| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed, treatment-naïve multiple myeloma (MM) who are ineligible for autologous stem cell transplant (auto-SCT). |
| Trattamento di soggetti con mieloma multiplo di nuova diagnosi e naive al trattamento, non idonei al trapianto autologo di cellule staminali (auto-SCT) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly diagnosed, never treated multiple myeloma (MM) who are not eligible for his/her own stem cell transplant (auto-SCT). |
| Trattamento di soggetti con mieloma multiplo di nuova diagnosin mai trattati e che non sono idonei al trapianto delle proprie cellule staminali (auto-SCT) |
|
| 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 independent central review according to the International Myeloma Working Group response criteria, (IMWG criteria) between treatment arms. |
| Confrontare la sopravvivenza senza progressione (PFS) valutata con revisione centrale in cieco del CAC, secondo i criteri IMWG tra i 2 bracci di trattamento. |
|
| E.2.2 | Secondary objectives of the trial |
1. Compare the Overall Survival (OS) between treatment arms.
2. Evaluate Overall Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR) and second Progression Free Survival (PFS2) as assessed by CAC blinded central review using IMWG criteria between treatment arms.
3. To evaluate the safety and tolerability in both treatment arms. |
1. Confrontare la sopravvivenza complessiva (OS) tra i bracci di trattamento.
2. Confrontare il tasso di risposta complessivo (ORR), la durata della risposta (DOR), il tasso di controllo della malattia (DCR) e la seconda sopravvivenza senza progressione (PFS2) valutati dal CAC mediante revisione centrale utilizzando i criteri IMWG tra i bracci di trattamento.
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. Newly diagnosed, treatment-naïve, ASCT ineligible, symptomatic MM (CRAB features).
2. Confirmed diagnosis of active MM and measurable disease defined as:
a. Serum monoclonal protein (M-protein) levels ≥ 0.5 g/dL or
b. Urine monoclonal protein (M-protein) levels ≥200 mg/24-hours or
c. 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)
d. Presence of CRAB features
3. Must be ineligible to receive treatment with ASCT due to age (≥65 years old) or coexisting medical condition. Subjects < 65 years old who refuse ASCT are not eligible for this study.
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. Mieloma multiplo (MM) di nuova diagnosi, naive al trattamento, non idonei all’auto-SCT
2. Presentare una diagnosi confermata di mieloma multiplo attivo e malattia misurabile, definito come:
a. Livelli sierici di proteina monoclonale (M proteina) ≥ 0,5 g/dl; oppure
b. Livelli urinari di proteina monoclonale (M proteina) ≥ 200 mg/24 ore; oppure
c. Per i soggetti senza livelli sierici e urinari misurabili di M proteina, un rapporto anomalo di catene leggere libere nel siero (FLC κ/λ) con livello di FLC coinvolte ≥ 100 mg/l. (Valore sierico normale di FLC κ/λ: 0,26 - 1,65).
d. Presenza di caratteristiche CRAB.
3. Non deve essere idoneo a ricevere un trattamento con auto-SCT a causa dell’età (≥ 65 anni) o della condizione medica coesistente. I soggetti di età < 65 anni che rifiutano di sottoporsi a un auto-SCT non sono idonei per questo studio.
4. Essere in grado di fornire materiale bioptico o aspirato di midollo osseo d’archivio (≤ 60 giorni) o fresco per la valutazione della malattia e l’analisi dei biomarker.
5. Avere un performance status di 0 o 1 sulla scala del Performance status dell’Eastern Cooperative Oncology Group (ECOG). |
|
| 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 prior anti-myeloma therapy including but not limited to dexamethasone, IMiDs, proteasome inhibitors, chemotherapy, monoclonal antibody, ASCT or radiation therapy.
4. Has undergone prior allogeneic hematopoetic stem cell transplantation (HSCT) within the last 5 years.
5. Has known hypersensitivity to dexamethasone.
6. Subjects with peripheral neuropathy ≥ Grade 2.
7. Has evidence of active, non-infectious pneumonitis.
8. 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. Presenta mieloma non secernente od oligosecretorio, mieloma multiplo asintomatico (SMM), gammopatia monoclonale di significato indeterminato (MGUS), leucemia plasmocellulare o macroglobulinemia di WaldenstrÖm.
2. Presenta un’anamnesi di infezioni ripetute, amiloidosi primaria, iperviscosità o sindrome di POEMS.
3. Ha ricevuto una precedente terapia antimieloma incluso (ma non limitato a) il desametasone a basso dosaggio, IMiD, inibitori del proteasoma, chemioterapia, anticorpi monoclonali, auto-SCT o radioterapia prima di entrare nello studio.
4. È stato sottoposto a un precedente trapianto allogenico di cellule staminali ematopoietiche negli ultimi 5 anni.
5. Presenti un’ipersensibilità nota a desametasone
6. Presenti una neuropatia periferica di Grado ≥ 2.
7. Presenti un'evidenza di polmonite non infettiva attiva.
8. 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 (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 consiste nel confrontare la sopravvivenza senza progressione (Progression Free Survival, PFS) valutata centralmente in cieco da un Clinical Adjudication Committee (CAC) secondo i criteri del International Myeloma Working Group (IMWG) tra i 2 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 |
1. Interim PFS Analysis: ~ 20 months after trial starts (when all subjects enrolled and ~ 115 PFS events are observed).
2. Final PFS Analysis: ~ 20 months after interim PFS analysis and ~227 PFS events are observed. |
1. Analisi ad interim di PSF: circa 20 mesi dopo l’inizio dello studio (quando tutti i soggetti sono stati arruolati e circa 115 eventi PSF sono stati osservati)
2. Analisi finale di PSF: circa 20 mesi dopo l’analisi ad interim di PSF e circa 227 eventi PSF sono stati osservati). |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival (OS): OS is defined as the time from randomization to death due to any cause.
2. Overall Response Rate (ORR): ORR is defined as the proportion of the subjects in the analysis population who have a complete response (CR)
or partial response (PR).
3. Duration of Response (DOR): For subjects who demonstrated CR or PR, response duration is defined as the time from first documented evidence
of CR or PR until disease progression or death.
4. Second Progression Free Survival (PFS2): PFS2 is the time from randomization to subsequent disease progression after initiation of new anti-cancer therapy, or death from any cause, whichever comes first. |
1. OS (Overall Survival) definita come tempo tra la randomizzazione e la morte per qualsiasi causa
2. ORR (Overall Response Rate) definita come percentuale di soggetti che ha una risposta completa (CR) o parziale (PR)
3. DOR (Duration of Response) per i soggetti con CR o PR è definita come il tempo tra la prima evidenza documentata di CR o PR fino alla progressione di malattia o morte
4. PFS2 (Second Progression Free Survival) defintia come il tempo tra la randomizzazione e successive progressione di malattia dopo l’inizio di una nuova terapia anti-tumorale, o morte per qualsiasi causa, in base all’evento che di verifica per primo. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| ~ 41 months after trial starts (when last subject completes its last phone call follow-up). |
| Circa 41 mesi dopo l’inizio dello studio (quando l'ultimo paziente ha ricevuto l'ultima telefonata di follow-up) |
|
| 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 | 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) | 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 | 42 |
| 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 |
| Brazil |
| Canada |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Norway |
| Russian Federation |
| South Africa |
| Spain |
| United Kingdom |
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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