| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with refractory or relapsed and refractory multiple myeloma (rrMM) who have failed at least 2 lines of prior treatment and have been previously exposed to an immunomodulatory drug (IMiDs) as lenalidomide or thalidomide and a proteasome inhibitor as bortezomib or carfilzomib. |
| Pazienti con mieloma multiplo refrattario oppure recidivante e refrattario (rrMM) che hanno fallito almeno 2 precedenti linee di trattamento e sono stati precedentemente esposti ad un farmaco immunomodulatore come lenalidomide o talidomide ed a un inibitore del proteasoma come bortezomib o carfilzomib. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with multiple myeloma that has progressed after receaving at least 2 lines of prior treatment. These treatments must have included lenalidomide or thalidomide and a proteasome inhibitor. |
| Pazienti con mieloma multiplo progredito dopo almeno 2 precedenti linee di trattamento. Questi trattamenti devono includere lenalidomide o talidomide e un inibitore del proteasoma. |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| Compare the Progression Free Survival (PFS) as assessed by CAC blinded central review according to the International Myeloma Working Group response criteria, (IMWG criteria) between treatment arms. |
| Confrontare la sopravvivenza libera da progressione (PFS) come valutata dall’analisi centrale in cieco del CAC secondo i criteri di risposta del International Myeloma Working Group (criteri IMWG) fra i due bracci di trattamento. |
|
| E.2.2 | Secondary objectives of the trial |
1. Compare the Overall Survival (OS).
2. Evaluate Overall Response Rate (ORR) and Disease Control Rate (DCR) as assessed by CAC blinded central review and as per investigator assessment using IMWG criteria or EBMT criteria for minor response only and Duration of Response (DOR) as assessed by CAC blinded central review and as per investigator assessment using IMWG criteria.
3. Compare the Progression Free Survival (PFS) as assessed by the investigator using IMWG criteria between treatment arms.
4.To evaluate the safety and tolerability in both treatment arms. |
1. confrontare la sopravvivenza complessiva (Overall Survival, OS).
2. Valutare il tasso di risposta complessiva (objective response rate, ORR) e il tasso di controllo della malattia (disease control rate, DCR) secondo la valutazione dell’analisi centrale in cieco del CAC, seguendo i criteri dell’IMWG o del European Group for Blood and Bone Marrow Transplant (EBMT) per la risposta minore e la durata della risposta (duration of response, DOR) secondo la valutazione dell’analisi centrale in cieco del CAC seguendo i criteri dell’IMWG.
3. Valutare la sicurezza e la tollerabilità in entrambi i bracci di trattamento. |
|
| 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 |
Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described
elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The
objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding
of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
Merck condurrà una Ricerca Biomedica Futura
su campioni di DNA (estratti dal sangue) raccolti nel corso di questo studio clinico. Tale ricerca ha lo scopo di esaminare vari biomarcatori per rispondere a domande che stanno emergendo e che non sono descritte in altre parti del protocollo (nell ambito
dello studio principale), e verrà condotta solo su campioni di soggetti che abbiano rilasciato apposito consenso. L'obiettivo della raccolta dei campioni per la Ricerca Biomedica Futura è quello di esplorare e identificare biomarcatori che contribuiscano
scientificamente alla comprensione delle malattie e/o delle relative terapie. L'obiettivo ultimo è quello di utilizzare tali informazioni per sviluppare farmaci più sicuri e più efficaci, e/o per garantire che i soggetti ricevano la dose giusta del giusto farmaco al momento giusto. |
|
| E.3 | Principal inclusion criteria |
1. Must have undergone prior treatment with ≥ 2 treatment lines of anti-myeloma therapy and must have failed their last line of treatment defined as documented disease progression during or within 60 days of completing their last anti-myeloma therapy (refractory to last line of treatment).
2. Prior anti-myeloma treatments must have included an IMiD (lenalidomide or thalidomide) AND proteasome inhibitor (bortezomib or carfilzomib) alone or in combination and subject must have failed therapy with an IMiD OR proteasome inhibitor defined as one of the following:
• Refractory: Documented progressive disease on or within 60 days of completing treatment with an IMiD and/or proteasome inhibitor OR
• Relapsed and refractory: In case of prior response [≥ partial response (PR)] to an IMiD or proteasome inhibitor, subjects must have relapsed within 6 months after stopping treatment with and IMiD and/or proteasome inhibitor containing regimens
3. Confirmed diagnosis of active MM and measurable disease defined as:
• Serum monoclonal protein (M-protein) levels ≥ 0.5 g/dL or
• Urine monoclonal protein (M-protein) levels ≥200 mg/24-hours or
• Subjects without measurable serum and urine M-protein levels, an abnormal serum free light chain ratio (FLC κ/λ) with involved FLC level ≥100 mg/L. (Normal serum FLC κ/λ value: 0.26 - 1.65)
• Presence of CRAB features
4. Provide, archival (≤60 days) or newly obtained bone marrow biopsy or aspirate material for disease assessment and biomarker analysis.
5. Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. |
1. Essere stato sottoposto in precedenza a ≥ 2 linee di trattamento di terapia anti-mieloma con fallimento dell’ultima linea di trattamento come definito da progressione documentata della malattia durante o entro 60 giorni dal completamento dell’ultima terapia anti-mieloma (refrattario all’ultima linea di trattamento).
2. I trattamenti anti-mieloma precedenti devono aver incluso un IMiD (lenalidomide o talidomide) E un inibitore del proteasoma (bortezomib o carfilzomib) da soli o in associazione e il soggetto non deve aver risposto alla terapia con un IMiD OPPURE un inibitore del proteasoma secondo una delle definizioni seguenti:
• Refrattario: malattia progressiva documentata a/entro 60 giorni dal completamento del trattamento con IMiD e/o inibitore del proteasoma
OPPURE
• Recidivante e refrattario: in caso di risposta precedente [≥ risposta parziale (RP)] a un IMiD o a un inibitore del proteasoma, i soggetti devono aver avuto una recidiva entro i 6 mesi successivi all’interruzione del trattamento con regimi contenenti un IMiD e/o un inibitore del proteasoma.
3. Avere una diagnosi confermata di mieloma multiplo attivo e malattia misurabile definita come segue:
• Livelli sierici di proteina monoclonale (M proteina) ≥ 0,5 g/dl o
• Livelli di proteina monoclonale (M proteina) nelle urine ≥ 200 mg/24 ore o
• Per i soggetti in cui i livelli di proteina M nel siero e nelle urine non siano misurabili, un tasso anormale del rapporto fra le catene libere leggere nel siero (Free light chains, FLC κ/λ) con livello della FLC coinvolta ≥ 100 mg/l. (Valore diFLC κ/λ nel siero normale: 0,26 - 1,65).
• Presenza di caratteristiche CRAB
4. Essere in grado di fornire biopsie di midollo osseo o materiale aspirato d’archivio (≤ 60 giorni) o prelevati ex novo per la valutazione della malattia e l’analisi dei biomarcatori allo screening.
5. Avere un Performance Status di 0 o 1 sulla scala ECOG (Eastern Cooperative Oncology Group) Performance Scale. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with non-secretory or oligo-secretory myeloma, smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukemia or Waldenström's macroglobulinemia.
2. History of repeated infections, primary amyloidosis, hyperviscosity or POEMS syndrome.
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
4. Has had prior anti-myeloma therapy including but not limited to dexamethasone, IMiDs, proteasome inhibitors, chemotherapy, or radiation therapy within 2 weeks prior to Study Day 1 who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
5. Has undergone prior allogeneic hematopoetic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease (GVHD).
6. Has received autologous stem cell transplant (auto-SCT) within 12 weeks before the first infusion or are planning for or are eligible for auto-SCT.
7. Has known hypersensitivity to thalidomide, lenalidomide or dexamethasone.
8. Has received previous therapy with pomalidomide.
9. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment.
10. Subjects with peripheral neuropathy ≥ Grade 2.
11. Has evidence of active, non-infectious pneumonitis.
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. |
1. Soggetti affetti da mieloma non secretorio o oligo-secretorio, mieloma multiplo asintomatico (smoldering multiple myeloma, SMM), gammopatia monoclonale di significato incerto (monoclonal gammopathy of undetermined significance, MGUS), leucemia delle cellule plasmatiche or macroglobulinemia di Waldenström.
2. Anamnesi di ripetute infezioni, amiloidosi primaria, iperviscosità o sindrome POEMS (discrasia delle cellule plasmatiche con polineuropatia, organomegalia, endocrinopatia, proteina monoclonale e alterazioni cutanee).
3. Ha già assunto un anticorpo monoclonale nelle 4 settimane precedenti il Giorno 1 dello studio o non si è ripreso (ossia ≤ Grado 1 o al basale) da eventi avversi dovuti agli agenti somministrati più di 4 settimane prima
4. Si è già sottoposto a terapia anti-mieloma compresi, ma non limitati a, desametasone, IMiD, inibitori del proteasoma, chemioterapia o radioterapia nelle 2 settimane precedenti il Giorno 1 dello studio o non ha avuto una ripresa (ossia ≤ Grado 1 o al basale) da eventi avversi dovuti ad un trattamento somministrato in precedenza.
5. È stato sottoposto a un trapianto precedente allogenico di cellule staminali ematopoietiche negli ultimi 5 anni. (I soggetti che hanno subito un trapianto da oltre i 5 anni sono idonei a condizione che non presentino sintomi di malattia del trapianto contro l’ospite (Graft versus Host Disease, GVHD).
6. Ha ricevuto un trapianto autologo di cellule staminali (auto-SCT) entro le 12 settimane precedenti la prima infusione oppure pianifica o è idoneo all’auto-SCT.
7. Presenta ipersensibilità nota al talidomide, al lenalidomide o al desametasone.
8. Ha ricevuto un trattamento precedente con pomalidomide.
9. Soggetti non in grado o non disposti a sottoporsi a profilassi tromboembolitica.
10. Soggetti con neuropatia periferica ≥ Grado 2.
11. Presenta evidenza di polmonite non infettiva attiva.
12.Ha ricevuto precedentemente una terapia con un farmaco anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 o un anticorpo anti-antigene 4 dei linfociti T citotossici (Cytotoxic T-lymphocyte-associated antigen-4, CTLA4). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary end point of the study is Progression-free survival (PFS) – the International Myeloma Working Group response criteria (IMWG 2006) by blinded central review. PFS is defined as the time from randomization to the first documented
disease progression per IMWG 2006 based on blinded central review or death due to any cause, whichever occurs first. |
L’obiettivo primario di questo studio è confrontare la sopravvivenza libera da progressione (PFS) valutata dall’analisi centrale in cieco del CAC, secondo i criteri dell’IMWG fra i due bracci di trattamento.
IL PSF è definito come il tempo che intercorre tra la randomizzazione e la prima progressione di malattia documentata secondo i criteri IMWG 2006 (valutata centralmente in cieco) o la morte per qualsiasi causa, in base all’evento che di verifica per primo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS Analysis/First OS Analysis: ~ 20 months after trial starts (when all subjects are enrolled, 230 PFS events and ~123 OS events are observed). |
| Analisi PSF/analisi sopravvivenza globale: circa 20 mesi dopo l’inizio dello studio (quando tutti i soggetti sono stati arruolati, e sono stati osservati 230 eventi PFS e circa 123 OS). |
|
| E.5.2 | Secondary end point(s) |
1. Compare the Overall Survival (OS).
2. Evaluate Overall Response Rate (ORR) and Disease Control Rate (DCR) as assessed by CAC blinded central review and as per investigator
assessment using IMWG criteria or EBMT criteria for minor response only and Duration of Response (DOR) as assessed by CAC blinded central review and as per investigator assessment using IMWG criteria
3. Compare the Progression Free Survival (PFS) as assessed by the investigator using IMWG criteria between treatment arms.
4. To evaluate the safety and tolerability in both treatment arms. |
1. Confrontare la sopravvivenza globale (OS).
2. Valutare il tasso di risposta complessiva (ORR), il tasso di controllo della malattia (DCR) valutata dall’analisi centrale in cieco del CAC e dello sperimentatore mediante i criteri IMWG o EBMT solo per risposte minori e la durata della risposta (DOR) valutata dall’analisi centrale in cieco del CAC e dello sperimentatore mediante i criteri IMWG.
3. Confrontare la sopravvivenza libera da progressione tra i bracci di trattamento valutata dallo sperimentatore mediante i criteri IMWG.
4. Valutare la sicurezza e la tollerabilità in entrambi i bracci di trattamento. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. An interim safety analysis will take place after 15 subjects in each treatment arm have completed 1 cycle of therapy.
2. Final OS Analysis: ~ 10 mos after main PFS analysis or ~ 185 OS events, whichever comes first. |
1. Verrà eseguita un’analisi ad interim di sicurezza quando 15 pazienti in ciascun braccio avranno completato il primo ciclo di terapia.
2. Analisi OS finale: circa 10 mesi l’analisi PSF o quando si verificano circa 185 eventi OS in base all’evento che di verifica per primo. |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Spain |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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