Clinical Trials Register

Summary
EudraCT Number:	2011-004672-11
Sponsor's Protocol Code Number:	SNOXA12C201
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:	2012-03-08
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

2011-004672-11

A.3

Full title of the trial

A multi-centre, open label, uncontrolled, Phase IIa clinical trial evaluating the safety and efficacy of NOX-A12 in combination with a background therapy of bendamustine and rituximab (BR) in previously treated patients with chronic lymphocytic leukemia (CLL)

A.3.1

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

A clinical trial of NOX-A12 in patients with chronic lymphocytic leukemia who have been previously treated and who will be receiving bendamustine and rituximab treatment

Studio clinico su NOX-A12 in pazienti con leucemia linfocitica cronica precedentemente trattati e che stanno per ricevere un trattamento con bendamustina e rituximab

A.3.2

Name or abbreviated title of the trial where available

NOX-A12 with a background therapy of bendamustine and rituximab in CLL

NOX-A12 with a background therapy of BR in CLL

A.4.1

Sponsor's protocol code number

SNOXA12C201

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	NOXXON PHARMA 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	NOXXON Pharma 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	AMS Advanced Medical Services
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	500 Chiswick High Road
B.5.3.2	Town/ city	Londra
B.5.3.3	Post code	W4 5RG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 020 8956 2606
B.5.5	Fax number	+44 020 8956 2358
B.5.6	E-mail	ams@ams-europe.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	NOX-A12
D.3.2	Product code	NOX-A12
D.3.4	Pharmaceutical form	Solution for injection
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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NOX-A12
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	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	14.66
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
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

Relapsed chronic lymphocytic leukemia

Leucemia linfocitica cronica recidivante

E.1.1.1

Medical condition in easily understood language

Chronic lymphocytic leukemia which has been previously treated and disease has returned

Leucemia linfociticca cronica che è stata precedentemente trattata ma è ricomparsa

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10008958
E.1.2	Term	Chronic lymphocytic leukaemia
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 assess the safety and tolerability of NOX-A12 alone (pilot group only) and in combination with BR. To determine the complete remission (CR) rate.

Valutare la sicurezza e la tollerabilità di NOX-A12 da solo (solo gruppo pilota) e in associazione a BR. Determinare il tasso di remissione completa (CR).

E.2.2

Secondary objectives of the trial

To determine the effect of NOX-A12 alone and combined with BR on the mobilization of peripheral blood CD34+ cells and CLL cells. To determine the overall response rate (ORR=CR + PR) rate. To determine time to event endpoints such as progression free survival (PFS), event free survival (EFS), time to progression (TTP), duration of response (DOR) and overall survival (OS) after treatment with NOX-A12 in combination with BR. To determine the plasma concentration of SDF-1 after treatment with NOX-A12 alone (pilot group only) and in combination with BR. To determine the pharmacokinetics of NOX-A12 alone (pilot group only) and in combination with BR.

• Determinare l'effetto di NOX-A12 da solo e in associazione a BR sulla mobilitazione delle cellule CD34+ e delle cellule LLC al sangue periferico. • Determinare il tasso di risposta generale (ORR = CR + PR). • Determinare il tempo di eventi endpoint quali il tasso di sopravvivenza senza progressione della malattia (PFS), il tasso di sopravvivenza senza eventi patologici (EFS), il tempo alla progressione (TTP), la durata della risposta (DOR) e la sopravvivenza globale (OS) in seguito a trattamento con NOX-A12 in associazione a BR. • Determinare la concentrazione plasmatica di SDF-1 in seguito al trattamento con NOX-A12 da solo (solo gruppo pilota) e in associazione a BR. • Determinare le caratteristiche farmacocinetiche di NOX-A12 da solo (solo gruppo pilota) e in associazione a BR.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male of female, age ≥18 2. Diagnosis of B cell CLL 3. Relapsed, bendamustine-sensitive (response duration of at least 6 months as assessed by prior treating physician) or bendamustine-naive patients after at least one but not more than 3 prior treatment of their disease. 4. CLL in need of treatment (Binet C or A/B with active disease) according to the IWCLL guidelines 5. Subject must have measurable disease according to IWCLL guidelines 6. Pre-study WHO performance status of ≤2 and modified cumulative illness rating scale (CIRS) of less than 7 7. Signed and dated, written informed consent 8. Men and women of reproductive potential must agree to follow accepted birth control methods during treatment and for 3 months after completion of treatment 9. Acceptable liver function at screening: bilirubin ≤1.5 x ULN, AST and/or ALT ≤2.5 x ULN 10. Acceptable heamatological status: platelet count ≥75 x10 9/L, ANC > 0.75 x 10 9/L 11. Acceptable renal function: serum creatinine ≤1.5 ULN and/or creatinine clearance ≥50 ml/min (Cockcroft Gault formula) 12. No clinical significant abnormalities of liver volume, liver heamodynamics or elasticity, measured by abdominal ultrasound.

1. Diagnosi di leucemia linfocitica cronica ai danni delle cellule B. 2. Pazienti recidivanti, sensibili alla bendamustina (almeno risposta parziale con una durata di almeno sei mesi) o mai trattati con bendamustina in seguito ad almeno uno, ma non più di 3 precedenti trattamenti della loro malattia. 3. CLL bisognosi di cure (Binet C o A/B con malattia in fase attiva) secondo le linee guida IWCLL (Hallek et al 2008; Blood 111:5446-5456). 4. I soggetti devono presentare una malattia misurabile secondo i criteri IWCLL (per dettagli vedere Hallek et al.). 5. OMS performance status pre-studio ≤ 2 e indice di comorbidità modificato (CIRS) inferiore a 7. 6. Consenso informato scritto, firmato e datato. 7. Uomini e donne in età fertile devono accettare di seguire metodi di controllo delle nascite accettati durante il trattamento e per 3 mesi in seguito al completamento del trattamento. 8. Funzionalità epatica accettabile al momento dello screening: bilirubina ≤ 1,5 volte il limite superiore rispetto al valore normale (ULN), AST (SGOT) e/o ALT (SGPT) ≤ 2,5 x ULN. 9. Stato ematologico accettabile: conta piastrinica ≥ 75 x 109/l, ANC> 0,75x109/l. 10. Funzionalità renale accettabile: creatinina sierica ≤ 1,5 ULN e/o clearance creatinina calcolata (Cockroft - Gault Formula) ≥ 50 ml/min 11. Maschio o femmina, età ≥ 18 12. Nessuna anormalità clinicamente significativa del volume del fegato, dell'emodinamica o dell’elasticità epatica, misurate mediante ecografia addominale.

E.4

Principal exclusion criteria

1. Relapse of B-cell CLL within 6 months after last chemotherapy 2. Subjects who have progressed to more aggressive B-cell cancers such as Richter's syndrome 3. CLL with either deletion of the short arm of chromosome 17 (17p-) or mutations associated with the loss of p53 4. The subject has a history of or is clinically suspicious of cancer related CNS disease 5. Hyperleukocytosis of > 50,000 WBC/μL 6. Autoimmune hemolytic anemia 7. Prior allogeneic stem cell transplant or patients who are considered to be candidates for allo SCT as assessed by their treating physician 8. Patient has a history of other active malignancies within three years prior to study entry, with the exception of: adequately treated in situ carcinoma of the cervix uteri; basal or squamous cell carcinoma of the skin; in situ carcinoma of the bladder; previous malignancy confirmed and surgically resected with curative intent. 9. The patient exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to: uncontrolled systemic infection (viral, bacterial or fungal); diagnosis of fever and neutropenia within 1 week prior to study drug administration 10. Female subject is pregnant or breast feeding 11. Known infection with HIV, active Hepatitis B or Hepatitis C 12. The patient has a history of prior toxicity from bendamustine or rituximab that resulted in permanent discontinuation of treatments. 13. Treatment with other investigational drugs, or participation in another clinical trial within 30 days prior to study drug administration 14. Uncontrolled hypertension (defined as systolic blood pressure (BP) > 160 mmHg or diastolic BP >100mmHg) 15. Myocardial infarction or unstable angina within the past 6 months prior to study drug administration 16. Systemic illnesses or other severe concurrent disease including alcoholism which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and efficacy of the investigational treatment 17. Known or suspected of not being able to comply with the trial protocol 18. Having previously enrolled in this clinical trial

1. Recidiva di LLC a cellule B entro 6 mesi in seguito all’ultima chemioterapia. 2. Soggetti che hanno progredito a tumori più aggressivi delle cellule B, come la sindrome di Richter. 3. LLC con delezione del braccio corto del cromosoma 17 (17p-) o mutazioni associate alla perdita di p53. 4. Soggetti che hanno una storia di o sono clinicamente sospettati di essere affetti da malattie del Sistema Nervoso Centrale associate a cancro. 5. Iperleucocitosi > 50.000 GB/ml. 6. Anemia emolitica autoimmune. 7. Precedente trapianto allogenico di cellule staminali o pazienti che sono considerati candidati a trapianto allogenico di cellule staminali secondo valutazione del loro medico curante. 8. Pazienti che hanno una storia di altre neoplasie attive nei tre anni precedenti all'ingresso nello studio, ad eccezione di: carcinoma in situ della cervice uterina adeguatamente trattato; carcinoma basocellulare o squamoso della cute; carcinoma in situ della vescica; precedente neoplasia confinata e resecata chirurgicamente con intento curativo. 9. Pazienti che mostrano prova di altre condizioni clinicamente significative incontrollate ivi incluse, ma senza limitazione a: infezioni sistemiche incontrollate (virali, batteriche o fungine); diagnosi di febbre e neutropenia entro 1 settimana prima della somministrazione del farmaco oggetto dello studio. 10. Soggetti femminili in stato di gravidanza o in allattamento. 11. Infezione nota da HIV, epatite B o epatite C attive. 12. Pazienti che presentano una storia di precedente tossicità da bendamustina o rituximab che ha provocato l'interruzione permanente dei trattamenti. 13. Trattamento con altri farmaci sperimentali o partecipazione ad un altro studio clinico nei 30 giorni precedenti la somministrazione del farmaco oggetto dello studio. 14. Ipertensione non controllata (definita come pressione sistolica (BP)> 160 mmHg o pressione diastolica> 100 mmHg). 15. Infarto miocardico o angina instabile negli ultimi 6 mesi precedenti alla somministrazione del farmaco oggetto dello studio. 16. Malattie sistemiche o altre gravi malattie concomitanti tra cui l'alcolismo che, a giudizio dello sperimentatore, renderebbe il paziente inadeguato per l'ingresso nello studio o interferirebbe significativamente con la corretta valutazione della sicurezza e dell'efficacia dei trattamenti oggetto dello studio. 17. Pazienti dei quali è noto o si sospetta non siano in grado di rispettare il protocollo della sperimentazione. 18. Pazienti che sono stati precedentemente arruolati in questo studio clinico.

E.5 End points

E.5.1

Primary end point(s)

Safety the safety evaluation will be based on the following assessments: - adverse events - vital signs - 12 lead ECG - laboratory parameters (CBC, platelets, differential WBC count, serum chemistry, coagulation parameters, urinalysis) - immunogenicity - physical examinations Remission Rates Assessment of overall tumour response - as measured by lymphadenopathy, splenamegaly, hepatomegaly, bone marrow cell counts, peripheral platelet and neutophil counts and heamoglobin measurements.

Sicurezza: La valutazione della sicurezza si baserà sulle seguenti valutazioni: • eventi avversi • segni vitali • ECG a 12 derivazioni • parametri di laboratorio (emocromo, piastrine, conta differenziale dei leucociti, parametri chimici nel siero, coagulazione, esame delle urine) • immunogenicità • esame obiettivo Tassi di remissione Valutazione della risposta generale del tumore - come misurata da linfoadenopatia, splenomegalia, epatomegalia, conta cellulare del midollo osseo, conta di piastrine e neutrofili periferici e misurazioni dell'emoglobina.

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety - throughout the treatment period and for 30 days post last dose Efficacy - at the end of Cycle 3 and Cycle 6 of treatment

Sicurezza - durante il periodo di trattamento e per 30 giorni dopo l'ultima dose Efficacia - alla fine del Ciclo 3 e del Ciclo 6 di trattamento

E.5.2

Secondary end point(s)

mobilization of CD34+ and CLL cells
immunophenotyping and cell surface antigens of disease assessment, as per the primary endpoint
survival free of disease
death
pharmacokinetic analysis of SDF-1 in plasma
pharmacokinetic analysis of NOX-A12 in plasma

- mobilitazione delle cellule CD34+ e delle cellule LLC
- immunofenotipo e antigeni delle cellule CD34+ e delle cellule CLL
- valutazione della malattia, come da endpoint primario
- sopravvivenza libera da malattia
- decesso
- analisi farmacocinetica di SDF-1 nel plasma
- analisi farmacocinetica di NOX-A12 nel plasma

E.5.2.1

Timepoint(s) of evaluation of this end point

Characterisation of circulating blood cells - Pilot group only - Day 1,2 and
4 post first dose. All patients - Day 1 and 2, Cycle 1 and 4

Pharmacokinetic analysis - Pilot group only - Day 1, 2 and 4 post first
dose. All patients - Day 1 Cycle 1 and 4

Progression - 12 weekly intervals for 30 months post end of treatment

Caratterizzazione delle cellule nel sangue - Solo gruppo pilota - Giorno 1, 2 e 4 dopo la prima dose. Tutti i pazienti - Giorno 1 e 2, Cicli 1 e 4

Analisi farmacocinetica - Solo gruppo pilota - Giorno 1, 2 e 4 dopo la prima dose. Tutti i pazienti - Giorno 1 Cicli 1 e 4

Progressione - intervalli di 12 settimane per 30 mesi dopo la fine del 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

Yes

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

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

The end of the trial will be the date of the last patient last contact in
the expansion phase of the trial

La fine dello studio coinciderà con la data dell'ultimo contatto dell'ultimo paziente nella fase di espansione dello studio.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Following completion of up to 6 cycles of NOX-A12 treatment prior to
the receipt of BR, patients will continue under normal local treatment
practices. Patients who have experienced a response will be followed
for the duration of their response, but may receive any care - including
transplantation - which may be available to them locally.

A seguito del completamento del trattamento fino a 6 cicli con NOX-A12 prima di ricevere BR, i pazienti continueranno a seguire la normale pratica clinica locale. I pazienti che hanno ottenuto risposta saranno seguiti per la durata della loro risposta, ma potranno ricevere qualsiasi cura - incluso il trapianto - che sia disponibile per loro localmente.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-02-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-04-24

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