| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| AL amyloidosis |
| Amiloidosi AL |
|
| 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 | HLGT |
| E.1.2 | Classification code | 10035227 |
| E.1.2 | Term | Plasma cell neoplasms |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic 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 Assess Overall Hematologic Response Rate
(CR + VGPR) at the completion of 6 cycles of Daratumumab in patients with AL Amyloidosis not in CR or VGPR after any previous therapy |
Determinare la percentuale di pazienti con amiloidosi AL, che non hanno ottenuto almeno una
risposta parziale molto buona (VGPR) dopo i precedenti trattamenti, che raggiungono VGPR o una risposta completa (CR) al completamento di 6 cicli di terapia con Daratumumab |
|
| E.2.2 | Secondary objectives of the trial |
¿To determine safety and tolerability of Daratumumab (type, frequency, severity, and relationship of adverse events to study treatment).
¿To Assess in all patients according to their disease history
- Overall Hematologic Response Rate (CR+VGPR+PR) at the completion of 1 and 3 the cycles.
- The Overall Hematologic Response Rate including PR at the completion of 6 cycles
- the duration of hematologic response
- the rate of organ response and organ improvement, according to standard criteria
- the time to hematologic and organ response
- the hematologic disease progression free survival (PFS) and 1-year PFS
- the overall survival (OS) and 1-year OS
¿ Assess QoL using EORTC QLQ30, EQ5D-3L and Amyloidosis Symptoms Scale |
¿ Determinare la sicurezza e la tollerabilit¿ di Daratumumab (tipo di evento avverso, frequenza,
seriet¿, sospensione del trattamento a causa di tossicit¿, modificazione o ritardo nella dose).
¿ Determinare in tutti i pazienti, e in relazione alla loro storia clinica (una linea di trattamento contro
due o pi¿ linee):
- Tasso di risposta ematologica totale (CR+VGPR+PR) al completamento di 1 e 3 cicli
- Tasso di risposta ematologica totale (includendo una PR) al completamento di 6 mesi di trattamento.
- La durata della risposta ematologica.
- Il tasso di risposta d¿organo e miglioramento della funzionalit¿ d¿organo.-o Il tempo per il raggiungimento della risposta
ematologica e d¿organo.
- La sopravvivenza libera da progressione ematologica (PFS) e la PFS a un anno
- La sopravvivenza complessiva (OS) e dopo un anno
¿ La qualit¿ della vita (EORTC QLQ30, EQ5D 3L e scala dei sintomi dell¿amiloidosi). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must be =18 years of age
2. Histologic diagnosis of AL amyloidosis
3. Patients without a clear evidence of ¿ or ¿ light chains positivity of amyloid deposits by immunohistochemistry who present: 1) with peripheral neuropathy as the dominant organ involvement should have a genetic testing negative for transthyretin mutations associated with hereditary amyloidosis, 2) who present with cardiac involvement as the dominant organ involvement should have a (99m)Tc-HMDP-scintigraphy to rule out TTR amyloidosis.
4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
5. Patients should have received at least one line with an alkylating agent and/or a proteasome inhibitor and dexamethasone and not be in VGPR or CR at the time of inclusion (patients who did not reach VGPR or patients who reached VGPR or better but have an hematological relapse can be included).
6. Measurable hematologic disease: difference between involved and uninvolved FLC > 50 mg/L with an abnormal ¿/¿ ratio (with Freelite® test kits, The Binding Site)
7. Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system)
8. Wash-out period of at least 4 weeks from previous antitumor therapy or any investigational treatment or 5 half-lives from previous antibodies, whichever is longer
9. Adequate bone marrow function prior to 1 drug intake (C1D1), without transfusion or growth factor support within 5 days prior to 1 drug intake, defined as:
Absolute neutrophils = 1000/mm
Platelets = 50000/mm
Hemoglobin = 8.5g/dl
10. Adequate organ function defined as:
Serum SGOT/AST or SGPT/ALT < 3.0 X Upper Limit Of The Normal Range (ULN)
Serum total bilirubin < 2.0 mg/dL, unless the patient has Gilbert’s syndrome where the direct bilirubin should then be < 2.0 mg/dL
11. Women who are partners of men and with childbearing potential* must be practicing one of the following methods of birth control : subcutaneous hormonal implant, levonorgestrel releasing intra-uterine system, medroxyprogesterone acetate depot, tubal sterilization, ovulation inhibitory progesterone only pills, or sexual intercourse with a vasectomized male partner (vasectomy must be confirmed by 2 negative semen analyses). Or women will commit to absolute and continuous abstinence confirmed to her physician on a monthly basis*. Contraception will start at the beginning of therapy including dose interruptions, and for 3 months after discontinuation of Daratumumab
12. A woman with childbearing potential must have negative serum or urine pregnancy tests at screening and within 48H prior to dosing, and remain on a highly effective method of birth control. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed.
13. A woman of childbearing potential must remain on a highly effective method of birth control. Contraception must start prior initiating treatment with Daratumumab, during therapy, during dose interruptions and for 3 months following discontinuation of Daratumumab. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy
14. A man who has not had a vasectomy and who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control e.g. condom with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 3 months following discontinuation of Daratumumab. The exception to this restriction is that if the subject’s female partner is surgically sterile
15. Only patients who are informed of the investigational nature of this study and sign and give written informed consent in accordance with institutional, national and European guidelines are eligible to participate
16. Subjects affiliated with an appropriate social security system |
- età >= 18 anni.
-Diagnosi bioptica di amiloidosi AL.
-Performance status (ECOG) 0, 1 o 2.
-I pazienti devono aver ricevuto almeno una linea di trattamento con un agente alchilante e/o con un inibitore del proteasoma e desametasone e non devono avere raggiunto una risposta parziale molto buona o una risposta complete al momento dell’inclusione in questo studio (possono essere inclusi pazienti che non hanno raggiunto una VGPR o pazienti che hanno raggiunto VGPR o CR ma hanno avuto una ricaduta ematologica).
-Malattia misurabile: differenza tra la concentrazione delle catene leggere libere coinvolte e non coinvolte >50 mg/L; con rapporto k/l al di fuori dell’intervallo di riferimento
- Coinvolgimento d’organo sintomatico (cuore, rene, fegato/tratto gastrointestinale e sistema nervoso periferico).
-Interruzione di almeno 4 settimane rispetto alla precedente terapia chemioterapica o di qualsiasi altro farmaco sperimentale o di 5 emivite se si tratta di terapie che comprendono anticorpi
-Adeguata funzione midollare prima del giorno 1 del mese 1, ottenuta senza supporto nè trasfusionale nè di fattori di crescita nei 5 giorni precedenti l’inizio della terapia, definita come:
Emoglobina =8.5 g/dL, conta dei neutrofili =1000/µL, piastrine =50000/µL.
- Adeguata funzione d’organo:
- SGOT/AST o SGPT/ALT < 3.0 X limite superior dell’intevallo di riferimento
- bilirubina totale sierica < 2.0 mg/dL, a meno che il paziente sia affetto dalla Sindrome di Gilbert, in tal caso la bilirubina diretta deve essere < 2.0 mg/dL
-Le donne in età fertile con partner devono essere d’accordo a praticare uno dei metodi contraccettivi seguenti: impianti ormonali sottocutanei, sistemi intrauterini a rilascio di levonorgestrel, sistemi depot di medrossiprogesterone acetato, sterilizzazione delle tube, pillole di solo progesterone inibitorie
dell’ovulazione, o avere rapporti con un partner maschio vasectomizzato (la vasectomia deve essere confermata da due analisi dello sperma negative). Oppure acconsentire all’astinenza complete e continua, che deve essere confermata dal medico su base mensile. In caso di donna in età fertile la contraccezione dovrà iniziare all’inizio della terapia con Daratumumabe e continuare fino a tre mesi dopo la conclusione del trattamento.
Gli uomini, non sottoposti a vasectomia e sessualmente attivi con partner in età fertile, dovranno accettare l’utilizzo di metodi contraccettivi ritenuti efficaci per l’intera durata dello studio e per i tre mesi successivi al termine del trattamento con Daratumumab. Devono inoltre accettare di non effettuare donazioni di sperma per l’intera durata dello studio e per i tre mesi successivi. E’ fatta eccezione per soggetti che hanno partner chirurgicamente sterile.
-Potranno essere arruolati solo i pazienti dai quali è acquisito un consenso scritto in accordo con le linee guida istituzionali, nazionali ed europee.
-Soggetti che sono iscritti al Sistema Sanitario Nazionale. |
|
| E.4 | Principal exclusion criteria |
1. Amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura as the only evidence of disease. The finding of isolated vascular amyloid in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis 2.Isolated soft tissue involvement
3.Presence of non-AL amyloidosis
4.Bone marrow plasma cells >30% on bone marrow aspirate at screening
5.Cardiac mayo stage IIIb disease. (i.e. cardio mayo stage III with NT-proBNP >= 8500 ng/L
6.Repetitive ventricular arrhythmias on 24h Holter ECG despite anti-arrhythmic treatment, except if a pacemaker has been
implanted.
7.Chronic atrial fibrillation
8.Supine systolic blood pressure <100 mmHg
9.Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while
enrolled in this study or within 3 months after the last dose of any component of the treatment regimen
10.Clinically overt multiple myeloma with lytic bone lesions
11.Patients with uncontrolled infection or active malignancy with the exception of
-adequately treated basal cell or squamous cell skin cancer,
-in situ cervical cancer
-low grade (Gleason 3+3 or less) prostate cancer or in situ breast carcinoma if surgically treated
-adequately treated Stage I cancer from which the patient is currently in complete remission,
-or any other cancer from which the patient has been disease-free for 3 years.
12.Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator including:
- NYHA functional classification IV congestive heart failure
- LVEF (Left Ventricular Ejection Fraction) <45%
- Uncontrolled angina, hypertension or arrhythmia
- Myocardial infarction in the past 6 months
13.Subjects with psychiatric illnesses or social situations that would preclude them understanding the informed consent, study compliance or the ability to tolerate study procedures and/or study therapy
14.Subjects with known/underlying medical conditions that, in the investigator’s opinion would make the administration of the study drug hazardous (ie: uncontrolled diabetes or uncontrolled coronary artery disease)
15.Subjects with 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 patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal
16.Subject has known moderate or severe persistent asthma within the past 2 years (see APPENDIX 8), 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)
17.Previous anti-CD38 therapy
18.Hypersensitivity to Dexamethasone that would prohibit treatment with study therapy
19.Known positive for HIV or active hepatitis B or C
20.Refusal to consent or protected by legal regime |
1. Sindromi amiloide-specifiche, quali sindrome del tunnel carpale o porpora cutanea, come unica
manifestazione della malattia. La presenza di depositi di amiloide a livello delle pareti dei vasi rilevate all’analisi di una biopsia osteomidollare o in un plasmocitoma, non è indicativa di amiloidosi
sistemica.
2. Coinvolgimento isolato dei tessuti molli.
3. Presenza di amiloidosi non-AL.
4. Infiltrato plasmacellulare nel midollo osseo >30% allo screening.
5. Interessamento cardiaco di stadio III (Mayo stage) (con NT-proBNP ³ 8500ng/L) .
6. Presenza di aritmie ventricolari ripetitive ad un ECG dinamico secondo Holter nonostante l’utilizzo di farmaci antiaritmici.ad eccezione di pazienti con pacemaker
7. Fibrillazione atriale cronica.
8. Pressione sistolica arteriosa in clinostatismo <100 mmHg
9. Pazienti in gravidanza, o in allattamento, o che stanno pianificando una gravidanza al momento
dell’arruolamento o entro tre mesi dalla data dell’ultima somministrazione di qualsiasi componente del regime di trattamento. O pazienti di sesso maschile che pianificano di diventare padri al momento dell’arruolamento o entro tre mesi dall’ultima somministrazione di qualsiasi componente del regime di trattamento.
10. Presenza di mieloma multiplo con lesioni ossee litiche.
11. Pazienti con infezioni non controllate o malattie proliferative in fase attiva ad eccezione di tumori
cutanei a cellule basali o squamose adeguatamente trattati, tumore in situ della cervice uterina, tumore della prostata di basso
grado (Gleason 3+3 o meno) o tumore in situ del seno se trattato chirurgicamente, tumori in stadio I adeguatamente trattati e dai quali il paziente è in remissione completa o qualsiasi altra forma tumorale dalla quale il paziente è in remissione da almeno 3 anni.
12. Pazienti con qualsiasi patologia cardiovascolare o polmonare di grado severo e non controllata determinate dal medico dello
studio, inclusi:
- classificazione NYHA IV insufficienza cardiaca congestiva
- Frazione di eiezione<45%
- angina non controllata, ipertensione o aritmie
- infarto del miocardio negli ultimi 6 mesi
13. Pazienti con malattie psichiatriche che potrebbero interferire con la comprensione del consenso informato, con la partecipazione e/o la compliance allo studio o la capacità di comprendere le procedure dello studio.
14. Pazienti con patologie che a discrezione dell’investigatore, potrebbero rendere pericolosa l’assunzione del farmaco dello studio
(es. diabete non controllato, coronaropatia non controllata).
15. Pazienti con malattia polmonare ostruttiva cronica (COPD) con un Volume Espiratorio Forzato in 1 secondo (FEV1) < 50% del valore normale predetto. Considerare che la valutazione FEV1 è richiesta per pazienti con sospetta COPD e i pazienti devono essere esclusi qualora FEV1 sia <50% del valore normale predetto
16. Pazienti che hanno avuto asma persistente severa o moderata negli ultimi due anni, o che presentano attualmente asma non controllata di qualsiasi classificazione. (I pazienti che presentano asma intermittente controllata o asma persistente controllata sono eligibili)
17. Precedente terapia con farmaci anti-CD38
18. Ipersensibilità al Desametasone tale da impedirne l’assunzione di questo farmaco durante lo studio.
19. Positività al test dell’HIV, epatite B o C in fase attiva.
20. Incapacità di comprendere e indisponibilità a firmare un modulo di consenso informato prima di
avviare qualsiasi procedura dello studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Thee Overall Response Rate (CR+VGPR) in patients with AL Amyloidosis not in CR or VGPR after any previous therapy, using the new response criteria. |
| La percentuale di pazienti con amiloidosi AL che non hanno ottenuto almeno una risposta parziale molto buona (VGPR) dopo i precedenti trattamenti, che raggiungono VGPR o una risposta completa (CR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 6 cycles |
| Dopo 6 cicli |
|
| E.5.2 | Secondary end point(s) |
1. Type, frequency, severity, relationship of adverse events to study treatment and changes in vital signs, physical exams, incidence of Treatment Emergent Adverses E vents ( TEAE), Serious Adverses Events (SAE), drug discontinuation for toxicity, dose modification/delay and laboratory abnormalities will be assessed using NCI-CTCAE V4.03
2. In all patients according to their disease history
2.1. the overall hematologic response rate (CR + VGPR + PR) at the completion of 1 and 3 cycles
2.2. the Overall Hematologic Response Rate including PR at the completion of 6 cycles
2.3. the time to hematologic disease progression
2.4. the rate of organ response and organ improvement, according to standard criteria
2.5. the time to hematologic and organ response
2.6. the hematologic disease progression free survival (PFS) and 1-year PFS
2.7. the overall survival (OS) and 1-year OS
The data used for the primary statistical analysis will be central laboratories data. Key parameters will be M-protein, serum free light chain dosage and ratio, and DIRA when applicable.
3. QoL using EORTC QLQ30, EQ5D-3L, Amyloidosis Symptoms Scale |
1. Type, frequency, severity, relationship of adverse events to study treatment and changes in vital signs, physical exams, incidence of Treatment Emergent Adverses E vents ( TEAE), Serious Adverses Events (SAE), drug discontinuation for toxicity, dose modification/delay and laboratory abnormalities will be assessed using NCI-CTCAE V4.03
2. In all patients according to their disease history
2.1. the overall hematologic response rate (CR + VGPR + PR) at the completion of 1 and 3 cycles
2.2. the Overall Hematologic Response Rate including PR at the completion of 6 cycles
2.3. the time to hematologic disease progression
2.4. the rate of organ response and organ improvement, according to standard criteria
2.5. the time to hematologic and organ response
2.6. the hematologic disease progression free survival (PFS) and 1-year PFS
2.7. the overall survival (OS) and 1-year OS
The data used for the primary statistical analysis will be central laboratories data. Key parameters will be M-protein, serum free light chain dosage and ratio, and DIRA when applicable.
3. QoL using EORTC QLQ30, EQ5D-3L, Amyloidosis Symptoms Scale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety is evaluated at the start of each cycle Responses at the completion of 1 and 3 cycles
The Overall Hematologic Response Rate including PR at the completion of 6 cycles |
La sicurezza viene valutata all'inizio di ogni ciclo
La risposta ematologica al completamento dei cicli 1 e 3.
Il tasso di risposta ematologica totale al completamento dei 6 cicli |
|
| 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 | 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
| 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 | 24 |
| 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 | 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
