| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Multiple Myeloma |
| Relapsed/Refractory Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed / Refectory Multiple Myeloma |
| Relapsed / Refectory Multiple Myeloma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy of belantamab mafodotin in combination with pomalidomide and dexamethasone (BPd) with that of pomalidomide, bortezomib and dexamethasone (PVd) in participants with relapsed/refractory multiple myeloma (RRMM) |
| Confrontare l’efficacia di belantamab mafodotin in combinazione con pomalidomide e desametasone (B-Pd) e quella di pomalidomide, bortezomib e desametasone (PVd) nei partecipanti affetti da MMRR |
|
| E.2.2 | Secondary objectives of the trial |
To further compare the efficacy of belantamab mafodotin in combination with pomalidomide and dexamethasone (B-Pd) with that of pomalidomide, bortezomib and dexamethasone (PVd) in participants with RRMM
To further assess the efficacy of B-Pd in terms of other efficacy outcomes in participants with RRMM
To evaluate the safety and tolerability of belantamab mafodotin when administered in combination with pomalidomide and dexamethasone
To document exposure of belantamab mafodotin when administered in combination with pomalidomide and dexamethasone
To evaluate the PK of pomalidomide in combination with belantamab mafodotin and dexamethasone, in a subset of participants
To assess anti-drug antibodies against belantamab mafodotin
To evaluate the safety and tolerability of belantamab mafodotin based on selfreported symptomatic AEs when administered in combination with pomalidomide and dexamethasone
To evaluate and compare changes in symptoms and health-related quality of life |
Confrontare ulteriormente l’efficacia di belantamab mafodotin in combinazione con pomalidomide e desametasone (B-Pd) e quella di pomalidomide, bortezomib e desametasone (PVd) nei partecipanti affetti da MMRR
Valutare ulteriormente l’efficacia di belantamab mafodotin in combinazione con pomalidomide e desametasone in termini di altri esiti di efficacia nei partecipanti affetti da MMRR
Valutare la sicurezza e la tollerabilità di belantamab mafodotin somministrato in combinazione con pomalidomide e desametasone
Valutare la farmacocinetica di pomalidomide in combinazione con belantamab mafodotin e desametasone in un sottogruppo di partecipanti
Valutare gli anticorpi anti-farmaco (ADA) contro belantamab mafodotin
Valutare la sicurezza e la tollerabilità di belantamab mafodotin, sulla base degli effetti avversi sintomatici autosegnalati, somministrato in combinazione con pomalidomide e desametasone
Valutare e confrontare i cambiamenti nei sintomi e la qualità della vita correlata alla salute |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria are met:
1. Capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Male or female, 18 years or older (at the time consent is obtained).
3. Have a confirmed diagnosis of multiple myeloma as defined by the IMWG criteria [Rajkumar, 2016].
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Section 10.6).
5. Have been previously treated with at least 1 prior line of MM therapy including a lenalidomide-containing regimen (lenalidomide must have been administered for at least 2 consecutive cycles) and must have documented disease progression during or after their most recent therapy.
Note: Participants intolerant or refractory to bortezomib at 1.3 mg/m2 dose twice weekly dosing schedule are not eligible.
6. Must have at least ONE aspect of measurable disease, defined as one the following:
a. Urine M-protein excretion =200 mg/24 h, or
b. Serum M-protein concentration =0.5 g/dL (=5.0 g/L), or
c. Serum free light chain (FLC) assay: involved FLC level =10 mg/dL (=100 mg/L) and an abnormal serum free light chain ratio (<0.26 or >1.65) only if patient has no measurable urine or serum M spike.
7. Have undergone autologous stem cell transplant (SCT) or are considered transplant ineligible. Participants with a history of autologous SCT are eligible for study participation provided the following eligibility criteria are met:
a. Autologous SCT was >100 days prior to the first dose of study medication
b. No active bacterial, viral, or fungal infection(s) present
8. All prior treatment-related toxicities (defined by National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI-CTCAE] v5.0) must be =Grade 1 at the time of enrolment, except for alopecia.
9. Adequate organ system functions as defined by the laboratory assessments listed in the protocol |
Il soggetto è in grado di fornire un consenso informato firmato, come descritto alla Sezione 10.1.3, che includa la conformità ai requisiti e alle restrizioni elencati nel modulo di consenso informato (ICF) e nel presente protocollo.
2. Sesso maschile o femminile e almeno 18 anni di età (nel momento in cui viene ottenuto il consenso).
3. Avere una diagnosi confermata di mieloma multiplo, come definito dai criteri dell’IMWG [Rajkumar, 2016].
4.Stato prestazionale secondo il Gruppo cooperativo orientale di oncologia (ECOG) di 0-2
5. Essere stati precedentemente trattati con almeno 1 precedente linea di terapia per il MM, tra cui un regime terapeutico contenente lenalidomide (lenalidomide deve essere stato somministrato per almeno 2 cicli consecutivi) e devono presentare progressione della malattia documentata durante o dopo la terapia più recente.
7. Nota: non sono idonei i partecipanti intolleranti o refrattari allo schema di somministrazione che include bortezomib alla dose di 1,3 mg/m2 due volte a settimana.
8. Devono presentare almeno UN aspetto di malattia misurabile definita come segue:
a. Escrezione di proteina M nelle urine =200 mg/24 h, oppure
b. Concentrazione di proteina M nel siero =0,5 g/dl (=5,0 g/l) oppure
c. Esame per le FLC: livello di FLC coinvolte =10 mg/dl (=100 mg/l) e rapporto anomalo della catena leggera libera nel siero (<0,26 o >1,65) solo se il paziente non ha un picco di M urinario o sierico misurabile.
Sono stati sopposti a trapianto autologo di cellule staminali (SCT) o sono considerati non idonei al trapianto. I partecipanti con un’anamnesi di SCT autologo sono idonei per la partecipazione allo studio a condizione che i seguenti criteri di idoneità siano soddisfatti:
a. Il trapianto autologo di cellule staminali è stato eseguito >100 giorni prima della prima dose del farmaco dello studio
b. Nessuna infezione batterica, virale o micotica attiva presente
10. Tutte le precedenti tossicità correlate al trattamento (definite in base ai Criteri comuni di tossicità per gli eventi avversi [NCI-CTCAE] v.5.0) devono essere di Grado =1 al momento dell’arruolamento, ad eccezione dell’alopecia.
11.Funzioni del sistema d’organo adeguate, come definito dalle valutazioni di laboratorio |
|
| E.4 | Principal exclusion criteria |
A participant will not be eligible for inclusion in this study if any of the following criteria are met:
1. Active plasma cell leukemia at the time of screening. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, and skin changes).
2. Participants after prior allogeneic SCT.
3. Systemic anti-myeloma therapy (including chemotherapy and systemic steroids) or use of an investigational drug within 14 days or five half-lives (whichever is shorter) preceding the first dose of study drug; Prior treatment with a monoclonal antibody drug within 30 days of receiving the first dose of study drugs.
4. Plasmapheresis within 7 days prior to the first dose of study drug.
5. Received prior treatment with or intolerant to pomalidomide.
6. Received prior BCMA targeted therapy.
7. Intolerant to bortezomib or refractory to bortezomib (i.e., participant experienced progressive disease during treatment, or within 60 days of completing treatment, with a bortezomib-containing regimen of 1.3 mg/m2 twice weekly).
8. Evidence of cardiovascular risk including any of the following:
a. Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities including 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block.
b. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of Screening.
c. Class III or IV heart failure as defined by the New York Heart Association functional classification system (Section 10.8)
d. Uncontrolled hypertension.
9. Any major surgery within the last 4 weeks.
10. Previous or concurrent invasive malignancy other than multiple myeloma, except:
• The disease must be considered medically stable for at least 2 years; or
• The participant must not be receiving active therapy, other than hormonal therapy for this disease.
11. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to belantamab mafodotin or drugs chemically related to belantamab mafodotin, or any of the components of the study treatment.
12. Evidence of active mucosal or internal bleeding.
13. Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice.
14. Active infection requiring treatment.
15. Known human immunodeficiency virus (HIV) infection.
16. Presence of hepatitis B surface antigen (HbsAg), or hepatitis B core antibody (HbcAb) at Screening or within 3 months prior to first dose of study treatment).
17. Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment.
18. Intolerance or contraindications to anti-viral prophylaxis.
19. Presence of active renal conditions (e.g. infection, severe renal impairment requiring dialysis or any other condition that could affect participant’s safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil criteria given in Table 4.
20. Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain.
21. Active or history of venous thromboembolism within the past 3 months.
22. Contraindications to or unwilling to undergo protocol-required anti-thrombotic prophylaxis
23. Current corneal disease except for mild punctuate keratopathy (Section 10.9).
24. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures.
26. Pregnant or lactating female. |
1. Leucemia plasmacellulare attiva al momento dello screening. Amiloidosi sintomatica, sindrome di POEMS (polineuropatia, organomegalia, endocrinopatia, disturbo proliferativo delle plasmacellule monoclonali e alterazioni cutanee).
2. Partecipanti dopo pregresso SCT allogenico.
3. Terapia sistemica antimieloma (incluse chemioterapia e steroidi sistemici) o uso di un farmaco sperimentale entro 14 giorni o cinque emivite (a seconda di quale sia più breve) precedenti la prima dose del farmaco dello studio; precedente trattamento con un farmaco basato su anticorpo monoclonale entro 30 giorni dalla somministrazione della prima dose dei farmaci dello studio.
4. Plasmaferesi entro 7 giorni prima della prima dose del farmaco dello studio.
5. Previo/a trattamento o intolleranza a pomalidomide.
6. Previa terapia mirata contro BCMA.
7. Intollerante a bortezomib o refrattario a bortezomib (ovvero, il partecipante ha manifestato una progressione della malattia durante il trattamento, oppure entro 60 giorni dal completamento del trattamento, con un regime terapeutico contenente bortezomib da 1,3 mg/m2 due volte a settimana).
8. Evidenza di rischio cardiovascolare incluso uno qualsiasi dei seguenti:
a. Evidenza di attuali aritmie clinicamente significative non trattate tra cui anomalie all’ECG clinicamente significative tra cui blocco atrioventricolare (AV) di 2º grado (tipo Mobitz II) o di 3º grado.
b. Anamnesi di infarto miocardico acuto, sindromi coronariche acute (compresa angina instabile), angioplastica coronarica o stent o bypass coronarico entro 3 mesi dallo screening.
c. Insufficienza cardiaca di classe III o IV, come definita dal sistema di classificazione funzionale della New York Heart Association (Sezione 10.8).
d. Ipertensione non controllata.
9. Qualsiasi intervento chirurgico maggiore entro le ultime 4 settimane.
10. Neoplasia maligna invasiva pregressa o concomitante diversa dal mieloma multiplo, fatta eccezione per quanto segue:
• la malattia deve essere considerata clinicamente stabile per almeno 2 anni; o
• il partecipante non deve essere trattato con terapia attiva, a parte la terapia ormonale, per questa malattia.
12. Evidenza di sanguinamento mucosale o interno attivo.
13. Cirrosi o attuale malattia epatica o biliare instabile secondo la valutazione dello sperimentatore, definita dalla presenza di ascite, encefalopatia, coagulopatia, ipoalbuminemia, varici esofagee o gastriche, itterizia persistente.
14. Infezione attiva che richiede trattamento.
15. Nota infezione da virus dell’immunodeficienza umana (HIV).
16. Presenza di antigene di superficie dell’epatite B (HbsAg) o anticorpo del anti-core dell’epatite B (HbcAb) allo screening o nei 3 mesi precedenti la prima dose del trattamento dello studio.
17. Esito positivo del test per gli anticorpi dell’C o esito positivo al test dell’RNA dell’epatite C allo screening o nei 3 mesi precedenti la prima dose del trattamento dello studio.
18. Intolleranza o controindicazioni alla profilassi antivirale.
19. Presenza di condizioni renali attive (ad esempio infezione, grave disfunzione renale che richiede la dialisi o qualsiasi altra condizione che potrebbe influire sulla sicurezza del partecipante). I partecipanti con proteinuria isolata derivante da MM sono idonei, a condizione che soddisfino i criteri forniti nella Tabella 4.
20. Neuropatia periferica o dolore neuropatico in corso di grado 2 o superiore
21. Tromboembolia venosa attiva o pregressa negli ultimi 3 mesi.
22. Controindicazioni a mancata disponibilità a sottoporsi alla profilassi antitrombotica richiesta dal protocollo
23. Attuale malattia della cornea, fatta eccezione per una lieve cheratopatia puntata (Sezione 10.9). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free Survival (PFS), defined as the time from the date of randomization until the earliest date of documented disease progression or death due to any cause |
| Sopravvivenza libera da progressione (PFS), definita come tempo dalla data di randomizzazione fino alla prima data della progressione o morte |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•Minimal Residual Disease (MRD) negativity rate, defined as the percentage of participants who are MRD negative by next-generation sequencing (NGS)
•Overall Response Rate (ORR), defined as the percentage of participants with a confirmed partial response (PR) or better (i.e., PR, VGPR, CR, and sCR)
•Complete Response Rate (CRR), defined as the percentage of participants with a confirmed CR or better (i.e., CR, and sCR)
•VGPR or better rate, defined as the percentage of participants with a confirmed Very Good Partial Response (VGPR) or better (i.e., VGPR, CR, and
sCR)
•Duration of Response (DoR), defined as the time from first documented evidence of PR or better until progressive disease (PD) or death due to PD among participants who achieve confirmed PR or better
•Time to Best Response (TTBR), defined as the interval of time between the date of randomization and the earliest date of achieving best response
among participants with a confirmed PR or better
•Time to Response (TTR), defined as the time between the date of randomization and the first documented evidence of response (PR or better)
among participants who achieve confirmed PR or better
•Time to Progression (TTP), defined as the time from the date of randomization until the earliest date of documented PD or death due to PD
•Overall Survival (OS), defined as the time from the date of randomization until the date of death due to any cause
•PFS2, defined as time from randomization to disease progression after initiation of new anti-cancer therapy or death from any cause, whichever is earlier. If disease progression after new anti-cancer therapy cannot be measured, a PFS event is defined as the date of discontinuation of new anti-cancer therapy, or death from any cause, whichever is earlier
•Incidence of adverse events (AEs) and changes in laboratory parameters
•Ocular findings on ophthalmic exam
•Plasma concentrations of belantamab mafodotin, total mAb and cys-mcMMAF
•Derived pomalidomide pharmacokinetic parameter values, as data permit
•Incidence and titers of ADAs against belantamab mafodotin
•Changes from baseline in symptoms and related impacts as measured by PRO-CTCAE
•Change from baseline in HRQOL as measured by EORTC QLQ-C30, EORTC IL52 (the disease symptoms domain of the EORTC QLQ-MY20) |
Tasso di negatività per la malattia minima residua (MRD), definito come la percentuale di partecipanti risultati negativi alla MRD mediante il sequenziamento di nuova generazione (NGS)
Tasso di risposta complessiva (ORR), definito come la percentuale di partecipanti con una risposta parziale (PR) confermata o esito migliore (ovvero PR, VGPR, CR e sCR)
• Tasso di risposta completa (CRR), definito come la percentuale di partecipanti con CR o esito migliore (ovvero CR e sCR)
• Tasso VGPR o esito migliore, definito come la percentuale di partecipanti con una risposta parziale molto buona (VGPR) o esito migliore (ovvero VGPR, CR e sCR)
• Durata della risposta (DoR)
• Tempo alla migliore risposta (TTBR)
• Tempo alla risposta (TTR)
• Tempo alla progressione (TTP)
• Sopravvivenza globale (OS)
• Sopravvivenza libera da progressione 2 (PFS2)
Incidenza di eventi avversi (EA) e variazioni nei parametri di laboratorio
• Riscontri oculari all’esame oftalmologico
Concentrazioni plasmatiche di belantamab mafodotin, anticorpi monoclonali (mAb) totali e cys-mcMMAF
Valori dei parametri di farmacocinetica derivati, come consentito dai dati
Incidenza e titoli di ADA contro belantamab mafodotin
Variazioni dal basale nei sintomi e relativo impatto misurato mediante PRO-CTCAE
Variazione dal basale nella HRQOL misurata tramite EORTC QLQ-C30 e EORTC IL52 (il dominio dei sintomi della malattia di EORTC QLQ-MY20) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | Yes |
| 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) | 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 | 6 |
| 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 |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Spain |
| Turkey |
| 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
|
| End of study is defined as 5 years from Last Subject First Visit (LSFV), or when all participants have died, withdrawn consent or have been lost to follow-up, whichever occurs first. |
| la fine dello studio è definita da 5 anni dalla LSLF, o quando tutti i artecipanti saranno deceduti, usciti dallo studio o persi al FU a seconda di quello che accadrà prima |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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