| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple Myeloma patients candidate to high-dose therapy |
| Mieloma multiplo in pazienti candati ad una terapia ad alte dosi |
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| E.1.1.1 | Medical condition in easily understood language |
| Multiple myeloma (MM) is an incurable neoplastic disease characterized by a proliferation of monoclonal bone marrow plasmacells with a median age at presentation of about 65 years. |
| Il mieloma multiplo e' una malattia neoplastica inguaribile caratterizzata dalla proliferazione di una popolazione di plasmacellule clonali, che si presenta nei soggetti di circa 65 anni. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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) |
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| 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 if the combination of Panobinostat, Bortezomib and high-dose Dexamethasone as induction therapy can increase the complete response (CR) rate in subjects with previously untreated multiple myeloma who are candidates to autologous stem cell transplantation (ASCT). |
| Valutare se la terapia con Panobinostat, Bortezomib e alte dosi di Desametasone incrementa le risposte complete (RC) nei pazienti con Mieloma Multiplo non precedentemente trattati, candidati ad una terapia ad alte dosi con supporto di cellule staminali periferiche (ASCT). |
|
| E.2.2 | Secondary objectives of the trial |
| 1. to determine if Panobinostat has an impact on peripheral blood stem cell mobilization (PBSC); 2. to evaluate if this high-dose protocol improves the outcome increasing the overall response rate (ORR), improving time to response (TTR) and prolonging progression free survival (PFS), overall survival (OS), duration of response (DOR), time to progression (TTP), time to next treatment (TNT), treatment free interval (TFI). 3. to determine the feasibility and toxicity of the protocol. |
| 1) valutare se Panobinostat abbia un impatto sulla mobilizzazione di cellule staminali periferiche (PBSC); 2) valutare se il regime ad alte dosi dello studio prolunga il tempo alla progressione (TTP),la sopravvivenza libera da progressione (PFS),la durata della risposta (DOR),il tempo al trattamento successivo (TNT),il tempo senza trattamento (TFI) e la sopravvivenza globale (OS); 3) valutare la fattibilita' e la tossicita' del protocollo. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
OTHER SUBSTUDIES:
Biological study
Objective: to find a panel of biomarkers that can be related to disease response, overall sulrvival and relapsed risk in MM patients.
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ALTRI SOTTOSTUDI:
Sottostudio biologico
Obiettivo: individuare un pannello di biomarcatori che possano essere correlati a risposta clinica, sopravvivenza e rischio di ricaduta nei pazienti con MM.
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| E.3 | Principal inclusion criteria |
| • Diagnosis of Symptomatic Multiple Myeloma based on IMWG 2003 criteria (all three required): • Monoclonal protein present in the serum and/or urine • Monoclonal plasma cells in the bone marrow ≥10% and/or presence of a biopsy-proven plasmacytoma • Myeloma-related organ dysfunction (at least one of the following) [C] Calcium elevation in the blood (serum calcium >10.5 mg/dl or upper limit of normal) [R] Renal insufficiency (serum creatinine >2 mg/dl) [A] Anemia (hemoglobin <10 g/dl or 2 g < normal) [B] Lytic bone lesions or osteoporosis • Patient has to be previously untreated except for emergency use of a short course [maximum 4 days] of steroids. • Patient is between 18 and 65 years of age at time of signing informed consent • Patient has measurable disease, defined as any quantifiable serum M-protein value ≥ 1g/dL and/or urine M-protein of ≥200 mg/24 hours • Absence of severe associated pulmonary, cardiac, metabolic, neurologic diseases or concomitant neoplasia • Negativity of HBV, HCV, HIV • Performance status score ≥ 60% • Agree to use as acceptable barrier methods for contraception for the duration of the induction phase (for male subject). If female subjects are still having menstrual periods or are not surgically sterile, they must be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study and have negative serum beta-HCG pregnancy at screening. • Have pre-treatment clinical laboratory values meeting the criteria specified in the protocol • Patient voluntarily participates by giving written informed consent • Patient is able to swallow capsules and is able to take or tolerate oral medications on a continuous basis • Patient is available for periodic blood sampling, study assessments, and management at the treating institution for the duration of the study • Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to start of study treatment • Patient should be eligible for an autologous stem cell transplant |
| • Diagnosi di Mieloma Multiplo sintomatico definito secondo i seguenti 3 criteri (tutti e 3 presenti): -Infiltrato plasmacellulare midollare ≥10% e/o presenza di un plasmocitoma dimostrato istologicamente; -Presenza di una componente monoclonale nel siero o nelle urine; -Danno d’organo correlato al mieloma (almeno uno dei seguenti) [C] IperCalcemia (calico sierico >10.5 mg/l o superiore al limite di normalita')[R] Insufficienza Renale (creatinina >2 mg/dl) [A] Anemia (emoglobina <10 g/dl or 2 g < normale) [B] Presenza di lesioni litiche ossee o osteoporosi (Bone) • Eta' compresa fra 18 e 65 anni alla data della firma del consenso informato • Il paziente non deve aver ricevuto alcun trattamento precedente ad eccezione di un breve ciclo (massimo 4 giorni) di steroidi • Malattia misurabile, definita come presenza di componente monoclonale sierica misurabile ≥1 g/dL e/o componente monoclonale nelle urine ≥200 mg/24 ore • Assenza di patologie severe polmonari cardiache, metaboliche, neurologiche o neoplasie concomitanti. • Negativita' per HBV; HCV; HIV • Performance status ≥60% • Consenso ad adottare contraccettivi di barriera durante tutta la fase di induzione (per i soggetti di sesso maschile). I soggetti di sesso femminile, con cicli mestruali ancora presenti o che non siano chirurgicamente sterili, dovranno assumere un contraccettivo (contraccettivi orali, e.v., dispositivi intrauterini, dispositivi di barriera doppi, cerotti contraccettivi, partner maschili sterili) prima dell’arruolamento, per tutta la durata dello studio e dovranno avere valori negativi di -HCG allo screening. • Valori di laboratorio eseguiti nei 14 giorni precedenti l’arruolamento nei limiti indicati nel protocollo • Sottoscrizione di consenso informato scritto • Il paziente deve essere in grado di assumere i farmaci per via orale in maniera continuativa • Il paziente deve acconsentire ad effettuare i prelievi di sangue periodicamente previsti dallo studio insieme alle altre procedure previste per l’intera durata della sperimentazione • Le donne in eta' potenzialmente fertile devono avere un test di gravidanza negativo entro 7 giorni dall’inizio dello studio • Il paziente deve essere eleggibile per il trapianto autologo di cellule staminali |
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| E.4 | Principal exclusion criteria |
| • Diagnosis of smoldering myeloma or MGUS or Waldenstrom’s disease or other conditions in which IgM M-protein is presenting the absence of a clonal plasma cell infiltration with lytic bone lesions. • Diagnosis of plasma cell leukaemia, • Prior or current systemic therapy for multiple myeloma including steroids before randomisation • Prior treatment with HDAC as treatment for cancer except for Valproic Acid used for non-cancer indications such as migraine prevention and seizure disorder. • Radiotherapy within 30 days before entry and with more than 25% of bone marrow reserve irradiated • Plasmapheresis within 30 days before entry • Major surgery within 30 days before entry • Patient has a history of a gastrointestinal surgery or other procedures that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s) • History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances • Uncontrolled diabetes • Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure (Attachment 4, NYHA Classification of Cardiac Disease), uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis • Patient has pre-existing NCI CTC Grade 1 neuropathy with pain or ≥Grade 2 neuropathy • Patient is a regular user or had a recent history (within the last year) of any illicit drugs, or substance abuse • Serious medical or psychiatric illness likely to interfere with participation in the clinical study • Receipt of experimental drug or used an experimental medical device within 4 weeks before the planned start of treatment. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study • Other malignancy within the past 5 years. Exceptions for the following if treated and not active: basal cell or non metastatic squamous cell carcinoma of the skin, cervical carcinoma in situ or International Federation of Gynaecology and Obstetrics stage 1 carcinoma of the cervix • Pregnant or breastfeeding • Women of childbearing potential (WOCBP) not willing to use a double method of contraception during the study and 3 months after the study evaluation completion treatment, of which one must be a barrier method. • Patient is a male not willing to use a barrier method of contraception during the study and for 3 months after the study evaluation completion treatment. • Known hypersensitivity allergy or inability to tolerate any of the agent employed • Patient receiving treatment with any medications which have a relative risk of prolonging the QT interval or inducing Torsades de points. |
| • Diagnosi di Mieloma Multiplo asintomatico o MGUS o M. di Waldenstrom o altre patologie in cui siano presenti componenti monoclinali IgM in assenza di infiltrato plasmocitario clonale. • Diagnosi di Leucemia Plasmacellulare • Precedente o concomitante terapia sistemica per Mieloma compresa terapia steroidea prima della randomizzazione • Radioterapia nei 30 giorni precedenti l’arruolamento e con piu' del 25% di riserva del midollo osseo irradiato • Plasmaferesi nei 30 giorni precedenti l’arruolamento • Chirurgia maggiore nei 30 giorni precedenti l’arruolamento • Chirurgia gastrica che a giudizio dello sperimentatore possa interferire con l’assorbimento della terapia per os • Precedente terapia con Panobinostat o altri inibitori dell’HDAC o altri farmaci con attivita' similari come l’acido valproico. I pazienti che assumono questi farmaci per altre ragioni (es. epilessia) possono essere arruolati dopo un periodo di sospensione di almeno 30 giorni. • Patologie epatiche o renali rilevanti in storia medica. Patologie cardiologiche, vascolari, polmonari, gastrointestinali, endocrine, neurologiche, reumatologiche, ematologiche, psichiatriche o metaboliche rilevanti. • Diabete scompensato • Patologie cardiovascolari severe o non controllate incluso infarto del miocardio nei sei mesi precedenti l’arruolamento, scompenso cardiaco di classe III o IV secondo NYHA, angina instabile, patologie pericardiche clinicamente significative, amiloidosi cardiaca. • Neuropatia di grado 1 NCI con dolore o di grado ≥ 2 • Abuso di sostanze illecite (entro l’anno precedente) • Gravidanza o allattamento • Radioterapia estesa o chemioterapia sistemica o assunzione di altri farmaci antineoplastici prima dell’arruolamento • Patologie psichiatriche severe che controindichino la partecipazione allo studio • Assunzione di farmaci sperimentali o uso di dispositivi medici sperimentali nelle 4 settimane precedenti l’inizio della terapia • La partecipazione a studi non comprensivi di terapia e' permessa se non interferisce nella corretta partecipazione alle procedure dello studio in oggetto • Altre neoplasie nei 5 anni precedenti. Ad eccezione di: carcinoma basocellulare o carcinoma squamocellulare non metastatico della cute, carcinoma della cervice in situ o carcinoma della cervice in stadio 1 secondo IFGO |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage of complete response (CR). |
| Percentuale di risposte complete (CR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Not applicable. |
| Non applicabile. |
|
| E.5.2 | Secondary end point(s) |
| ORR: comprising CR, near CR, VGPR (Very Good Partial Reponse) and partial response (PR); TTR, PFS, OS, DOR, TTP, TNT, TFI. Secondary safety endpoints: AEs, ECG parameters, laboratory parameters |
| ORR incluso CR, near CR, VGPR (Very Good Partial Reponse) e PR (Partial Response); TTR, PFS, OS, DOR, TTP, TNT, TFI. Endpoints di safety: Eventi avversi, parametri elettrocardiografici, parametri di laboratorio. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Not applicable. |
| Non applicabile. |
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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 | 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 | 12 |
| 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 | 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 | 80 |
| E.8.9.1 | In the Member State concerned days | 0 |
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