| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients affected by relapsed/refractory DLBCL or HGBCL failing CAR T-cell therapy |
| Pazienti affetti da DLBCL o HGBCL recidivante/refrattario che non hanno superato la terapia con cellule CAR-T |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients affected by relapsed/refractory DLBCL or HGBCL failing CAR T-cell therapy |
| Pazienti affetti da DLBCL o HGBCL recidivante/refrattario che non hanno superato la terapia con cellule CAR-T |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084346 |
| E.1.2 | Term | B-cell non-Hodgkin's lymphoma |
| 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 |
| Assess the efficacy of loncastuximab tesirine as measured by overall response rate (ORR) in DLBCL and HGBCL patients failing CAR-T cell therapy |
| Valutare l’efficacia di loncastuximab tesirina misurata in base al tasso di risposta globale (ORR) nei pazienti con DLBCL e HGBCL che non hanno superato la terapia con cellule CAR-T |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
• Evaluate survival outcomes after Loncastuximab Tesirine
• Evaluate the safety of loncastuximab tesirine
Exploratory Objectives
• Assess the changes in blood serum markers of disease and inflammation during the study course
• Explore the correlation between clinical activity and changes in plasma circulating tumor DNA (ctDNA) during the study course |
Obiettivi secondari
• Valutare i risultati di sopravvivenza dopo Loncastuximab Tesirina
• Valutare la sicurezza di loncastuximab tesirina
Obiettivi esploratori
• Valutare le variazioni dei marker sierici di malattia e infiammazione nel corso dello studio
• Esplorare la correlazione tra attività clinica e cambiamenti nel DNA tumorale circolante plasmatico (ctDNA) nel corso dello studio |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, aged =18 years.
2. Willing and able to give written, informed consent.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
4. Histologically confirmed DLBCL and large B cell lymphoma (at last relapse) subsets as defined by the 2016 WHO classification, including:
• DLBCL, Not Otherwise Specified (NOS)
• Transformed DLBCL from indolent lymphoma
• HGBCL with MYC and BCL2 and/or BCL6 rearrangements (double/triple hit)
5. Patients failing CAR T-cell therapy, defined as:
• Stable disease (SD) 1 month after CAR T-cell infusion
• Progressive disease (PD) at any time
• Partial Remission (PR) at 6 months after CAR T-cell infusion.
6. Measurable disease as defined by the 2014 Lugano Classification as assessed by positron-emission tomography (PET)- computed tomography (CT) or by CT or MRI if tumor is not FDG-avid on screening PET-CT.
7. Previous treatment with loncastuximab tesirine is allowed, provided that the patient was in CR or PR at the time of drug withdrawal.
8. Negative beta-human chorionic gonadotropin (ß-HCG) pregnancy test within 7 days prior to start of study drug (C1D1) for women of childbearing potential.
9. Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 9 months after the last dose of loncastuximab tesirine. Men with female partners who are of childbearing potential must agree that they will use a highly effective method of contraception from the time of giving informed consent until at least 6 months after the patient receives his last dose of loncastuximab tesirine.
10. Adequate renal, hepatic, pulmonary, and cardiac function defined as:
• Creatinine clearance =40 ml/min.
• Serum alanine aminotransferase / aspartate aminotransferase =2.5 x ULN.
• Total bilirubin =1.5 x ULN, except in subjects with Gilbert's syndrome.
• LVEF =50% unless the institutional lower limit of normal is lower.
• Baseline oxygen saturation >92% on room air and =Grade 1 dyspnea.
11. Adequate Bone Marrow (BM) function without requiring ongoing blood product or granulocyte-colony stimulating factor support (GCSF) and meeting the following criteria:
• Absolute neutrophil count =1.0 × 10^6/dL.
• Hemoglobin =9.0 g/dL
• Platelets =50 × 10^6/dL |
1. Maschio o femmina, di età =18 anni.
2. Volontà e capacità di prestare il consenso informato scritto.
3. Performance status dell’Eastern Cooperative Oncology Group (ECOG) da 0 a 2.
4. Sottoinsiemi DLBCL e linfoma a grandi cellule B (all’ultima ricaduta) confermati istologicamente come definiti dalla classificazione dell’OMS 2016, tra cui:
• DLBCL, non altrimenti specificato (NOS)
• DLBCL trasformato da linfoma indolente
• HGBCL con riarrangiamenti MYC e BCL2 e/o BCL6 (double/triple hit)
5. Pazienti che hanno fallito la terapia CAR-T, definiti come:
• Malattia stabile (SD) 1 mese dopo l’infusione di cellule CAR-T
• Malattia progressiva (PD) in qualsiasi momento
• Remissione parziale (PR) a 6 mesi dall’infusione di cellule CAR-T.
6. Malattia misurabile come definita dalla Classificazione Lugano 2014 valutata mediante tomografia a emissione di positroni (PET)- tomografia computerizzata (TC) o mediante TC o RM se il tumore non è FDG-avid allo screening PET-TC.
7. È consentito un precedente trattamento con loncastuximab tesirina, a condizione che il paziente fosse in CR o PR al momento della sospensione del farmaco.
8. Test di gravidanza negativo per la gonadotropina corionica beta umana (ß-HCG) entro 7 giorni prima dell’inizio del farmaco in studio (C1D1) per le donne in età fertile.
9. Le donne in età fertile devono accettare di utilizzare un metodo contraccettivo altamente efficace dal momento del consenso informato fino ad almeno 9 mesi dopo l’ultima dose di loncastuximab tesirina. Gli uomini con partner di sesso femminile in età fertile devono concordare all’utilizzo di un metodo contraccettivo altamente efficace dal momento in cui hanno dato il consenso informato fino ad almeno 6 mesi dopo che il paziente ha ricevuto l’ultima dose di loncastuximab tesirina.
10. Adeguata funzione renale, epatica, polmonare e cardiaca definita come:
• Clearance della creatinina =40 ml/min.
• Alanina aminotransferasi/aspartato aminotransferasi sierica =2,5 x ULN.
• Bilirubina totale =1,5 x ULN, eccetto nei soggetti con sindrome di Gilbert.
• LVEF =50% a meno che il limite inferiore normale del centro non sia inferiore.
• Saturazione di ossigeno al basale >92% nell’aria ambiente e dispnea =Grado 1.
11. Adeguata funzione del midollo osseo (BM) senza richiedere il supporto continuo di emoderivati o fattore stimolante le colonie di granulociti (GCSF) e soddisfare i seguenti criteri:
• Conta assoluta dei neutrofili =1,0 × 10^6/dL.
• Emoglobina =9,0 g/dL
• Piastrine =50 × 10^6/dL |
|
| E.4 | Principal exclusion criteria |
1. Known history of hypersensitivity to or positive serum human antidrug antibody (ADA) to a CD19 antibody.
2. Females who are pregnant or lactating.
3. Active second primary malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor's medical monitor and Investigator agree and document should not be exclusionary.
4. Lymphoma with active CNS involvement at the time of screening, including leptomeningeal disease.
5. Bulky disease, defined as largest tumor diameter >10 cm.
6. Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV).
7. Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath)
8. Significant medical comorbidities, including but not limited to, uncontrolled hypertension (blood pressure =160/100 mm Hg repeatedly), unstable angina, congestive heart failure (greater than New York Heart Association class II), electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial infarction within 6 months prior to screening, uncontrolled atrial or ventricular cardiac arrhythmia, poorly controlled diabetes, or severe chronic pulmonary disease.
9. Active autoimmune disease, motor neuropathy considered of autoimmune origin, and other central nervous system (CNS) autoimmune disease.
10. History of Steven's Johnson's syndrome or toxic epidermal necrolysis syndrome.
11. Major surgery, radiotherapy, chemotherapy or other anti-neoplastic therapy within 14 days prior to start of study drug (C1D1), except shorter if approved by the Sponsor.
12. Planned live vaccine administration after starting study drug (C1D1).
13. Use of any other experimental medication within 14 days prior to start of study drug (C1D1).
14. Failure to recover to Grade =1 (Common Terminology Criteria for Adverse Events version 5.0 [CTCAE v5.0]) from acute non-hematologic toxicity (Grade =2 neuropathy or alopecia) due to previous therapy prior to screening.
15. Any other significant medical illness, abnormality, or condition that would, in the Investigator’s judgment, make the patient inappropriate for study participation or put the patient at risk. |
1. Storia nota di ipersensibilità o di positività human antidrug antibody (ADA) sierico ad un anticorpo CD19.
2. Donne in gravidanza o in allattamento.
3. Secondo tumore maligno primitivo attivo diverso da tumori cutanei non melanoma, carcinoma prostatico non metastatico, carcinoma cervicale in situ, carcinoma duttale o lobulare in situ della mammella o altro tumore maligno che il monitor dello studio e lo sperimentatore concordano e documentano non dovrebbe essere escludente.
4. Linfoma con coinvolgimento attivo del SNC al momento dello screening, inclusa la malattia leptomeningea.
5. Malattia voluminosa, definita come misura del diametro grande del tumore >10 cm.
6. Nota sieropositività e che richiede una terapia antivirale per il virus dell’immunodeficienza umana (HIV), il virus dell’epatite B (HBV) o il virus dell’epatite C (HCV).
7. Accumulo clinicamente significativo di liquidi nel terzo spazio (cioè ascite che richiede drenaggio o versamento pleurico che richiede drenaggio o è associato a mancanza di respiro)
8. Comorbilità mediche significative, incluse, a titolo esemplificativo ma non esaustivo, ipertensione non controllata (pressione sanguigna =160/100 mmHg ripetutamente), angina instabile, insufficienza cardiaca congestizia (superiore alla classe II della New York Heart Association), evidenza elettrocardiografica di ischemia acuta, angioplastica o infarto del miocardio entro 6 mesi prima dello screening, aritmia cardiaca atriale o ventricolare non controllata, diabete scarsamente controllato o grave malattia polmonare cronica.
9. Malattia autoimmune attiva, neuropatia motoria considerata di origine autoimmune e altre malattie autoimmuni del sistema nervoso centrale (SNC).
10. Anamnesi di sindrome di Steven Johnson o sindrome da necrolisi epidermica tossica.
11. Chirurgia, radioterapia, chemioterapia o altra terapia anti-neoplastica entro 14 giorni prima dell’inizio del farmaco in studio (C1D1), salvo abbreviazione se approvata dallo Sponsor.
12. Somministrazione pianificata del vaccino vivo dopo l’inizio del farmaco in studio (C1D1).
13. Uso di qualsiasi altro farmaco sperimentale entro 14 giorni prima dell’inizio del farmaco in studio (C1D1).
14. Mancato recupero al Grado =1 (Common Terminology Criteria for Adverse Events versione 5.0 [CTCAE v5.0]) da tossicità acuta non ematologica (neuropatia o alopecia di Grado =2) a causa di una precedente terapia prima dello screening.
15. Qualsiasi altra malattia, anomalia o condizione medica significativa che, a giudizio dello sperimentatore, renderebbe il paziente inappropriato per la partecipazione allo studio o lo metterebbe a rischio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Tasso di risposta globale (ORR) definito come la porzione di pazienti che raggiungono la migliore risposta globale al trattamento di studio, in termini di risposta completa (CR) o risposta parziale (PR) secondo la Classificazione Lugano 2014 |
| Overall response rate (ORR) defined as patients in achieving a best overall response of complete response (CR) or partial response (PR) to study treatment, according to the 2014 Lugano Classification |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6 months since start of treatment |
| 6 mesi dall'inizio del trattamento |
|
| E.5.2 | Secondary end point(s) |
Secondary
• Progression-free survival (PFS) defined as the time between first dose administration and the first documentation of recurrence or progression by independent central review, or death
• Overall survival (OS) defined as the time between first dose administration and death from any cause
• Duration of Response (DOR) defined as the time from first documentation of response to recurrence or progression by independent central review, or death
• Frequency and severity of adverse events (AEs) and severeserious adverse events (SAEs)
Exploratory
• Relationship between blood serum markers of disease and inflammation (LDH, CRP, ferritin) and selected efficacy endpoints
• Relationship between changes in plasma ctDNA and selected efficacy endpoints |
Secondario
• Sopravvivenza libera da progressione (PFS) definita come il tempo che intercorre tra la prima somministrazione e la prima documentazione di recidiva o progressione mediante revisione centrale indipendente o morte
• Sopravvivenza globale (OS) definita come il tempo che intercorre tra la prima somministrazione e la morte avvenuta per qualsiasi causa
• Durata della risposta (DOR) definita come il tempo che intercorre tra la prima documentazione della risposta e la recidiva o progressione mediante revisione centrale indipendente o morte
• Frequenza e gravità degli eventi avversi (AE) e degli eventi avversi seri (SAE)
Esploratorio
• Relazione tra marcatori sierici di malattia e infiammazione (LDH, CRP, ferritina) e gli endpoint di efficacia selezionati
• Relazione tra le variazioni del ctDNA plasmatico e gli endpoint di efficacia selezionati |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• End of study
• End of study
• End of study + 2 years since the end of study
• Continuosly during the trial |
• End of study
• End of study
• End of study + 2 anni dall'end of study
• Continuamente durante lo studio |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | 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 | No |
| 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 | 1 |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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