E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia(CMML), or acute myeloid leukemia (AML) |
Sindromi mielodisplastiche (MDS), leucemia mielomonocitica cronica (CMML) o leucemia mieloide acuta (AML) |
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E.1.1.1 | Medical condition in easily understood language |
Myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia(CMML), or acute myeloid leukemia (AML) |
Sindromi mielodisplastiche (MDS), leucemia mielomonocitica cronica (CMML) o leucemia mieloide acuta (AML) |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009018 |
E.1.2 | Term | Chronic myelomonocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
As of amendment 2, primary objective of the phase Ib has been met. The primary objective of the Phase IIb part is to assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at RPIID relative to treatment with single agent 5-Aza through the assessment of composite CR (CR or CRi or bone marrow CR) |
Con l'emendamento 2, Valutare l’efficacia preliminare del trattamento con l’associazione di panobinostat e 5-Aza alla RPIID rispetto al trattamento con 5-Aza in monoterapia mediante la determinazione della CR composita (CR o Cri o CR del midollo osseo). |
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E.2.2 | Secondary objectives of the trial |
•To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at RPIID relative to treatment with single agent 5- Aza through the assessment of clinical response other than the composite CR specified in the primary objective, 1-year survival, and time to progression (TTP); •To characterize the safety and tolerability of panobinostat at RPIID in combination with 5-AZA, as well as, 5-AZA alone in the target patient population. |
- Valutare l’efficacia preliminare del trattamento con l’associazione di panobinostat e 5-Aza alla RPIID rispetto al trattamento con 5-Aza in monoterapia mediante la determinazione della risposta clinica diversa dalla CR composita specificata nell’obiettivo primario, sopravvivenza a 1 anno e tempo alla progressione (TTP); - Caratterizzare la sicurezza d’impiego e la tollerabilità di panobinostat alla RPIID somministrato in associazione a 5-Aza e di 5-Aza in monoterapia, nelle popolazioni target di pazienti. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Adult patients (age ≥ 18 years) who are candidates for treatment with 5-Aza and present with one of the following: • intermediate-2 or high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS). OR • AML with multilineage dysplasia and maximum of 30% blasts (former RAEB-T according to FAB) OR • chronic myelomonocytic leukemia (CMML) • ECOG performance status ≤ 2 • Patients must have the following laboratory values unless elevations are considered due to MDS or leukemia: AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN; serum creatinine ≤ 1.5 x ULN; serum bilirubin (total and direct) ≤ 2 x ULN; electrolyte panel within normal ranges (WNL) for the institution. • Negative pregnancy test • Clinically euthyroid (hypothyroidism corrected with supplementation is permitted). • Written informed consent obtained prior to any screening procedures |
1. Pazienti adulti (età > 18 anni) che sono candidati al trattamento con 5-Aza e che presentano uno dei riscontri seguenti: Sindromi mielodisplastiche a rischio intermedio-2 o ad alto rischio in base all’International Prognostic Scoring Systema (IPSS), OPPURE AML con displasia multilinea e un massimo di 30% di blasti (precedente RAEB-T in base a FAB), OPPURE Leucemia mielomonocitica cronica (CMML); 2. ECOG performance status ≤ 2; 3. I pazienti devono presentare i seguenti valori di laboratorio a meno che gli innalzamenti siano considerati dovuti alla MDS o alla leucemia. AST//SGOT e/o ALT/SGPT ≤ 2,5 x ULN; creatininemia ≤ 1,5 x ULN; bilirubinemia (totale e diretta) ≤2 x ULN; profilo elettrolitico entro i limiti della norma (WNL) per il laboratorio; 4. Test di gravidanza negativo; 5. Condizione di eutiroidismo clinico (è consentito l’ipotiroidismo corretto con supplementi); 6. Consenso informato scritto ottenuto prima di qualsiasi procedura di screening. |
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E.4 | Principal exclusion criteria |
• Planned hematopoietic stem-cell transplantation (HSCT) • Patients with therapy-related MDS • Patients with therapy-related AML and/or relapsed/refractory AML • Clinical symptoms suggesting CNS leukemia • Concurrent therapy with any other investigational agent • Prior treatment with deacetylase inhibitor(s) • Prior treatment with 5-Azacytidine or 5-aza-2'-deoxycytidine • Time windows for prior therapies: Last dose of therapy, including cytokines and/or retinoids, immunotherapy, low-dose ara-C, investigational agent less than 28 days with the exception of hydroxyurea (24 hours) prior to receipt of study medication or AEs that have not recovered at least to NCI CTCAE Grade 1. • Patients with impaired cardiac function including any of the following: • Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmia, clinically significant resting bradycardia (<50 beats per minute), QTcF > 460 ms on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block) • Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients with stable atrial fibrillation are eligible provided they do not meet the other cardiac exclusion criteria • Previous history of angina pectoris or acute MI within 6 months • Screening LVEF <45% by echocardiography or MUGA • Other clinically significant heart disease (e.g. uncontrolled hypertension or history of poor compliance with an antihypertensive regimen). • Drugs which may cause QT prolongation and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. • Any of concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study. For example: • Uncontrolled diabetes • Active or uncontrolled infection • Uncontrolled hypothyroidism • Acute or chronic liver or renal disease • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative diseases, diarrhea, malabsorption syndrome, or small bowel resection). • HIV, Hepatitis B/C infection according to the medical history (testing will not be performed). • Female patients who are pregnant or breast feeding or patients of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and for 3 months following the last dose of study drug. • Male patients whose sexual partner(s) are WOCBP who are not willing to use a double barrier method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment. • Suspected hypersensitivity to 5-Aza or Mannitol • Inability to swallow capsules • Unwilling or unable to comply with the protocol • Patient has evidence of clinically significant mucosal or internal bleeding |
1. Trapianto di cellule staminali ematopoietiche (HSCT) pianificato;2. Pazienti con MDS correlata alla terapia. 3. Pazienti con AML correlata alla terapia e/o AML in recidiva/refrattaria;4. Sintomi clinici suggestivi di leucemia del SNC;5. Terapia concomitante con qualsiasi altro farmaco sperimentale;6. Terapia precedente con inibitore(i) della deacetilasi;7. Terapia precedente con 5-Azacitidina o 5-aza-2’-deossicitidina;8. Intervallo di tempo per le terapie precedenti: ultima dose di terapia, comprese citochine e/o retinoidi, immunoterapia, basse dosi di ara-C, farmaci sperimentali, con l’eccezione di idrossiurea (24 ore): inferiore a 28 giorni dall’inizio della somministrazione del trattamento in studio o presenza di eventi avversi (AE) che non si sono risolti almeno a NCI CTCAE Grado 1;9. Pazienti con compromissione della funzionalità cardiaca compresi uno qualsiasi dei riscontri seguenti:Blocco di branca sinistra completo o impiego di pacemaker cardiaco permanente, sindrome del QT lungo congenita, evidenza pregressa o attuale di tachiaritmia ventricolare, bradicardia a riposo clinicamente rilevante (< 50 battiti per minuto), QTcF > 460 ms all’ECG di screening o blocco di branca destro + emiblocco anteriore sinistro (blocco bifascicolare) Presenza di fibrillazione atriale instabile (frequenza di risposta ventricolare > 100 battiti/minuto). I pazienti con fibrillazione atriale stabile sono eleggibili ammesso che non presentino gli altri criteri di esclusione cardiaci Evidenza pregressa di angina pectoris o infarto miocardico acuto entro i 6 mesi precedenti LVEF allo screening < 45% mediante ecocardiografia o MUGA Altre cardiopatie clinicamente rilevanti (ad es: ipertensione arteriosa non controllata o anamnesi positiva per scarsa aderenza al trattamento antipertensivo);10. Farmaci che possono determinare prolungamento del QT e che non possono essere sospesi o sostituiti con un altro farmaco prima dell’inizio della somministrazione del trattamento in studio;11. Qualsiasi patologia concomitante grave e/o non controllata che possa compromettere la partecipazione allo studio;12. Compromissione della funzionalità gastrointestinale (GI) o patologia gastrointestinale che possa alterare significativamente l’assorbimento di panobinostat orale (ad es: patologia ulcerosa, diarrea, sindrome da malassorbimento o resezione dell’intestino tenue);13. Infezioni da HIV, epatite B/C in base all’anamnesi (non saranno eseguiti i test);14. Donne in gravidanza o allattamento o donne potenzialmente fertili che non desiderano impiegare un metodo contraccettivo di doppia barriera durante lo studio e nei 3 mesi successivi all’ultima somministrazione del trattamento in studio;15. Pazienti di sesso maschile, con partner potenzialmente fertili, che non desiderano impiegare un metodo contraccettivo di doppia barriera, uno dei quali deve essere il preservativo, durante lo studio e nei 3 mesi successivi alla fine del trattamento;16. Sospetta ipersensibilità a 5-Aza o Mannitolo;17. Pazienti che non possono deglutire le capsule;18. Incapacità o non volontà di aderire al protocollo;19. Pazienti con evidenza di sanguinamento delle mucose o sanguinamento interno clinicamente rilevante. |
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E.5 End points |
E.5.1 | Primary end point(s) |
As of amendment 2, primary endpoint is Composite CR (CR or CRi or bone marrow CR) |
Con l'emendamento 2, CR composita (CR o Cri o CR del midollo osseo) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 8 weeks and at end of trial |
Ogni 8 settimane e alla fine dello studio |
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E.5.2 | Secondary end point(s) |
•Clinical response for AML: PR; for MDS/CMML: PR and Hematologic Improvement (HI) •Overall response (CR or CRi or bone marrow CR or PR) •1-year survival •Time to progression (TTP) based on the Guidelines for Implementation of IWG response criteria in AML, MDS and CMML according to Cheson 2003 and 2006 Post-text supplement 1 •Type, duration, frequency and relatedness of Adverse Events (AE). AE severity will be assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) •Laboratory (biochemistry, hematology) •ECG monitoring (central review by eRT) |
- Risposta clinica per AML: PR; per MDS/CMML: PR e miglioramento ematologico (HI). - Risposta globale (CR or CRi o CR del midollo osseo o PR). - Sopravvivenza a 1 anno. - Tempo alla progressione (TTP) in base alle linee-guida per l’implementazione dei criteri di risposta IWG nelle AML, MDS e CMML in base a Cheson 2003 e 2006 (Post-text supplement 1). - Tipo, durata, frequenza e correlazione degli eventi avversi (AE). Inoltre, la gravità degli AE sarà stabilita in base al National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0). - Esami di laboratorio (biochimica, ematologia) - Monitoraggio ECG (revisione centralizzata mediante eRT) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As per visit schedules |
Come programmato per visita |
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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 | 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 |
Explore if gene mutation status of specific target genes known are associated with outcome |
Esplorare se lo status di mutazione di specifici geni bersaglio è associato con l'esito |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
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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
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 16 |
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 | 19 |
E.8.9.2 | In all countries concerned by the trial days | 0 |