E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Multiple myeloma (current protocol) |
Mieloma multiplo (attuale protocollo) |
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E.1.1.1 | Medical condition in easily understood language |
Multiple myeloma |
Multiple myeloma |
|
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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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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 establish the tolerability of the combination of nivolumab and daratumumab in subjects with relapsed/refractory MM. |
Stabilire la tollerabilità della combinazione di nivolumab e daraturumab in soggetti con MM recidivo/refrattario |
|
E.2.2 | Secondary objectives of the trial |
-To assess the minimal residual disease (MRD) status for MM subjects in each treatment regimen group
-To assess overall response rates (ORR) and duration of response (DOR) for MM subjects in each treatment
regimen group
-To assess progression free survival (PFS) for MM subjects in each treatment regimen group
-To characterize the immunogenicity of nivolumab when administered in combination with daratumumab
-To characterize the pharmacokinetics of nivolumab when administered in combination with daratumumab |
Per i soggetti con MM in ciascun gruppo di trattamento: - Determinare lo stato di malattia minima residua (MRD) - determinare il tasso di risposta globale (ORR) e la durata della risposta (DOR) - determinare la sopravvivenza libera da malattia (PFS) - Caratterizzare l’immunogenicità di nivolumab quando somministrato in combinazione con daraturumab - Caratterizzare la farmacocinetica di nivolumab quando somministrato in combinazione con daraturumab |
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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 |
Pharmacogenetics Version: 14 Date: 15/02/2018 Title: Multiple Phase 1/2 Cohorts of Nivolumab Monotherapy or Nivolumab Combination Regimens Across Relapsed/Refractory Hematologic Malignancies-Refer to section 5.8 of the protocol. Objectives: To establish the tolerability of the combination of nivolumab and daratumumab in subjects with relapsed/refractory MM.
Pharmacogenomics Version: 14 Date: 15/02/2018 Title: Multiple Phase 1/2 Cohorts of Nivolumab Monotherapy or Nivolumab Combination Regimens Across Relapsed/Refractory Hematologic Malignancies-Refer to section 5.8 of the protocol. Objectives: To establish the tolerability of the combination of nivolumab and daratumumab in subjects with relapsed/refractory MM.
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Farmacogenetica Versione: 14 Data: 15/02/2018 Titolo: Studio di Fase 1/2 a Coorti multiple dei regimi di nivolumab in monoterapia o nivolumab in associazione nelle neoplasie ematologiche maligne recidivate/refrattarie -Sez. 5.8 del presente protocollo Obiettivi: Espandere la ricerca e sviluppo traslazionale, aiutare la comprensione delle malattie e delle opzioni di trattamento.
Farmacogenomica Versione: 14 Data: 15/02/2018 Titolo: Studio di Fase 1/2 a Coorti multiple dei regimi di nivolumab in monoterapia o nivolumab in associazione nelle neoplasie ematologiche maligne recidivate/refrattarie -Sez. 5.8 del presente protocollo Obiettivi: Espandere la ricerca e sviluppo traslazionale, aiutare la comprensione delle malattie e delle opzioni di trattamento.
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E.3 | Principal inclusion criteria |
-Have received at least 3 prior lines of therapy, including a proteasome
inhibitor [PI] and an immunomodulatory agent [IMiD] OR have disease
that is double refractory to a PI and IMiD
- More than 12 weeks post-transplant of your own blood forming stem
cells (autologous transplant)
- Have detectable disease measured by a specific protein in your blood
and/or urine
- Must consent to bone marrow aspirate or biopsy. |
• Aver ricevuto almeno 3 linee di trattamento precedenti di terapia, incluse un inibitore di proteasi (PI) e un agente immunomodulatorio (ImiD) OPPURE avere malattia che è doppio refrattaria sia a PI che a ImiD • Siano trascorse almeno 12 settimane da trapianto autologo • Avere malattia determinabile misurata da specifiche proteine di sangue e/o urina • Esprimere consenso al prelievo di aspirato midollare o biopsia |
|
E.4 | Principal exclusion criteria |
- Solitary bone or extramedullary plasmacytoma as the only evidence of
plasma cell dyscrasia, or monoclonal gammopathy of undetermined
significance (MGUS), smoldering multiple myeloma (SMM), primary
amyloidosis, Waldenstrom’s macroglobulinemia, POEMS syndrome or
active plasma cell leukemia
- Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti
CTLA 4, or anti-CD38 antibody, or allogeneic stem cell transplantation
- Seropositive for human immunodeficiency virus (HIV), Hepatitis B
surface antigen or Hepatitis C antibody positive (except if HCV-RNA
negative), or history of active chronic hepatitis B or C
- History of central nervous system involvement or symptoms
suggestive of central nervous system involvement by multiple myeloma |
• Plasmacitoma extramidollare o solo osseo come unica evidenza di discrasia del plasma cellulare, o gammopatia monoclonale di significato indeterminato (MGUS), mieloma smoldering multiplo (SMM), amiloidosi primaria, macroglobulinemia di Waldenstrom, sindrome di POEMS o leucemia plasma cellulare attiva • Precedenti terapie con anticorpi anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA4, anti-CD38 , • Trapianto allogenico • Sieropositività per l’HIV, epatite B con antigene di superficie o epatite C positiva all’anticorpo (ad eccezione se HCV-RNA negativi), o storia di epatite B o C attiva cronica • Storia di coinvolgimento del sistema nervoso centrale o sintomi suggestivi di coinvolgimento di mieloma multiplo al sistema nervoso centrale |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability of Nivolumab alone and in combination as measured
by incidence of drug related adverse events (AEs), serious drug related AEs,
dose-limiting toxicities, and laboratory test abnormalities |
Sicurezza e tollerabilità di nivolumab da solo e in combinazione come misurato dall'incidenza di eventi avversi farmaco relati (AEs), eventi avversi seri farmaco relati, tossicitià limitanti la dose, anormalità da test di laboratorio |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to 100 days after the last dose of study (expected to be no more than
225 weeks) |
Fino a 100 giorni dall'ultima dose durante lo Studio (atteso che non sia oltre le 225 settimane) |
|
E.5.2 | Secondary end point(s) |
a)Maximum observed serum concentration (Cmax)
b)Serum concentration achieved at the end of dosing interval (trough concentration, all participants) [Cmin]
c)Time of maximum observed serum concentration (Tmax)
d)Area under the plasma concentration time curve from time zero to the last
time of the last quantifiable concentration [AUC(0-T)]
e)Area under the concentration-time curve in one dosing interval [AUC(TAU)]
f)Serum concentration achieved at the end of study drug infusion (Ceoinf)
g)Best Overall Response (BOR)
h)ORR
I)Duration of Objective Response
j)Progression Free Survival Rate (PFSR)
k)Modified Severity Weighted Assessment Tool (mSWAT) for patients with cutaneous T cell lymphoma
l)Immunogenicity as measured by the anti-drug antibody (ADA) status both at sample level and at patient level
m)Minimal Residual Disease (MRD) in patients with multiple myeloma
receiving nivolumab in combination with daratumumab
n)PD-L1 expression |
a) Concentrazione massima di siero osservata (Cmax) b) Concentrazione serica osservata alla fine dell’intervallo di dose (mediante concentrazione, tutti i soggetti partecipanti) (Cmin) c) Tempo massimo osservato di concentrazione serica (Tmax) d) Area sotto la curva di concentrazione-tempo dal tempo zero all’ultimo momento dell’ultima concentrazione quantificabile (AUC(0-T)) e) Area sotto la curva di concentrazione-tempo in un intervallo di dose (AUC(TAU)) f) Concentrazione serica raggiunta alla fine dell’infusione del farmaco in studio (Ceoinf) g) Miglior risposta (BOR) h) ORR i) Durata della risposta obiettiva j) Tasso di sopravvivenza libera da malattia (PFSR) k) mSWAT per pazienti con CTCL l) immunogenicità misurata dall’anticorpo anti-farmaco (ADA) sia a livello di campione che di paziente m) malattia minima residua (MRD) in pazienti con mieloma multiplo che ricevono nivolumab in combinazione con daraturumab n) espressione del PD-L1 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
a)b)c)d)e)f) 7 time points up to 20 weeks
g)Baseline (within 28 days of treatment), until disease progression in patients, up to week 156
h)Baseline up to week 156
I)Baseline until disease progression in patients with multiple myeloma
receiving nivolumab in combination with daratumumab, up to week 156
j)k) Baseline up to week 156
l)Baseline, 6 timepoints up to 120 days after the last dose of study drug
m)Up to 41 months
n)up to 20 weeks |
- a)b)c)d)e)f): 7 time points fino a 20 settimane • g: baseline (entro 28 giorni prima del trattamento) fino a progressione, fino a 156 settimane • h: baseline fino a 156 settimane • l: baseline fion a progressione di malattia in pazienti con mieloma multiplo che ricevono nivo in combo con dara, fino a 156 settimane • j) k)): baseline fino a 156 settimane • l): baseline, 6 timepoints fino a 120 giorni dall’ultima dose del farmaco in studio • m): fino a 41 mesi • n): fino a 20 settimane |
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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 | 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 | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
This is a Phase 1/2, open-label, multicenter, dose-escalation, and multidose study of nivolumab |
questo è uno Studio di fase 1/2, in aperto, multicentrico, con dose-escalation e molteplici dosei di |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
Randomizzato , In aperto |
Randomised, open |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 |
Canada |
United States |
Belgium |
France |
Greece |
Italy |
Poland |
|
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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |