E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients with relapsed and/or refractory Philadelphia Chromosome- positive B-precursor ALL |
leucemia linfoblastica acuta in soggetti adulti da precursori delle cellule B positiva per il cromosoma Philadelphia recidiva/refrattaria |
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E.1.1.1 | Medical condition in easily understood language |
Acute lymphoblastic leukemia - a cancer of the blood and marrow |
eucemia linfoblastica acuta – un tumore del sangue e del midollo |
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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 | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063625 |
E.1.2 | Term | Acute lymphoblastic leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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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 rate of complete remission/complete remission with partial hematological recovery (CR/CRh*) in adult subjects with Relapsed/Refractory (R/R) Philadelphia Chromosome Positive (Ph+) B-precursor Acute Lymphoblastic Leukemia (ALL) who receive blinatumomab |
Valutare il tasso di remissione completa/remissione completa con recupero ematologico parziale (CR/CRh*) in soggetti adulti affetti da LLA, R/R, da precursori delle cellule B Ph+ trattati con blinatumomab |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
• To evaluate the rate of Minimal Residual Disease (MRD) remission in adult subjects with R/R Ph+ B-precursor ALL
• To evaluate other measures of efficacy of blinatumomab in adult subjects with R/R Ph+ B-precursor ALL
• To estimate the safety of blinatumomab in adult subjects with R/R Ph+ B-precursor ALL
• To evaluate pharmacokinetics (PK) of blinatumomab in adult subjects with R/R Ph+ B-precursor ALL
Exploratory Objectives:
• To evaluate the duration of MRD response
• To evaluate the efficacy of blinatumomab against specific bcr-abl mutations |
Valutare il tasso di remissione della malattia residua minima (Minimal Residual Disease, MRD) in soggetti adulti affetti da LLA, R/R, da precursori delle cellule B Ph+
Valutare altre misure di efficacia di blinatumomab in soggetti adulti affetti da LLA, R/R, da precursori delle cellule B Ph+
Valutare la sicurezza di blinatumomab in soggetti adulti affetti da LLA, R/R, da precursori delle cellule B Ph+
Valutare la farmacocinetica di blinatumomab in soggetti adulti affetti da LLA, R/R, da precursori delle cellule B Ph+
Obiettivi esplorativi:
Valutare la durata della risposta MRD
Valutare l’efficacia di blinatumomab nei confronti di specifiche mutazioni bcr-abl
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|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with Ph+ B-precursor ALL, with any of the following:
• Relapsed or refractory to at least one second generation TKI (dasatinib, nilotinib, bosutinib, ponatinib)
OR intolerant to second generation TKI and intolerant or refractory to imatinib mesylate
2. Greater than 5% blasts in bone marrow
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
4. Age ≥ 18 years of age, at the time of informed consent
5. Subject has provided informed consent or subject’s legally acceptable representative has provided informed consent when the subject has any kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent. |
nello studio vengono arruolati soggetti adulti affetti da LLA da precursori delle cellule B Ph+ R/R. Per un elenco completo dei criteri di eleggibilità, consultare le Sezioni 4.1 e 4.2 del protocollo. |
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E.4 | Principal exclusion criteria |
1. History of malignancy other than ALL within 5 years prior to start of protocol-required therapy with the exception of:
− Malignancy treated with curative intent and with no known active disease present for 5 years before enrollment and felt to be at low risk for recurrence by the treating physician
− Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
− Adequately treated cervical carcinoma in situ without evidence of disease
− Adequately treated breast ductal carcinoma in situ without evidence of disease
− Prostatic intraepithelial neoplasia without evidence of prostate cancer
2. History or presence of clinically relevant CNS pathology as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, psychosis
− With the exception of CNS leukemia that is well controlled with intrathecal therapy
3. Active ALL in the CNS (confirmed by CSF analysis) or testes (no clinical sign thereof)
4. Isolated extramedullary disease
5. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
6. Allogeneic HSCT within 12 weeks prior to start of blinatumomab
7. Any active acute Graft-versus-Host Disease (GvHD) grade 2 to grade 4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
8. Any systemic therapy against GvHD within 2 weeks prior to start of blinatumomab
9. Cancer chemotherapy within 2 weeks prior to start of blinatumomab (intrathecal chemotherapy and dexamethasone are allowed until start of blinatumomab). In addition, any subject whose organ toxicity (excluding hematologic) from prior ALL treatment has not resolved to no more than CTCAE grade 1.
10. Immunotherapy (eg, rituximab) within 4 weeks prior to start of blinatumomab
11. Subject received prior anti-CD19 therapy
12. Eligibility for alloHSCT at the time of enrollment (as defined by disease status, performance status and availability of donor)
13. Abnormal screening laboratory values as defined below:
− AST (SGOT) and/or ALT (SGPT) and/or alkaline phosphatase ≥ 5 x upper limit of normal (ULN)
− Total bilirubin ≥ 1.5 x ULN (unless related to Gilbert´s or Meulengracht disease)
− Creatinine ≥ 1.5 ULN or creatinine clearance < 60 mL/min (calculated)
14. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive).
15. Subject is pregnant or breast feeding, or might become pregnant within 3 months after the last dose of protocol-specified therapy
16. Woman of childbearing potential and is not willing to use 2 highly effective methods of contraception while receiving blinatumomab and for an additional 3 months after the last dose of protocol-specified therapy
17. Male who has a female partner of childbearing potential, and is not willing to use 2 highly effective forms of contraception for at least an additional 3 months after the last dose of protocol-specified therapy
18. Male who has a pregnant partner, and is not willing to use a condom during sexual activity for 3 months after the last dose of protocol-specified therapy
19. Currently receiving treatment in another investigational device or drug study or less than 30 days since ending treatment on another investigational device or drug study(s). The 30 days is calculated from day 1 of blinatumomab treatment.
20. Other investigational procedures while participating in the treatment portion of this study are excluded.
21. Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing.
22. Subject previously entered into this study or previous treatment with blinatumomab.
23. Subject likely to not be available to complete all protocol-required study isits or procedures, including follow-up visits, and/or to comply with all required study procedures including writing tests to the best of the subject and Investigator’s knowledge.
24. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion. |
1. Storia di neoplasia diversa da ALL entro cinque anni prima dell'inizio della terapia del protocollo ad eccezione di:
- Malignità trattate con intento curativo e di cui non si conosce malattia attiva presenta per 5 anni prima dell’arruolamento e di essere a basso rischio per recidiva parere del medico curante
- cancro della pelle non-melanoma ,o lentigo malignaadeguatamente trattato senza evidenza di malattia
- carcinoma cervicale in situ adeguatamente trattato, senza evidenza di malattia
- carcinoma seno duttale in situ adeguatamente trattato senza prove
di malattie
- Neoplasia prostatica intraepiteliale senza evidenza di cancro alla prostata
2. Storia o presenza di patologie clinicamente rilevanti al SNC come l'epilessia, , paresi, afasia, ictus cerebrali, lesioni, demenza, morbo di Parkinson, malattia cerebellare, sindrome cerebrale organica, psicosi
- Con l'eccezione di leucemia del SNC che è ben controllata mediante
terapia intratecale
3. Attivo ALL nel sistema nervoso centrale (confermato da analisi CSF) o dei testicoli (senza segno clinico della stessa)
4. Malattia extramidollare isolata
5. Malattia autoimmune in corso o storia di malattia autoimmune con potenziale coinvolgimento del SNC
6. HSCT allogenico entro 12 settimane dall'inizio di blinatumomab
7. Qualsiasi malattia di Graft-versus-Host Disease (GvHD) di grado 2 al grado 4 secondo i criteri Glucksberg o GvHD cronica attiva che richiede trattamento sistemico
8. Qualsiasi terapia sistemica contro GvHD entro 2 settimane prima dell'inizio di blinatumomab
9. chemioterapia tumorale entro 2 settimane prima dell'inizio della blinatumomab (Chemioterapia intratecale e desametasone sono consentiti fino all'inizio del blinatumomab).
10. Immunoterapia (ad esempio, rituximab) entro 4 settimane prima dell'inizio di blinatumomab
11. Soggetti che hanno ricevuto precedente terapia anti-CD19
12. Idoneità alla HSCT al momento dell’arruolamento (come definito dallo stato di malattia, performance status e la disponibilità dei donatori)
13. Anormali valori di laboratorio di screening, come definite di seguito:
- AST (SGOT) e / o ALT (SGPT) e / o fosfatasi alcalina ≥ 5 x
limite superiore della norma (ULN)
- Bilirubina totale ≥ 1.5 x ULN (a meno che sia legato a malattia di Gilbert o
Meulengracht)
- Creatinina ≥ 1,5 ULN o clearance della creatinina <60 ml / min
(Calcolato)
14. Un'infezione nota da virus dell'immunodeficienza umana (HIV) o
infezione cronica da virus dell'epatite B (HBsAg positiva) o dell'epatite C virus (anti-HCV).
15. Il soggetto è in stato di gravidanza o allattamento, o potrebbe iniziare una gravidanza entro 3 mesi dopo l'ultima dose della terapia specificat nel protocollo
16. Donna in età fertile e non è disposta a utilizzare 2 metodi contraccettivi altamente efficaci durante il trattamento con blinatumomab e per altri 3 mesi dopo l'ultima dose di terapia
17. Maschio che ha un partner femminile in età fertile, e non è disposta a usare due forme altamente efficaci di contraccezione per almeno ulteriori 3 mesi dopo l'ultima dose della terapia specificata nel protocollo
18. Maschio che ha un partner incinta, e non è disposto a usare il preservativo durante l'attività sessuale per 3 mesi dopo l'ultima dose della terapia specificata nel protocollo
19. Attualmente in cura in un altro dispositivo sperimentale o farmaco in sperimentazione o che siano trascorsi meno di 30 giorni dalla conclusione del trattamento con altro dispositivo sperimentale o farmaco. I 30 giorni sono calcolati dal1 giorno di trattamento blinatumomab.
20. Altre procedure di sperimentazione durante la partecipazione nella parte di trattamento di questo studio sono escluse.
21. Soggetto con note sensibilità alle immunoglobuline o qualsiasi dei
prodotti o componenti da somministrare durante il dosaggio.
22. Soggetto precedentemente arruolato in questo studio o in un precedente trattamento con blinatumomab.
23. Soggetto che probabilmente non sia disponibile a completare tutte le visite del protocollo o procedure di studio, comprese le visite di follow-up, e / o per conformarsi
con tutte le procedure di studio richieste, compresa la compliazione dei test al meglio delle conoscenze del soggetto e dello speriemntatore
24. Storia o evidenza di qualsiasi altro disturbo clinicamente significativo,
condizione o malattia (ad eccezione di quelli sopra menzionati) che, a
parere del medico sperimentatore o Amgen, se consultatati, potrebbe
mettere a rischio la sicurezza dei soggetti o interferire con la valutazione dello studio, le procedure o il suo completamento
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E.5 End points |
E.5.1 | Primary end point(s) |
CR/CRh* rate within 2 cycles of treatment with blinatumomab |
Tasso di CR/CRh* in 2 cicli di trattamento con blinatumomab |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessment at the end of the first and second treatment cycle |
Valutazione alla fine del primo e del secondo ciclo di trattamento |
|
E.5.2 | Secondary end point(s) |
Secondary Endpoints:
1. Rate of MRD remission within 2 cycles of treatment with blinatumomab
2. Duration of CR or CRh*
3. CR rate within 2 cycles of treatment with blinatumomab
4. CRh* rate within 2 cycles of treatment with blinatumomab
5. CR+CRh*+ Complete Response incomplete (CRi) rate within 2 cycles of treatment with blinatumomab
6. Overall survival
7. Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) and 100-day mortality after alloHSCT
8. Incidence of adverse events and antibody formation
9. Pharmacokinetic parameters: Serum concentration of blinatumomab
Exploratory Endpoints:
1. Duration of MRD Remission with blinatumomab treatment
2. Efficacy of blinatumomab against specific bcr-abl mutations |
Endpoint secondari:
1. Tasso di remissione MRD in 2 cicli di trattamento con blinatumomab
2. Durata di CR o CRh*
3. Tasso di CR in 2 cicli di trattamento con blinatumomab
4. Tasso di CRh* in 2 cicli di trattamento con blinatumomab
5. Tasso di CR+CRh*+risposta completa con recupero incompleto (CRi) in 2 cicli di trattamento con blinatumomab
6. Sopravvivenza globale
7. Trapianto allogenico di cellule staminali ematopoietiche (Hematopoietic Stem Cell Transplantation, HSCT) e mortalità a 100 giorni post-trapianto
8. Incidenza di eventi avversi e formazione di anticorpi
9. Parametri farmacocinetici:
a. Concentrazione sierica di blinatumomab
Endpoint esplorativi:
1. Durata della remissione MRD con il trattamento a base di blinatumomab
2. Efficacia di blinatumomab nei confronti di specifiche mutazioni bcr-abl |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoints:
1+3+4+5: Assessment at the end of the first and second treatment cycle
2: Assessment at the end of each treatment cycle, 30 days after last dose (safety follow-up) and up to 18 months long-term follow-up (every 3 months)
6: Assessment throughout entire study including treatment, 30 days safety follow-up and up to 18 months long-term follow-up
7: Assessment throughout entire study and 100 days after alloHSCT
8: Assessment throughout treatment period and 30 days after last dose (safety follow-up)
9: Assessment at day 8 of cycle1 and day 1 of cycle 2
Exploratory Endpoints:
1+2: Assessment at the end of each treatment cycle, 30 days after last dose (safety follow-up) and up to 18 months long-term follow-up (every 3 months) |
1 +3 +4 +5: Valuta. al termine del primo e del secondo ciclo di trattamento
2: Valut. al termine di ogni ciclo di trattamento, a 30 giorni dopo ultima dose (safety follow-up) e fino al follow-up a lungo termine a 18 mesi (ogni 3 mesi) 6: Valut. durante tutto lo studio compreso il trattamento, i 30 giorni di safety follow-up e fino ai 18 mesi di follow-up a lungo termine
7: Valut.e durante tutto lo studio e a 100 giorni dopo il “alloHSCT”
8: Valut. per tutto il periodo di trattamento e a 30 giorni dopo l'ultima dose (safety follow-up)
9: Valutazione a giorno 8 del ciclo 1 e giorno 1 del ciclo di 2
Endpoint esplorativi:
1 2: Valut. al termine di ogni ciclo di trattamento, a 30 giorni dopo l'ultima dose (safety follow-up) e fino al follow-up a lungo termine a 18 mesi (ogni 3 mesi)
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | 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.8.3 |
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 | 14 |
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 | No |
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 |
France |
Germany |
Italy |
United Kingdom |
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
|
when the last subject is assessed or receives an intervention for evaluation in the study; including survival assessments |
Quando l’ultimo soggetto è valutato o riceve una procedura per la valutazione dello studio, incluso la verifica della sopravvivenza |
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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 | 0 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |