (TP53 WT) - Analisi primaria, approssimativamente 5.5 anni dopo l'inizio dello studio |
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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 | No |
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 | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
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 | 17 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
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 |
Canada |
Israel |
Korea, Republic of |
New Zealand |
Russian Federation |
Taiwan |
Austria |
Belgium |
Finland |
France |
Germany |
Italy |
Netherlands |
Norway |
Spain |
Switzerland |
United Kingdom |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |