Clinical Trials Register

Summary
EudraCT Number:	2011-002257-61
Sponsor's Protocol Code Number:	MT103-211
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-01
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-002257-61

A.3

Full title of the trial

An open label, multicenter, phase II study to evaluate efficacy and safety of the BiTE antibody blinatumomab in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL)

Studio multicentrico, in aperto, di Fase II per valutare l'efficacia e la sicurezza dell'anticorpo del tipo BITE, blinatumomab, in pazienti adulti con leucemia linfoblastica acuta (LLA) da precursori delle cellule B, recidivante/refrattaria.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Clinical phase II study to evaluate the efficacy and safety of the bispecific antibody blinatumomab (MT103) in adult patients with acute lymphoblastic leukemia (ALL) that did not respond to previous therapy or that relapsed after initially successful previous therapy

Studio clinico di fase II per valutare l'efficacia e la sicurezza dell'anticorpo bispecifico blinatumomab (MT103) in pazienti adulti con leucemia linfoblastica acuta (LLA) che non hanno risposto alla precedente terapia o che hanno avuto una recidiva dopo un'iniziale risposta alla precedente terapia

A.4.1

Sponsor's protocol code number

MT103-211

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	MICROMET AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MICROMET AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MICROMET AG
B.5.2	Functional name of contact point	Clinical Development Department
B.5.3	Address:
B.5.3.1	Street Address	STAFFELSEESTRASSE 2
B.5.3.2	Town/ city	MONACO DI BAVIERA
B.5.3.3	Post code	81477
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 89 89 52 77 367
B.5.5	Fax number	na
B.5.6	E-mail	clinicaltrials@micromet.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/09/650
D.3 Description of the IMP
D.3.1	Product name	blinatumomab
D.3.2	Product code	MT103
D.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Blinatumomab
D.3.9.1	CAS number	853426-35-4
D.3.9.2	Current sponsor code	MT103
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	33
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL)

Pazienti adulti con Leucemia Linfoblastica Acuta (LLA)da precursori di cellule B, recidivante/refrattaria

E.1.1.1

Medical condition in easily understood language

Acute lymphoblastic leukemia-a cancer of the blood and marrow.

Leucemia linfoblastica acuta--un cancro del sangue e del midollo.

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10000845
E.1.2	Term	Acute lymphoblastic leukemia
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate efficacy of blinatumomab in patients with relapsed/refractory B-precursor ALL

Valutare l'efficacia in pazienti adulti con LLA da precursori delle cellule B, recidivan-te/refrattaria.

E.2.2

Secondary objectives of the trial

To evaluate safety of blinatumomab in patients with relapsed/refractory B-precursor ALL. To evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of blinatumomab

Valutare la safety di blinatumomab in pazienti adulti con LLA da precursori delle cellule B, recidivante/refrattaria. Valutare la farmacocinetica (PK) e la farmacodinamica (PD) di blinatumomab

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Patients with Ph-negative B-precursor All, with any of the following: - relapsed or refractory with first remission duration ≤ to 12 months in first salvage or -relapsed or refractory after first salvage therapy or -relapsed or refractory within 12 months of allogenic HSCT or -if age 60 years or older:relapsed or refractory disease in first or later salvage independent of first remission duration 2. 10% or more blasts in bone marrow 3. In case of clinical signs of additional extramedullary disease:measurable disease (at least one lesion≥1.5 cm) 4.Eastern Cooperative Oncology Group (ECOG) performance status≤2 5. Age≥18 years 6.Ability to understand and willingness to sign a written informed consent 7.Signed and dated written informed consent is available

1. Pazienti con LLA Ph-negativi da precursori delle cellule B, con uno dei seguenti parametri: - recidiva o refrattarietà con durata della remissione ≤12 mesi in primo trattamento di salvatag-gio o - recidiva o refrattarietà dopo la prima terapia di salvataggio o - recidiva o refrattarietà entro 12 mesi dall’HSCT allogenico o - se età ≥60 anni: malattia refrattaria o recidivante nel primo o successivo trattamento di salva-taggio indipendentemente dalla durata di prima remissione 2. ≥10% di blasti nel midollo osseo 3. In caso di segni clinici di malattia extramidollare aggiuntivi: malattia misurabile (almeno una lesione ≥1,5 cm) 4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2 5. Età ≥18 anni 6. Capacità di comprendere e decidere di firmare un consenso informato 7. Disponibilità di un consenso informato scritto, firmato e datato

E.4

Principal exclusion criteria

1. Patients with Ph-positive ALL 2. History or presence of clinically relevant CNS pathology as epilepsy, seizure, paresis, aphasia. stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis 3. Active ALL in the CNS or testes 4. Current autoimmune diesase or history of autoimmune disease with potential CNS involvement 5. Autologous HSCT within six weeks prior to start of blinatumomab treatment 6. Allogenic HSCT within three months prior to start of blinatumomab treatment 7. Any active acute Graft-versus-Host Disease (GvHD), or active chronic GvHD Grade 2-4 8. Immunosuppressive therapy against GvHD within two weeks prior to start of blinatumomab treatment 9. Cancer chemotherapy within two weeks prior to start of blinatumomab treatment (intrathecal prophylaxis and pre-phase with dexamethasone are allowed until start of blinatumomab treatment) 10. Radiotherapy within four weeks prior to start of blinatumomab treatment 11. Immunotherapy (e.g., rituximab) within four weeks prior to start of blinatumomab treatment 12. Any investigational anti-leukemic product within four weeks prior to start of blinatumomab treatment 13. Treatment with any other investigational medicinal product (IMP) after signature of informed consent 14. Known hypersensitivity to immunoglobulins or to any other component of the IMP formulation 15. Abnormal laboratory values as defined below: a. AST (SGOT) and/or ALT (SGPT) and/or AP≥ 5X upper limit of normal (ULN) b. Total bilirubin ≥ 1.5 x ULN (unless related to Gilbert's or Meulengracht disease) c. Creatinine≥ 1.5 ULN or Creatinine clearance < 50 ml/min (calculated) d. Hemoglobin (Hb)≤9 g/dl (trasfusion allowed) 16. Active malignancy requiring treatment other than ALL within two years prior to start of blinatumomab treatment with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma ''in situ'' of the cervix 17. Active uncontrolled infection, any other concurrent disease or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator 18. Infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive) 19. Pregnant or nursing women 20. Women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least three months thereafter. Male patients not willing to ensure not to beget a child during participation in the study and at least three months thereafter 21. Previous treatment with blinatumomab

1. Pazienti con LLA Ph-positivi 2. Storia o presenza di patologia del SNC clinicamente rilevante come epilessia, convulsioni, paresi, afasia, ictus, gravi lesioni cerebrali, demenza, morbo di Parkinson, malattia cerebellare, sindrome cerebrale organica, psicosi 3. LLA attiva nel SNC o nei testicoli 4. Malattia autoimmune in corso o anamnesi positiva di malattia autoimmune con potenziale interessamento del SNC 5. HSCT autologo entro sei settimane prima dell'inizio del trattamento con blinatumomab 6. HSCT allogenico nei tre mesi precedenti l'inizio del trattamento con blinatumomab 7. Qualsiasi malattia da trapianto verso ospite (GvHD) attiva acuta o GvHD cronica attiva di Grado 2-4 8. Terapia immunosoppressiva contro GvHD entro due settimane prima dell'inizio del tratta-mento con blinatumomab 9. Chemioterapia nelle due settimane precedenti l'inizio del trattamento con blinatumomab (la profilassi intratecale e il pre-trattamento con desametasone sono consentiti prima dell’inizio del trattamento con blinatumomab) 10. Radioterapia entro quattro settimane dall'inizio del trattamento con blinatumomab 11. Immunoterapia (ad esempio, rituximab) entro quattro settimane prima dell'inizio del trat-tamento con blinatumomab 12. Qualsiasi prodotto sperimentale anti-leucemico entro quattro settimane dall'inizio del trat-tamento con blinatumomab 13. Trattamento con qualsiasi altro medicinale sperimentale (IMP) dopo la firma del consenso informato 14. Ipersensibilità alle immunoglobuline o a qualsiasi altro componente della formulazione dell’IMP 15. Valori di laboratorio anormali di seguito definiti: a. AST (SGOT) e/o ALT (SGPT) e/o FALC ≥5 volte il limite superiore del range di normalità (ULN) b. Bilirubina totale ≥1,5 volte l’ULN (a meno che non sia presente un Gilbert o la malattia di Meulengracht) c. Creatinina ≥1,5 volte l'ULN o clearance della creatinina <50 ml/min (calcolata) d. Emoglobina (Hb) ≤9 g/dl (trasfusione consentita) 16. Neoplasie attive che richiedono un trattamento diverso dalla LLA nei due anni precedenti l'inizio del trattamento con blinatumomab con l'eccezione di carcinoma a cellule basali o a cellule squamose della pelle, o carcinoma in situ della cervice 17. Infezione attiva non controllata, o qualsiasi altra malattia concomitante o condizione medi-ca che si ritiene possa interferire con l'esecuzione dello studio in base al giudizio dello speri-mentatore 18. Infezione da virus dell'immunodeficienza umana (HIV) o infezione cronica da virus dell'e-patite B (HBsAg positivo) o C (anti-HCV positivi) 19. Donne in gravidanza o in allattamento 20. Donne in età fertile che non vogliono utilizzare una forma efficace di contraccezione du-rante la partecipazione allo studio e almeno nei tre mesi successivi. Pazienti di sesso maschile non disposti a garantire di non generare un figlio durante la partecipazione allo studio e almeno nei tre mesi successivi 21. Precedente trattamento con blinatumomab

E.5 End points

E.5.1

Primary end point(s)

CR (Complete response/remission)+CRh* (Complete response/remission with partial recovery of peripheral blood counts)rate within two cycles of treatment with blinatumomab

Tasso di RC (Risposta/remissione completa)+RCh* (risposta/remissione completa con recupero parziale della conta del sangue periferico) entro due cicli di trattamento con blinatumomab

E.5.1.1

Timepoint(s) of evaluation of this end point

At screening and at the end of each treatment cycle a bone marrow aspiration/biopsy will be performed to evaluate the efficacy of blinatumomab. Following the last treatment cycle, there will be efficacy follow-up visits at three, six, nine, 12, 18 and 24 months after treatment start for patients who did not undergo allogenic HSCT.

Al momento di screening e alla fine di ogni ciclo di trattamento un'aspirazione/biopsia del midollo osseo sarà praticata per valutare l'efficacia del blinatumomab. Successivamente all'ultimo ciclo di trattamento, ci sarà una visita di follow-up pee valutare l'efficacia a 3,6,9,12,18 e 24 mesi dopo l'inizio del trattamento per pazienti che non hanno praticato un HSCT allogenico.

E.5.2

Secondary end point(s)

1.Duration of CR and CRh* 2.Proportion of patients eligible for allogenic HSCT whi undergo the procedure after treatment with blinatumomab 3.CR rate within two cycles of treatment with blinatumomab 4.CRh*rate within two cycles of treatment with blinatumomab 5.PR rate within two cycles of treatment with blinatumomab 6.Relapse-free survival 7.Overall survival 8.Overall incidence and severity of AEs 9.100-day mortality after allogenic HSCT 10.Pharmacokinetic parameters:steady state concentration of blinatumomab 11.Serum cytokine concentration

1.Durata della RC/RCh* 2.Percentuale di pazienti eleggibili per HSCT allogenico che si sottopongono alla procedura dopo trattamento con blinatumomab 3.Tasso di RC entro due cicli di trattamento con blinatumomab 4.Tasso di RCh* entro due cicli di trattamento con blinatumomab 5.Tasso di RP entro due cicli di trattamento con blinatumomab 6.Sopravvivenza libera da recidiva 7.Sopravvivenza globale 8.Incidenza complessiva e gravità degli EA 9.Mortalità a 100 giorni dopo HSCT allogenico 10.Parametri farmacocinetici: concentrazione di blinatumomab allo steady state 11.Concentrazioni seriche di citochine

E.5.2.1

Timepoint(s) of evaluation of this end point

1.Assessment at the end of each treatment cycle (and optionally at day 15 of the first cycle) and during efficacy follow up (until 24 months after treatment start at most) 2.Until patient's last follow up (until 3 years after treatment start at most) 3-5. At the end of the first and second treatment cycle and optionally at day 15 of the first cycle 6-8. Throughout entire study, until three years after treatment start at most 9. 100 days after HSCT, if applicable 10-11. At baseline and during the first two treatment cycles. Exploratory endpoints 1-2.At the end of each treatment cycle (and optionallt at day 15 of the first cycle) 3. At baseline, during the first two treatment cycles, and during efficacy follow-up (2 years after treatment start at most)

1.Valutazione alla fine di ogni ciclo di trattamento (opzionale al giorno 15 del primo ciclo)e durante il follow-up di efficacia (max fino a 24 mesi dopo l'inizio trattamento)2.Fino all'ultima visita di follow-up del paziente (masx fino a 3 anni dopo l'inizio trattamento)3-5.Alla fine del primo e del secondo ciclo di trattamento e opzionale al giorno 15 del primo ciclo 6-8. Durante tutta la durata dello studio, max fino a 3anni dall'inizio trattamento 9. 100 giorni dopo il HSCT,se applicabile 10-11.Al basale e durante i primi 2 cicli di trattamento. Endpoint esplorativi 1-2.Alla fine di ogni ciclo di trattamento (opzionale al giorno 15 del primo ciclo) 3.Al basale, durante i primi 2 cicli di trattamento e durante il follow-up di efficacia(max dopo2anni da inizio trattamento)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised