| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with newly diagnosed stage 3B AL amyloidosis
|
| Pazienti con nuova diagnosi di amiloidosi da catene leggere (AL) in stadio 3B |
|
| E.1.1.1 | Medical condition in easily understood language |
Patients with newly diagnosed stage 3B AL amyloidosis
|
| Pazienti con nuova diagnosi di amiloidosi da catene leggere (AL) in stadio 3B |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 | 10002022 |
| E.1.2 | Term | Amyloidosis |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| 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 evaluate the overall survival (OS) rate at 6 months following treatment with daratumumab in frontline AL patients with stage 3B disease
|
| Valutare il tasso di sopravvivenza complessiva (OS) 6 mesi dopo il trattamento con daratumumab in prima linea nei pazienti AL con malattia in stadio 3B. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the overall (ORR), very good partial (VGPR) and complete (CR) hematologic response rates at 3 and 6 months
• To evaluate the Major Organ Deterioration Progression-Free Survival (MOD-PFS). Will be defined from the start of study treatment until any one of the following events (whichever occurs first)
- Death
- Clinical manifestation of cardiac failure:
- Clinical manifestation of renal failure:
- Development of hematologic progression of disease (PD) as per consensus guidelines (two consecutive assessments are required)
• To evaluate PFS based on all-cause mortality and progression of disease
• To evaluate the organ response rate (OrRR)
o Heart
o Kidney
o Liver
• To evaluate treatment effects on patient-reported outcomes (PROs) such as SF-36, EQ-5D-5L and EORTC QLQ-C30
• To characterize time to and duration of response
• To assess the safety and tolerability of daratumumab in patients with stage 3B AL amyloidosis |
• Valutare il tasso di risposta ematologica complessiva (ORR), parziale molto buona (VGPR) e completa (CR) a 3 e 6 mesi
• Valutare la sopravvivenza libera da progressione con deterioramento degli organi principali (MOD-PFS). Sarà definito dall’inizio del trattamento fino a uno dei seguenti eventi:
- Decesso
- Manifestazione clinica di scompenso cardiaco:
- Manifestazione clinica di scompenso renale:
- Sviluppo della progressione della malattia (PD) ematologica secondo le linee guida di consenso (sono richieste due valutazioni consecutive)
• Valutare la PFS basata sulla mortalità per qualsiasi causa e sulla progressionedella malattia
• Valutare il tasso di risposta negli organi (OrRR) Cuore/Rene/Fegato
• Valutare gli effetti del trattamento negli esiti riferiti dal paziente (PRO), (questionari SF-36, EQ-5D-5L ed EORTC QLQ-C30)
• Caratterizzare tempi e durata della risposta
• Valutare la sicurezza e la tollerabilità di daratumumab nei pazienti con amiloidosiAL in stadio 3B |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men or women 18 years of age or older.
2. Diagnosis of amyloidosis, AL type, based on:
a. Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent material in Congo Red stained tissue specimens (excluding bone marrow) or characteristic electron microscopy appearance
AND
b. Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
- serum monoclonal protein ≥0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation performed at local lab)
- serum free light chain (FLC) ≥2.0 mg/dL (20 mg/L) with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥2mg/dL (20 mg/L). Serum FLCs will be measured using the Freelite assay at a central laboratory.
- Note: Measurable disease by Urine Bence-Jones Proteinuria is not sufficient for study enrolment.
AND
c. Cardiac involvement by AL amyloidosis according to consensus guidelines (See ATTACHMENT 3)
3. Mayo Stage 3B disease, defined as both A. increased cardiac troponin (hsTnT >54 pg/ml) AND B. increased NT-proBNP ≥ 8500 pg/ml
4. For subjects with congestive heart failure, symptoms should be optimally managed and clinically stable with no cardiovascular-related hospitalizations within 2 weeks prior to Cycle 1 Day 1, as assessed by the Principal Investigator. [See also exclusion criteria 3]
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1,2 or 3 (ATTACHMENT 1)
6. Subject must have pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase:
a. Absolute neutrophil count ≥1.0 × 109/L;
b. Hemoglobin level ≥10.0 g/dL (≥5 mmol/L)
c. Platelet count ≥75 × 109/L; platelet transfusions are NOT acceptable
d. Alanine aminotransferase level (ALT) ≤2.5 x ULN;
e. Aspartate aminotransferase (AST) ≤2.5 x ULN
f. Total bilirubin level ≤1.5 × ULN, except for subjects with history of Gilbert Syndrome, in which case direct bilirubin ≤ 2 × ULN
g. Estimated Glomerular Filtration Rate (eGFR) ≥20 mL/min; Please note that the eGFR is measured by using the CKD-EPI equation
7. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing and continue for 3 months after discontinuation of daratumumab. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
8. During the study and for 3 months after receiving the last dose of daratumumab, female subjects must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
9. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g. either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 3 months after discontinuation of daratumumab. All men must not donate sperm during the study and for 3 months after discontinuation of daratumumab.
10. Female subjects of childbearing potential must have a negative serum or urine pregnancy tests within 14 days prior to Cycle 1 Day 1. For requirements during the Treatment Phase, please see the Time and Events Schedule.
11. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of the procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF. |
1. Uomo o donna di età pari o superiore a 18 anni.
2. Diagnosi di amiloidosi, tipo AL, basata su:
a. Diagnosi istopatologica di amiloidosi basata sul rilevamento mediante immunoistochimica e microscopia in luce polarizzata di materiale verde birifrangente in campioni di tessuto colorati con rosso Congo (senza midollo osseo) o aspetto caratteristico al microscopio elettronico E
b. Amiloidosi da catene leggere misurabile definita almeno da UNO dei seguenti elementi:
- proteina monoclonale nel siero>=0,5 g/dl mediante elettroforesi delle proteine (elettroforesi delle sieroproteine di routine e immunofissazione eseguite in laboratorio locale),
- catene leggere libere sieriche (FLC) >=2,0 mg/dl (20 mg/l) con rapporto K/L anomalo o differenza tra catene leggere libere coinvolte e non coinvolte (dFLC) >=2 mg/dl (20 mg/l). La catene leggere libere sieriche (FLC) saranno misurate con il saggio Freelite in un laboratorio centrale
Nota: La malattia misurabile in base a proteinuria di Bence-Jones nelle urine non è sufficiente per l’arruolamento nello studio. E
c. Coinvolgimento cardiaco da amiloidosi AL secondo le linee guida di consenso
3. Malattia stadio 3B Mayo, definita come A. aumento della troponina cardiaca (hsTnT >54 pg/ml) E B. aumento NT-proBNP >= 8500 pg/ml.
4. Per i soggetti con insufficienza cardiaca congestizia, i sintomi devono essere gestiti in maniera ottimale e devono essere clinicamente stabili, senza ricoveri legati a problemi cardiovascolari nelle 2 settimane precedenti al Ciclo 1, Giorno 1, secondo la valutazione dello Sperimentatore principale. [Vedere anche il criterio di esclusione 3]
5. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) 0, 1, 2 o 3
6. Durante la fase di screening, il soggetto deve presentare valori clinici di laboratorio precedenti al trattamento in linea con i seguenti criteri:
a. Conta assoluta dei neutrofili >=1,0 × 109/l;
b. Emoglobina >=10,0 g/dl (>=5 mmol/l)
c. Conta piastrinica >=75 × 109/l; le trasfusioni di piastrine NON sono accettate
d. Alanina aminotransferasi (ALT) <=2,5 x limite superiore alla norma (ULN);
e. Aspartato aminotransferasi (AST) <=2,5 x ULN
f. Bilirubina totale <=1,5 × ULN, tranne nei soggetti con sindrome di Gilbert nell’
anamnesi, in tal caso bilirubina diretta <= 2 × ULN
g. Velocità di filtrazione glomerulare stimata (eGFR) >=20 ml/min; tenere presente che
eGFR viene misurata con l’equazione CKD-EPI
7. Le donne in età fertile devono impegnarsi ad utilizzare una forma altamente efficace di contraccezione che deve iniziare prima del dosaggio e continuare per 3 mesi dopo l’interruzione di daratumumab. Si consiglia un metodo di contraccezione affidabile anche con infertilità nell’anamnesi, a meno che non sia dovuta a isterectomia oppure ooforectomia bilaterale.
8. Durante lo studio e per 3 mesi dopo la somministrazione dell’ultima dose di daratumumab, i soggetti di sesso femminile devono accettare di non donare uova (ovuli, ovociti) a scopo di riproduzione assistita.
9. Gli uomini sessualmente attivi con donne in età fertile non sottoposti a vasectomia devono accettare di utilizzare un metodo contraccettivo barriera, durante il trattamento studio e fino a 3 mesi dopo l’interruzione di daratumumab. Gli uomini non devono donare sperma durante lo studio e per 3 mesi dopo l’interruzione di daratumumab.
10. I soggetti di sesso femminile in età fertile devono avere il test di gravidanza (siero o urine) negativo nei 14 giorni precedenti al Ciclo 1, Giorno 1.
11. Ogni soggetto deve firmare un modulo di consenso informato (ICF).
|
|
| E.4 | Principal exclusion criteria |
1.Prior therapy for AL amyloidosis or multiple myeloma with the exception of 160 mg dexamethasone (or equivalent steroid) maximum exposure prior to Cycle 1 Day 1.
2.Previous or current diagnosis of symptomatic multiple myeloma including the presence of lytic bone disease, plasmacytomas, ≥ 60% plasma cells in the bone marrow, and/or hypercalcemia.
3.Evidence of significant cardiovascular conditions as specified below:
a. New York Heart Association (NYHA) classification of heart failure, stages IIIB or IV
b. Heart failure that in the opinion of the investigator due to ischemic heart disease or uncorrected valvular disease, and not due to AL amyloid cardiomyopathy.
c. Hospitalization for unstable angina or myocardial infarction or percutaneous cardiac intervention with recent stent or coronary artery bypass grafting, all within the last 6 months prior to the first dose
d. Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/ICD is indicated but will not be placed (subjects who do have a pacemaker/ICD are allowed in the study)
e. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec. Subjects who have pacemaker may be included regardless of calculated QTc interval.
f. Supine systolic blood pressure <90 mmHg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of >20 mmHg despite medical management in the absence of volume depletion
4. Subjects planning to undergo a stem cell transplant during the first 6 cycles of protocol therapy are excluded. Stem cell collection during the first 6 cycles of protocol therapy is permitted.
5. Diagnosed or treated for malignancy other than AL, except:
a. Malignancy treated with curative intent and with no known active disease present for ≥24 months before Cycle 1 Day 1
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
c. Adequately treated carcinoma in situ (e.g. cervical, breast) with no evidence of disease
6. Subject has known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal
7. Subject has known moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
8. Subject is known to be seropositive for human immunodeficiency virus (HIV). HIV positive subjects who are stable on highly active antiretroviral therapy (HAART) with no opportunistic infections within the last 6 months are eligible.
9. Subjects known:
a. to be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.
b. seropositive for hepatitis C
10. Subject has any concurrent medical condition or disease that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
11. Any form of non-AL amyloidosis, including wild type or mutated (ATTR) amyloidosis.
12. Subject has known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products.
13. Subject is known or suspected of not being able to comply with the study protocol or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject or that could prevent, limit, or confound the protocol-specified assessments.
14. Subject is a woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 3 months following discontinuation of daratumumab.
15. Subject has received an investigational drug or used an invasive investigational medical device within 4 weeks prior to Cycle 1 Day 1
16. Subject has had major surgery within 2 weeks prior to Cycle 1, Day 1, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration |
1. Precedente terapia per amiloidosi AL o mieloma multiplo, con l’eccezione di desametasone da 160 mg (o steroide equivalente) prima del C1G1
2. Diagnosi attuale o passata di mieloma multiplo sintomatico, con la presenza di patologia ossea litica, plasmacitomi, >= 60% di cellule plasmatiche nel midollo osseo e/o ipercalcemia.
3. Prove di malattie cardiovascolari significative (Insufficienza cardiaca stadio NYHA IIIB o IV; Insufficienza cardiaca dovuta a patologia cardiaca ischemica o valvolare non corretta e non dovuta a cardiomiopatia da amiloidosi AL; Ricovero per angina instabile o infarto del miocardio o intervento cardiaco percutaneo con stent recente o innesto di bypass aorto-coronarico, entro 6 mesi dalla prima dose; tachicardia ventricolare sostenuta o fibrillazione ventricolare interrotta o di disfunzione del nodo atrioventricolare o seno-atriale per cui un pacemaker/ICD è indicato ma non inserito (i
soggetti con pacemaker/ ICD sono ammessi allo studio); ECG a 12 derivazioni allo screening con intervallo (QTcF) >500 msec. I soggetti con pacemaker possono essere ammessi indipendentemente dall’intervallo QTc calcolato; Pressione arteriosa sistolica supina <90 mmHg o ipotensione ortostatica sintomatica)
4. Programma di sottoporsi a un trapianto di cellule staminali nei primi 6 cicli della terapia del protocollo. È consentita la raccolta di cellule staminali nei primi 6 cicli della terapia del protocollo.
5. Diagnosi o trattamento per patologie maligne diverse da AL, tranne:
a. Patologie maligne trattate con intentato curativo, senza patologie attive note presenti per >=24 mesi prima del C1G1
b. Tumore della pelle non melanoma adeguatamente trattato o lentigo maligna senza evidenza di patologia
c. Carcinoma in situ (es. cervice, seno) adeguatamente trattato senza evidenza di patologia
6. Il soggetto presenta broncopneumopatia cronica ostruttiva (BPCO) con Volume espiratorio massimo nel 1° secondo (FEV1) <50% del valore normale previsto.
7. Il soggetto ha presentato asma persistente moderata o grave negli ultimi 2 anni o presenta attualmente asma non controllata di qualsiasi classificazione.
8. Il soggetto è noto come sieropositivo all'HIV. I soggetti positivi a HIV stabilmente trattati con terapia antiretrovirale altamente attiva (HAART) senza infezioni opportunistiche negli ultimi 6 mesi sono idonei.
9. Soggetti noti per:
a. Sieropositività all’epatite B (test positivo per [HBsAg]). I soggetti con infezione
risolta (cioè, i soggetti HBsAg negativi ma positivi agli anticorpi dell’antigene core dell’epatite B [anti-HBc] e/o agli anticorpi dell’antigene di superficie dell’epatite B [anti-HBs]) devono essere sottoposti a screening mediante PCR in tempo reale dei livelli di DNA del virus dell’epatite B (HBV). I soggetti con PCR positiva saranno esclusi.
b. Sieropositività all’epatite C
10. Soggetti con condizione medica o patologia concomitante (es. infezione sistemica attiva).
11. Qualsiasi forma di amiloidosi non AL, inclusa l’amiloidosi wild type o mutata (ATTR).
12. Allergie note, ipersensibilità o intolleranza agli anticorpi monoclonali o alle proteine umane o ai loro eccipienti o sensibilità nota ai prodotti derivati da mammiferi.
13. Il soggetto è noto o sospetto di non essere in grado di rispettare il protocollo dello studio o presenta una condizione per cui la partecipazione non risulterebbe nel miglior interesse del soggetto o potrebbe prevenire, limitare o confondere le valutazioni specificate dal protocollo.
14. Il soggetto è una donna incinta o in allattamento o prevede di rimanere incinta durante la partecipazione allo studio o nei 3 mesi seguenti all’interruzione di daratumumab.
15. Il soggetto ha ricevuto un farmaco sperimentale o ha utilizzato un dispositivo medico sperimentale invasivo nelle 4 settimane precedenti al C1G1
16. Il soggetto è stato sottoposto a un intervento chirurgico importante nelle 2 settimane precedenti al C1G1 o non ha recuperato completamente dall’intervento o ha pianificato un intervento nel periodo di partecipazione allo studio o nelle 2 settimane successive all’ultima dose del farmaco dello studio.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall survival rate
|
| Tasso di sopravvivenza globale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Overall (ORR), very good partial (VGPR) and complete (CR) hematologic response rates (3 & 6 months), Major Organ Deterioration Progression-Free Survival (MOD-PFS), PFS based on all-cause mortality and progression of disease (PD), organ response rate (OrRR), to evaluate treatment effects on patient related outcomes (PROs), to characterize time to and duration of response, and to asses the safety and tolerability of daratumumab in patients with stage 3B AL amyloidosis |
| Tasso di risposta ematologica complessiva (ORR), parziale molto buona (VGPR) e completa (CR) (a 3 e 6 mesi); sopravvivenza libera da progressione con deterioramento degli organi principali (MOD-PFS); PFS basata sulla mortalità per qualsiasi causa e sulla progressione della malattia (PD), tasso di risposta negli organi (OrRR), effetti del trattamento negli esiti riferiti dal paziente (PRO), Caratterizzare tempi e durata della risposta, sicurezza e la tollerabilità |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the entire duration of the study.
|
| Intera durata dello 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 | Yes |
| 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 | 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) | 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 | 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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 | No |
| 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
|
| 2 years after the last subject is enrolled |
| Due anni dopo l'arruolamento dell'ultimo paziente |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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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