| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | PT |
| E.1.2 | Classification code | 10025310 |
| E.1.2 | Term | Lymphoma |
| 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 1
-To characterize the safety and tolerability of isatuximab in combination
with cemiplimab in participants with relapsed and refractory classic
Hodgkin's lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL) or
peripheral T-cell lymphoma (PTCL), and to confirm the recommended
Phase 2 dose (RP2D).
Phase 2
- Cohort A1 (anti-programmed cell death protein 1/ligand 1 [PD-1/PDL1]
naive cHL): To assess the complete remission (CR) rate of
isatuximab in combination with cemiplimab.
- Cohort A2 (cHL progressing from PD-1/PD-L1), B (DLBCL) and C
(PTCL): To assess the objective response rate (ORR) of isatuximab in
combination with cemiplimab. |
Fase 1:
Definire la sicurezza e la tollerabilità di isatuximab in combinazione con cemiplimab in partecipanti affetti da linfoma di Hodgkin classico (classic Hodgkin’s Lymphoma, cHL), linfoma diffuso a grandi cellule B (Diffuse Large B-Cell Lymphoma, DLBCL) e linfoma a cellule T periferiche (Peripheral T-Cell Lymphoma, PTCL) e confermare la dose raccomandata di fase 2 (Recommended Phase 2 Dose, RP2D)
Fase 2:
1 - Coorte A1 (cHL naïve alla terapia anti-PD-1/PD-L1):Valutare il tasso di remissione completa (Complete Remission, CR) di isatuximab in combinazione con cemiplimab.
2 - Coorte A2 (cHL in fase di progressione a seguito di terapia PD-1/PD-L1), B (DLBCL) e C (PTCL): Valutare il tasso di risposta obiettiva (Objective Response Rate, ORR) di isatuximab in combinazione con cemiplimab |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of the RP2D of the combination of isatuximab
with cemiplimab.
- To evaluate the safety of the combination of isatuximab with
cemiplimab and radiotherapy in patients with cHL.
- To evaluate the immunogenicity of isatuximab and cemiplimab when
given in combination.
- To characterize the pharmacokinetic (PK) profile of isatuximab and
cemiplimab when given in combination.
-To assess overall efficacy of isatuximab in combination with cemiplimab
and isatuximab in combination with cemiplimab and radiotherapy. |
- Valutare la sicurezza della RP2D di isatuximab in combinazione con cemiplimab
- Valutare la sicurezza della combinazione di isatuximab con cemiplimab e radioterapia nei partecipanti con cHL.
- Valutare l’immunogenicità di isatuximab e cemiplimab quando utilizzati in combinazione.
- Determinare il profilo farmacocinetico (Pharmacokinetic, PK) di isatuximab e cemiplimab quando utilizzati in combinazione.
- Valutare l’efficacia complessiva di isatuximab in combinazione con cemiplimab e isatuximab in combinazione con cemiplimab e radioterapia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Participants must be >/= 12 years of age inclusive, at the time of signing
the informed consent
- Disease location amenable to tumor biopsy at baseline
- Measurable disease
- For Cohort A1 (classic Hodgkin's lymphoma [cHL] anti-programmed cell
death protein 1/ligand 1 [PD-1/PD-L1] inhibitor naïve): Histologically
confirmed advanced cHL that has relapsed or progressed after at least 3
lines of systemic therapy that may include autologous hematopoietic
stem cell transplant (auto-HSCT) or auto-HSCT and brentuximab
vedontin (BV)
- For Cohort A2 (cHL anti-PD-1/PD-L1inhibitor progressor):
Histologically confirmed advanced cHL which has relapsed or progressed
after one previous anti-PD-1/PD-L1 containing regimen as the most
recent prior therapy but no more than 4 lines of previous chemotherapy
including the anti-PD-1/PD-L1 containing regimen and documentation of
benefit during or after the anti-PD-1/PD-L1 containing regimen within 4
months prior to initiation of investigational medicinal product (IMP)
- For Cohort B (diffuse large B-cell lymphoma [DLBCL]):Histologically
confirmed advanced DLBCL that has relapsed or progressed after 2 lines
of systemic therapy including auto-HSCT or 2 lines of systemic therapy
for participants who are not eligible for auto-HSCT
- For Cohort C (peripheral T-cell lymphoma [PTCL]): Histologically
confirmed advanced PTCL that has relapsed or progressed after either
first-line chemotherapy and auto-HSCT as consolidation of first
remission or first-line chemotherapy if participants are ineligible for
auto-HSCT
- Body weight of > 45 kg |
- Il partecipante deve avere un’età >/= 12 anni compiuti al momento della firma del consenso informato
- Localizzazione della malattia suscettibile alla biopsia tumorale al basale
- Malattia misurabile
- Per Coorte A1 (cHL naïve alla terapia anti-PD-1/PD-L1): cHL in stadio avanzato, istologicamente confermato, che sia recidivato o progredito dopo:
almeno 3 linee di terapia sistemica che possono includere trapianto autologo di cellule staminali ematopoietiche (CSE) oppure Trapianto autologo di CSE e Brentuximab vedotin
- Per la Coorte A2 (cHL con progressione della malattia a seguito di terapia anti-PD-1/PD-L1): cHL in stadio avanzato, istologicamente confermato, che sia recidivato o progredito dopo un precedente regime contenente anti-PD-1/PD-L1, come terapia precedente più recente, ma non più di 4 linee di precedente chemioterapia compreso il regime contenente PD1/PD-L1 e documentazione di beneficio durante o dopo il regime contenente PD1/PD-L1 entro 4 mesi prima dell'inizio del trattamento con il farmaco sperimentale (IMP)
- Per la Coorte B (DLBCL): DLBCL in stadio avanzato, istologicamente confermato, che sia recidivato o progredito dopo:
- 2 linee di terapia sistemica, incluso il trapianto autologo di CSE, OPPURE
- 2 linee di terapia sistemica per i partecipanti che non siano idonei al trapianto autologo di CSE.
- Per la Coorte C (PTCL): PTCL in stadio avanzato, istologicamente confermato, che sia recidivato o progredito dopo:
- Chemioterapia e trapianto autologo di CSE come terapia di consolidamento della prima remissione, OPPURE
- Chemioterapia di prima linea, qualora i partecipanti non siano idonei per il trapianto autologo di CSE.
- Peso corporeo > 45 kg. |
|
| E.4 | Principal exclusion criteria |
-Prior exposure to agent that blocks CD38
- For patients with cHL (PD-1/PD-L1 naïve), DLBCL or PTCL prior
exposure to any agent (approved or investigational) that blocks the PD-
1/PD-L1, PD-L2, CD137, CTLA-4 or LAG-3
- Evidence of other immune related disease /conditions
- Has received a live-virus vaccination within 28 days of planned
treatment start; seasonal flu vaccines that do not contain live virus are
permitted
- Eastern Cooperative Oncology Group (ECOG) performance status (PS)
>/=2
- Poor bone marrow reserve
- Poor organ function |
- Precedente trattamento con un agente preposto al blocco di CD38
- Per i pazienti con cHL (PD-1/PD-L1 naive), DLBCL o PTCL precedente terapia (approvata o sperimentale) con anticorpi anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 o LAG-3
- Evidenza di ulteriori malattie/condizioni immuno correlate
- Ricezione di un vaccino vivo entro i 28 giorni precedenti l’inizio programmato del trattamento. Sono consentiti i vaccini antinfluenzali non contenenti virus vivi.
- Performance Status secondol’Eastern Cooperative Oncology Group (ECOG) >/= 2.
- Scarsa riserva di midollo osseo
- Scarsa funzionalità d'organo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1
1) Dose limiting toxicities (DLTs): DLTs as observed during DLT-observation
period
2) Recommended Phase 2 dose (RP2D): Dose selected for the Phase 2
portion
Phase 2
3) Cohort A1 (anti-PD-1/PD-L1 naive cHL): Complete Remission Rate:
The proportion of participants who have a Complete Remission as a best
overall response during the isatuximab + cemiplimab therapy period
using the 5-point scale per the Lugano classification where 1 is No
uptake, 2 is Uptake </= mediastinum, 3 is Uptake > mediastinum but </=
liver, 4 is Moderately increased uptake compared to the liver and 5 is
Markedly increased uptake compared to the liver and/or new lesions
4) Cohort A2 (cHL progressing from PD-1/PD-L1), B (DLBCL) and C
(PTCL): Response Rate : The proportion of participants who have a
Complete Response or Partial Response as a best overall response
during isatuximab + cemiplimab therapy period using the 5-point scale
per the Lugano classification where 1 is No uptake, 2 is Uptake </=
mediastinum, 3 is Uptake > mediastinum but </= liver, 4 is Moderately
increased uptake compared to the liver and 5 is Markedly increased
uptake compared to the liver and/or new lesions |
Fase 1:
1) Tossicità limitanti la dose (DLTs): DLT osservate durante il periodo di osservazione delle DLT
2) Dose raccomandata di Fase 2 (RP2D): dose selezionata per la Fase 2
Fase 2:
3) Coorte A1 (cHL naive alla terapia anti-PD-1/PD-L1): Tasso di remissione completa: percentuale di pazienti che presentano una remissione completa come migliore risposta complessiva nel corso del periodo di terapia con isatuximab + cemiplimab utilizzando la scala a 5 punti secondo la classificazione di Lugano in cui
1: no uptake
2: Uptake </= mediastinum,
3: Uptake > mediastinum ma </= liver,
4: Moderately increased uptake compared to the liver
5: Markedly increased uptake compared to the liver and/or new lesions
4) Coorte A2 (cHL in progressione della malattia a seguito di terapia anti-PD-1/PD-L1), B (DLBCL) e C (PTCL): tasso di risposta: percentuale di pazienti che presenta una risposta completa o una remissione parziale (Partial Remission, PR) come migliore risposta complessiva nel corso del periodo di terapia con isatuximab + cemiplimab utilizzando la scala a 5 punti secondo la classificazione di Lugano in cui
1: no uptake
2: Uptake </= mediastinum,
3: Uptake > mediastinum ma </= liver,
4: Moderately increased uptake compared to the liver
5: Markedly increased uptake compared to the liver and/or new lesions |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) and 2) 1st Cycle - 28 days
3) and 4) Up to 24 weeks after last patient treated in a given cohort |
1) e 2) Ciclo 1 - 28 giorni
3) e 4) Fino a 24 settimane dopo il trattamento dell'ultimo paziente in una determinata coorte |
|
| E.5.2 | Secondary end point(s) |
1) Adverse Events (AEs)/Serious Adverse Events (SAEs) for isatuximab
+ cemiplimab: Number of patients with AEs/SAEs
2) Adverse Events/Serious Adverse Events for isatuximab + cemiplimab
+ radiotherapy: Number of patients with AEs/SAEs in cohorts A1 and A2
3) Immunogenicity: Anti-drug antibody (ADA) levels against isatuximab
and against cemiplimab
4) Pharmacokinetic evaluation: Pharmacokinetic evaluation using non-compartmental
analysis for both compounds using serum concentrations
for cemiplimab and plasma concentrations for isatuximab
5) Tumor burden change: The best percent-change from baseline
6) Disease control rate: The sum of complete responses (CR) + partial
responses (PR) + stable disease (SD)
7) Duration of response: The time from the date of the first response (PR
or CR in radiographic objective response) that is subsequently confirmed
to the date of first confirmed disease progression or death, whichever
occurs first.
8) Progression free survival: The time from the first study treatment
administration to the date of first documentation of progressive disease or death, whichever come first |
1) AE/SAE per isatuximab + cemiplimab: numero di pazienti con AE/SAE
2) AE/SAE nei partecipanti trattati con isatuximab + cemiplimab + radioterapia: numero di pazienti con AE/SAE nelle coorti A1 e A2
3) Immunogenicità: livelli di anticorpi anti-farmaco (Anti-Drug Antibody, ADA) isatuximab e cemiplimab
4) Valutazione della PK utilizzando un’analisi non compartimentale per entrambi i composti mediante l’utilizzo di concentrazioni sieriche per cemiplimab e concentrazioni plasmatiche per isatuximab
5) Variazione del carico tumorale: la miglior variazione in percentuale dal basale
6) Tasso di controllo della malattia: la somma delle risposte complete (CR) + risposte parziali (PR)+malattia stabile (SD)
7) Durata della risposta: tempo dalla data della prima risposta (PR o CR nelle risposte radiografiche obiettive) successivamente confermata alla data della prima progressione di malattia documentata o di decesso, qualunque avvenga prima.
8) Sopravvivenza libera da progressione: tempo dalla prima somministrazione del farmaco in studio alla data della prima progressione di malattia documentata o di decesso, qualunque avvenga prima. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) to 4) Up to 90 days after last study treatment administration (Up to
approximately 27 months after first study treatment administration)
5) to 8) Up to 24 weeks after last patient treated in a given cohort |
Da 1) a 4) Fino a 90 giorni dopo l'ultima somministrazione del farmaco in studio (Fino a circa 27 mesi dopo la prima somministrazione del farmaco in studio)
Da 5) a 8) Fio a 24 settimane dopo il trattamento dell'ultimo paziente in una determinata coorte |
|
| 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) | 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 |
| Phase I/II study |
| Studio di fase I/II |
|
| 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 |
|
| 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 | 5 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Korea, Republic of |
| Taiwan |
| France |
| Italy |
| Netherlands |
| Portugal |
| Spain |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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