| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple Myeloma |
| Mieloma Multiplo |
|
| 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 | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| 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 determine the MTD of LBH589 when used in combination with a fixed dose of lenalidomide & dexamethasone. |
| Determinare la MTD di LBH589 somministrato per via orale in associazione a una dose fissa di lenalidomide e desametasone |
|
| E.2.2 | Secondary objectives of the trial |
| To characterize the safety and tolerability of the study treatment • To characterize the PK profile of LBH589 when it is administered in combination with lenalidomide & dexamethasone, and to evaluate the degree of influence of dexamethasone CYP450 moderate induction on LBH589 trough levels • To characterize the PD profile of the study treatment through the analysis of various biomarkers in the context of this combination • To assess the preliminary efficacy of the study treatment |
| • Caratterizzare la sicurezza e la tollerabilita' del trattamento in studio.• Caratterizzare il profilo farmacocinetico di LBH589 somministrato in associazione a lenalidomide e desametasone e valutare il grado di influenza della moderata induzione del CYP450 indotta da desametasone sui livelli 'trough' di LBH589.• Caratterizzare il profilo farmacodinamico del trattamento in studio mediante l'analisi di diversi indicatori biologici nel contesto dell'associazione in studio.• Valutare l'efficacia preliminare del trattamento in studio. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Patients must have a diagnosis of active multiple myeloma according to the International Myeloma Working Group criteria (IMWG, 2003), and be deemed by the investigator as requiring treatment. 2. Patients must have received at least one prior line of therapy and their disease has relapsed (Durie et. al., 2006). One prior line of therapy may consist of induction followed by autologous stem cell transplantation. 3. Patients must be suitable (according to their local product information) for treatment with lenalidomide & dexamethasone. Note: patients previously treated with lenalidomide & dexamethasone are eligible to participate in the trial. 4. Adults ≥ 18 years old 5. ECOG Performance Status ≤ 2 6. Life expectancy > 12 weeks 7. Patients must have the following laboratory values: • ANC ≥ 1.5 x 109/L • Hemoglobin ≥ 9 g/dl • Platelets ≥ 100x 109/L • Calculated CrCl ≥ 50 mL/min (MDRD Formula) • AST and ALT ≤ 2.5 x ULN • Serum bilirubin ≤ 1.5 x ULN • Albumin > 3.0 g/dl • Serum potassium ≥ LLN • Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN, • Serum magnesium ≥ LLN • Serum phosphorus ≥ LLN • TSH ≤ LLN and free T4 within normal limits. Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism. 8. Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal 9. Patients participating in the dose-expansion phase of the trial must be willing and able to undergo bone marrow aspirates as per protocol, with/without bone marrow biopsy according to their center's practice 10. Able to sign informed consent and to comply with the protocol |
| Principali criteri di inclusione: 1. Diagnosi di mieloma multiplo in fase attiva (secondo i criteri dell'IMWG, 2003) che, a giudizio dello sperimentatore, necessita di trattamento. 2. I pazienti devono aver precedentemente ricevuto trattamento con almeno una linea terapeutica (precedenti trattamenti con inibitori di IMID, HDAC e HSP90 non sono permessi) e devono aver manifestato recidiva. Una linea terapeutica precedente puo' essere rappresentata dall'induzione seguita da trapianto autologo di cellule staminali. 3. I pazienti devono essere idonei al trattamento con lenalidomide e desametasone. I pazienti precedentemente trattati con lenalidomide e desametasone sono eleggibili allo studio. 4. Eta' ≥ 18 anni 5. Performance status ECOG ≤ 2 6. Aspettativa di vita > 12 settimane. 7. I pazienti devono avere i seguenti parametri di laboratorio: • Conta assoluta dei neutrofili (ANC) ≥ 1.5 x 109/L • Emoglobina ≥ 9 g/dl • Piastrine ≥ 100 x 109/L • CrCl calcolata ≥ 50 mL/min (Formula MDRD) • AST e ALT ≤ 2.5 x ULN • Bilirubinemia ≤ 1.5 x ULN • Albuminemia ≥ 3.0 g/dl • Potassiemia ≥ limite inferiore della norma (LLN) • Calcemia totale (corretta per l'albumina sierica) o calcio ione ≥ LLN • Magnesiemia ≥ LLN • Fosforemia ≥ LLN • TSH ≤ LLN e T4 libero entro il limite della norma (i pazienti possono essere in terapia ormonale tiroidea sostitutiva per il trattamento dell'ipotiroidismo) 8. Il MUGA (Multiple Uptake Gated Acquisition) o l'ecocardiogramma basali devono mostrare una frazione di eiezione del ventricolo sinistro (LVEF) ≥ il limite inferiore della norma per il centro. 9. I pazienti che partecipano alla fase di espansione della dose dello studio devono accettare ed essere in condizione di essere sottoposti agli aspirati midollari previsti dal protocollo, con/senza biopsia midollare secondo la pratica clinica del centro. 10. Consenso informato scritto e compliance alle procedure previste dal protocollo di studio. |
|
| E.4 | Principal exclusion criteria |
| 1.Prior exposure to a HDAC inhibitor compound used in the treatment of MM. 2.Primary refractory MM 3.Patients who have received allogeneic stem cell transplantation < 12 months prior to entering the study 4.Patients who have had prior allogeneic stem cell transplantation and show evidence of active graft-versus-host disease that requires immunosuppressive therapy. 5.Peripheral neuropathy > CTCAE grade 2 6.Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: • Patients with congenital long QT syndrome • History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible but should be discussed with the Sponsor prior to enrollment) • Any history of ventricular fibrillation or torsade de pointes • Bradycardia defined as HR< 50 bpm.Patients with pacemakers are eligible if HR ≥ 50 bpm. • Screening ECG with a QTc > 450 msec • Right bundle branch block + left anterior hemiblock (bifascicular block) • Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug • Other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen) 7.Impairment of GI function or GI disease that may significantly alter the absorption of LBH589 8.Patients with diarrhea > CTCAE grade 1 9.Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol 10.Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug 11.Concomitant use of CYP3A4 inhibitors 12.Patients with a history of Deep Vein Thrombosis or thromboembolism within < 6 months prior to starting study treatment 13.Patients for whom prophylactic anticoagulation therapy (eg.325mg aspirin PO daily or warfarin (Coumadin) 1-2 mg/day, or any other coumarinderivative anticoagulants) is not an option. 14.Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (which ever is longer) and who have not recovered from side effects of those therapies. 15.Patients who have received either immunotherapy within < 8 weeks; chemotherapy within < 4 weeks; or radiation therapy to > 30% of marrowbearing bone within < 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies. 16.Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy 17.Women who are pregnant or breast feeding, or women of childbearing potential (WOCBP) who are unable to use two reliable forms of contraception simultaneously, unless continuous abstinence from heterosexual contact is the chosen method.WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses any time in the preceding 24 consecutive months).WOCBP should have 2 negative pregnancy tests (sensitivity of at least 50 mIU/L) prior to beginning therapy.The first test should be performed within 10-14 days of commencing study treatment, and the second test within 24hr prior to receiving the first dose of study treatment. 18.Male patients whose sexual partners are WOCBP and who are unable to use a latex condom during sexual contact (even if they have undergone a vasectomy). 19.Pls see protocol |
| Principali criteri di esclusione: 1. Trattamento precedente con un inibitore delle HDAC per il trattamento del mieloma. 2. Mieloma multiplo primario refrattario. 3. Pazienti sottoposti a trapianto allogenico di cellule staminali < 12 mesi dall'ingresso nello studio. 4. Pazienti sottoposti a trapianto allogenico di cellule staminali con evidenza di graft-versus-host disease (malattia del trapianto versus l'ospite) che necessitano di terapia immunosoppressiva. 5. Neuropatia periferica > grado 2 CTCAE. 6. Funzionalita' cardiaca alterata o patologia cardiaca significativa. 7. Alterazione della funzionalita' gastrointestinale (GI) o patologia GI che puo' alterare significativamente l'assorbimento di LBH589. 8. Pazienti con diarrea persistente > grado 1 CTCAE. 9. Qualsiasi altra condizione medica grave e/o non controllata (ad esempio, diabete non controllato o infezione attiva non controllata), compresa l'alterazione dei valori dei parametri di laboratorio, che possa comportare un rischio inaccettabile per la sicurezza o compromettere la compliance con il protocollo. 10. Uso concomitante di farmaci che possono prolungare l'intervallo QT o indurre torsioni di punta se la terapia non puo' essere interrotta o non puo' essere sostituita con altre terapie prima di iniziare il trattamento in studio. 11. Uso concomitante di inibitori del CYP3A4. 12. Anamnesi positiva per trombosi venosa profonda < 6 mesi prima dell'inizio del trattamento in studio. 13. Pazienti che necessitano di profilassi con anticoagulanti [ad es:, 325 mg di aspirina per via orale al giorno o 1-2 mg/die warfarin (Coumadin) o qualunque altro derivato cumarinico]. 14. Pazienti sottoposti a trattamento con agenti target-specifici nelle 2 settimane precedenti ( o 5 emivite) che non hanno presentato risoluzione degli eventi avversi di questi farmaci. 15. Pazienti sottoposti a trattamento precedente con immunoterapia < 8 settimane; chemioterapia < 4 settimane o radioterapia > 30% dell'osso contenente midollo < 2 settimane prima dell'inizio del trattamento in studio o che non hanno presentato risoluzione degli eventi avversi di questi trattamenti. 16. Pazienti che sono stati sottoposti a chirurgia maggiore ≤ 4 settimane precedenti l'inizio della terapia con il farmaco in studio o che non sono guariti dagli effetti collaterali di questa terapia. 17. Pazienti di sesso femminile in gravidanza o allattamento, o pazienti potenzialmente fertili che non utilizzano simultaneamente due metodi contraccettivi adeguati, ad eccezione delle donne che praticano astinenza da rapporti eterosessuali. 18. Pazienti di sesso maschile (anche se vasectomizzati) le cui partner sessuali siano in eta' fertile e non possono utilizzare il preservativo di lattice. 19. Anamnesi positiva per altre neoplasie primitive nei 5 anni precedenti eccetto carcinoma in situ della cervice dell'utero o basalioma o carcinoma squamocellulare della cute. 20. Mancanza di compliance alle terapie mediche nota o incapacita' di fornire un consenso informato o incapacita' di seguire le istruzioni ricevute dal personale dello studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To determine the MTD of LBH589 when used in combination with a fixed dose of lenalidomide & dexamethasone. |
| Primario: Determinare la MTD di LBH589 somministrato per via orale in associazione a una dose fissa di lenalidomide e desametasone. |
|
| 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | 27 |
| 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 | 27 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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