| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed multiple myeloma |
| Multiple mieloma di nuova diagnosi |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type of cancer of the white blood cells |
| Tipo di tumore dei globuli bianchi |
|
| 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 | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| 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 |
| Phase 2: To determine the combined response rate of CR + VGPR during the induction therapy period following a twice weekly administration of oral MLN9708 on Days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle when added to standard care MP on Days 1 through 4 of every cycle To determine the combined response rate of CR + VGPR during the induction therapy period following a once weekly administration of oral MLN9708 on Days 1, 8, and 15 of a 28-day cycle when added to standard care MP on Days 1 through 4 of every cycle |
| Phase 2: To determine the combined response rate of CR + VGPR during the induction therapy period following a twice weekly administration of oral MLN9708 on Days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle when added to standard care MP on Days 1 through 4 of every cycle To determine the combined response rate of CR + VGPR during the induction therapy period following a once weekly administration of oral MLN9708 on Days 1, 8, and 15 of a 28-day cycle when added to standard care MP on Days 1 through 4 of every cycle |
|
| E.2.2 | Secondary objectives of the trial |
| To determine the time to response during the induction therapy period To evaluate the duration of response (DOR) for patients who responded XML File Identifier: WoITorNlHdIXG7KRVAukHdNB5Js= Page 18/35 during the induction therapy period To determine ORR during the induction therapy period and through the entire study To assess the time to progression (TTP) To evaluate time to next therapy and treatment-free interval To evaluate the progression-free survival (PFS) rate To evaluate the overall survival (including 1-year survival rate) To determine the safety profile of MLN9708 To evaluate changes in quality of life (QOL) |
| To determine the time to response during the induction therapy period To evaluate the duration of response (DOR) for patients who responded XML File Identifier: WoITorNlHdIXG7KRVAukHdNB5Js= Page 18/35 during the induction therapy period To determine ORR during the induction therapy period and through the entire study To assess the time to progression (TTP) To evaluate time to next therapy and treatment-free interval To evaluate the progression-free survival (PFS) rate To evaluate the overall survival (including 1-year survival rate) To determine the safety profile of MLN9708 To evaluate changes in quality of life (QOL) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Male or female patient for whom standard MP treatment is indicated and who is not a candidate for HDT-SCT for 1 of the following reasons: The patient is 65 years of age or older. The patient is less than 65 years of age but has significant comorbid condition(s) that are likely to have a negative impact on tolerability of HDT-SCT. 2. Symptomatic MM or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria 3. Patients must have measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein ≥ 1 g/dL (≥ 10 g/L) Urine M-protein ≥ 200 mg/24 hours Serum free light chain assay: involved free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided that the serum free light chain ratio is abnormal 4. Patients must meet the following clinical laboratory criteria within 3 days before the first dose of study treatment to be enrolled in the study: Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3. platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to study drug dosing. Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN. Calculated creatinine clearance ≥ 30 mL/min 5. ECOG performance status of 0 to 2 6. Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study treatment, OR agree to completely abstain from heterosexual intercourse 7. Male patients, even if surgically sterilized (ie, status postvasectomy), who: Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study treatment, OR Agree to completely abstain from heterosexual intercourse Male patients must agree to not father a child and agree to use a latex condom during therapy and for 4 months after the last dose of study treatment, even if they have had a successful vasectomy, if their partner is of childbearing potential. 8. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. |
| 1. Pazienti di sesso maschile o femminile per i quali è indicato il trattamento MP standard e non candidati a HDT-SCT per uno dei seguenti motivi: • Il paziente ha un’età pari o superiore a 65 anni. • Il paziente ha meno di 65 anni ma presenta significative condizioni di comorbilità che possono avere un impatto negativo sulla tollerabilità dell’HDT-SCT. 2. MM sintomatico o mieloma asintomatico con danno agli organi correlato al mieloma diagnosticato secondo i criteri standard (vedere Sezioni 15.1 e 15.2) 3. I pazienti devono presentare una malattia misurabile definita tramite almeno una delle tre seguenti misurazioni: • Proteina M nel siero ≥ 1 g/dL (≥ 10 g/L) • Proteina M nell’urina ≥ 200 mg/24 ore • Analisi delle catene libere leggere nel siero: livello catene libere leggere coinvolte ≥ 10 mg/dL (≥ 100 mg/L), a condizione che il rapporto delle catene libere leggere nel siero sia anormale 4. Per poter essere arruolati nello studio, i pazienti devono soddisfare i seguenti criteri del laboratorio clinico nei 3 giorni precedenti la prima dose del farmaco dello studio: • Conta dei neutrofili (ANC) ≥ 1.000/mm3 e conta delle piastrine ≥ 75.000/mm3. Non sono consentite trasfusioni piastriniche che portino i pazienti a soddisfare i criteri di idoneità nei 3 giorni precedenti alla somministrazione del farmaco dello studio. • Bilirubina totale ≤ 1,5 volte il limite superiore della norma (ULN). • Alanina aminotransferasi (ALT) e aspartato aminotransferasi (AST) ≤ 3 volte l’ULN. • Clearance della creatinina calcolata ≥ 30 mL/min (vedere sezione 15.2). 5. Performance status secondo l’ECOG da 0 a 2 (vedere sezione 15.4). 6. Pazienti di sesso femminile: • In post-menopausa da almeno 1 anno prima della visita di screening OPPURE • Chirurgicamente sterili OPPURE • Se fertili, accettino di adottare contemporaneamente 2 metodi contraccettivi efficaci, dal momento della firma del consenso informato fino a 30 giorni dopo l’ultima dose del farmaco dello studio OPPURE accettino di astenersi completamente dall’avere rapporti eterosessuali 7. Pazienti di sesso maschile, anche se chirurgicamente sterilizzati (post-vasectomia): • Accettino di praticare una contraccezione a barriera efficace durante tutto il periodo dello studio e fino a 4 mesi dopo la somministrazione dell’ultima dose del farmaco dello studio OPPURE • Accettino di astenersi completamente dall’avere rapporti eterosessuali • I pazienti di sesso maschile, nel caso la loro partner sia fertile, devono accettare di non procreare e di usare un profilattico in lattice durante la terapia e nei 4 mesi successivi alla somministrazione dell’ultima dose del farmaco dello studio, anche se sono stati sottoposti a vasectomia con esito positivo. 8. Deve essere presentato il consenso volontario scritto prima dell’attuazione di qualunque procedura correlata allo studio non appartenente alle cure mediche standard, con la consapevolezza che il consenso può essere ritirato dal paziente in qualunque momento senza conseguenze sulle future cure mediche. |
|
| E.4 | Principal exclusion criteria |
| 1. Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period. 2. Female patients who are lactating or pregnant. 3. Major surgery within 14 days before the first dose of study drug. (Note: kyphoplasty or vertebroplasty is not considered major surgery.) 4. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study drug. 5. Diarrhea >Grade 1, based on the NCI CTCAE grading, in the absence of antidiarrheals. 6. Prior systemic therapy for MM, including investigational drugs. Prior treatment with corticosteroids or localized radiation therapy does not disqualify the patient (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone, a total of which can be given in a 2-week period. 7. Radiotherapy within 14 days before the first dose of study treatment. 8. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment. 9. Central nervous system involvement. 10. Diagnosis of smoldering MM, Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome. 11. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. 12. QTc > 470 msec on a 12-lead ECG obtained during the Screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG. 13. Known or suspected human immunodeficiency virus (HIV) positive. 14. Known or suspected hepatitis B surface antigen-positive status orknown or suspected active hepatitis C infection. 15. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. 16. Known allergy to any of the study medications, their analogues, or excipients in the various formulations. 17. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing. 18. Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. |
| 1. Neuropatia periferica ≥ grado 2 all’esame clinico durante il periodo di screening. 2. Donne in gravidanza o allattamento. 3. Intervento chirurgico importante nei 14 giorni precedenti la prima dose del farmaco dello studio. (Nota: la chifoplastica o la vertebroplastica non sono considerate interventi chirurgici importanti). 4. Infezione che necessiti di terapia antibiotica sistemica o altra grave infezione nei 14 giorni precedenti la prima dose del farmaco dello studio. 5. Crisi diarroica > grado 1, in base alla classificazione NCI CTCAE, in assenza di antidiarroici. 6. Precedente terapia sistemica per MM, compresi farmaci sperimentali. Il precedente trattamento con corticosteroidi o radioterapia localizzata non esclude il paziente (la dose massima di corticosteroidi non dovrà aver superato l’equivalente di 160 mg di desametasone e il suo totale potrà essere stato somministrato in un periodo di 2 settimane [per un elenco di dosi di steroidi equivalenti, vedere la sezione 15.5]). 7. Radioterapia nei 14 giorni precedenti la prima dose del farmaco dello studio. 8. Trattamento sistemico con potenti inibitori di CYP1A2 (fluvoxamina, enoxacina), potenti inibitori di CYP3A (claritromicina, telitromicina, itraconazolo, voriconazolo, ketoconazolo, nefazodone, posaconazolo) o potenti induttori di CYP3A (rifampina, rifapentina, rifabutina, carbamazepina, fenitoina, fenobarbital) o l’uso di Ginkgo biloba o iperico (erba di San Giovanni) nei 14 giorni precedenti la prima dose di farmaco dello studio. 9. Coinvolgimento del sistema nervoso centrale. 10. Diagnosi di MM a progressione lenta, macroglobulinemie di Waldenstrom, sindrome POEMS (polineuropatia, organomegalia, endocrinopatia, gammopatia monoclonale e alterazioni cutanee), leucemia plasmacellulare, amiloidosi primaria, sindrome mielodisplastica o sindrome mieloproliferativa (vedere sezione 15.2) 11. Evidenza di condizioni cardiovascolari correnti non controllate, tra cui ipertensione non controllata, aritmie cardiache non controllate, insufficienza cardiaca congestizia sintomatica, angina instabile o infarto miocardico negli ultimi 6 mesi. 12. QTc > 470 msec in un ECG a 12 derivazioni ottenuto durante il periodo di screening. Se un valore indicato dalla macchina è superiore a questo valore, l’ECG deve essere analizzato da un medico qualificato e confermato da un successivo ECG. 13. Positività accertata o sospetta al virus dell’immunodeficienza umana (HIV). 14. Positività accertata o sospetta all’antigene di superficie del virus dell’epatite B o infezione attiva, accertata o sospetta, da virus dell’epatite C. 15. Qualunque grave patologia medica o psichiatrica che potrebbe, secondo il giudizio dello sperimentatore, interferire potenzialmente con il completamento del trattamento previsto dal presente protocollo. 16. Allergia accertata verso uno dei farmaci dello studio, analoghi o eccipienti contenuti nelle varie formulazioni. 17. Malattia gastrointestinale (GI) accertata o intervento GI che potrebbe interferire con l’assorbimento orale o con la tolleranza del farmaco dello studio, tra cui la difficoltà di deglutizione. 18. Diagnosi o trattamento di altro tumore maligno nei 2 anni precedenti la prima dose o diagnosi precedente di altro tumore maligno con evidenza di malattia residua. I pazienti con cancro della pelle non melanoma o carcinoma in situ di qualunque tipo non sono esclusi se sono stati sottoposti a resezione completa. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Combined response rate of CR + VGPR in patients treated with MLN9708 when added to a standard care regimen of MP during the induction period |
| Tasso di risposta combinata di CR (risposta completa) + VGPR (risposta parziale molto buona) in pazienti trattati con MLN9708 con aggiunta di un regime di cura standard di melphelan durante il periodo di induzione. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Arm A Induction period: End of each 42 day cycle for up to 9 cycles. Arm B Induction Period: End of each 28 day cycle up to cycle 6 (and for every 2 cycles thereafter if in phase 1 for up to 12 cycles). |
Braccio A Periodo di induzione: fine di ogni ciclo di 42 giorni fino a 09 cicli.
Braccio B Periodo di induzione: fine di ogni ciclo di 28 giorni fino al ciclo 6 (e per ogni 2 cicli successivamente se in fase 1 fino a 12 cicli). |
|
| E.5.2 | Secondary end point(s) |
| To determine the time to response during the induction therapy period To evaluate the duration of response (DOR) for patients who responded during the induction therapy period To determine ORR during the induction therapy period and throughout the entire study To assess the time to progression (TTP) |
Per determinare il tempo di risposta durante il periodo di terapia di induzione
Per valutare la durata della risposta(DOR) per pazienti responsivi durante il periodo di induzione della terapia Per determinare il tasso di risposta complessivo (ORR)durante il periodo di induzione della terapia e attraverso l' intero studio. Per valutare il tempo di progressione(TTP. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Arm A Induction period: End of each 42 day cycle for up to 9 cycles. Arm B Induction Period: End of each 28 day cycle up to cycle 6 (and for every 2 cycles thereafter if in phase 1 for up to 12 cycles). Arm A&B Maintenance period: Every 2 cycles (28 day cycle) for up to 12 cycles |
Braccio A Periodo di induzione: fine di ogni ciclo di 42 giorni fino a 09 cicli.
Braccio B Periodo di induzione: fine di ogni ciclo di 28 giorni fino al ciclo 6 (e per ogni 2 cicli successivamente se in fase 1 fino a 12 cicli).
Braccio A e B Period di mantenimento: Ogni 2 cicli (ciclo di 28 giorni) fino a 12 cicli |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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 | 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Canada |
| Russian Federation |
| United States |
|
| 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
|
| Last patient, last visit. |
| ultima visita dell' ultimo paziente |
|
| 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 | 72 |
| 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 | 72 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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