Clinical Trials Register

Summary
EudraCT Number:	2011-004651-40
Sponsor's Protocol Code Number:	SNOXA12C301
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

2011-004651-40

A.3

Full title of the trial

A multi-center, open label, uncontrolled, Phase IIa clinical trial evaluating the safety and efficacy of NOX-A12 in combination with a background therapy of bortezomib and dexamethasone (VD) in previously treated patients with multiple myeloma (MM)

A multi-center, open label, uncontrolled, Phase IIa clinical trial evaluating the safety and efficacy of NOX-A12 in combination with a background therapy of bertozemib and dexamethasone (VD) in previously treated patients with multiple myeloma (MM)

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 multiple myeloma who have previously been treated and who will be receiving bortezomib and dexamethasone treatment

Studio clinico di NOX-A12 in pazienti con mieloma multiplo precedentemente trattati e che ricevereanno un trattamento con bortezomib e desametasone

A.3.2

Name or abbreviated title of the trial where available

NOX-A12 in combination with bortezomib and dexamethasone in Multiple Myeloma

NOX-A12 in combinazione con bortezomib e desametas

A.4.1

Sponsor's protocol code number

SNOXA12C301

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	London
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	NA
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 multiple myeloma

Mieloma multiplo recidivante

E.1.1.1

Medical condition in easily understood language

Multiple Myeloma which ha been previously treated nad disease has returned

Mieloma multiplo precedentemente trattato e che è ricomparso

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	10028228
E.1.2	Term	Multiple myeloma
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 VD

To determine the overall response rate according to IMWG uniform
response criteria (ORR = best response at least partial response(PR))

Valutare la sicurezza e la tollerabilità di NOX-A12 da solo (solo gruppo pilota) e in associazione a VD

Determinare il tasso di risposta generale (ORR = migliore risposta almeno alla risposta parziale (PR))

E.2.2

Secondary objectives of the trial

• To determine the effect of NOX A12 alone and in combination with VD
on the mobilization of peripheral blood CD34+ cells, plasma cells and
myeloma cells
• To determine additional response criteria adopted from the EBMT
criteria such as minor response (MR), immunophenotypic CR and
molecular CR after treatment with NOX-A12 combined with VD
• To determine time to event endpoints such as progression free survival
(PFS), time to progression (TTP) and duration of response (DOR) after
treatment with NOX A12 combined with VD
• To determine the plasma concentration of SDF-1 after treatment with
NOX-A12 alone (pilot group only) and in combination with VD
• To determine the pharmacokinetics of NOX A12 alone (pilot group
only) and in combination with VD

• Determinare l'effetto di NOX-A12 da solo e in associazione a VD sulla mobilitazione delle cellule CD34+, delle plasmacellule e delle cellule mielomatose al sangue periferico.
• Determinare criteri di risposta aggiuntivi, quali risposta minore (MR), risposta completa immunofenotipica e risposta completa molecolare dopo il trattamento con NOX-A12 in associazione a VD.
• Determinare il tempo di eventi endpoint quali il tasso di sopravvivenza senza progressione della malattia (PFS), il tempo alla progressione (TTP) e la durata della risposta (DOR) in seguito al trattamento con NOX-A12 in associazione a VD.
• Determinare la concentrazione plasmatica di SDF-1 in seguito al trattamento con NOX-A12 da solo (solo gruppo pilota) e in associazione a VD.
• Determinare le caratteristiche farmacocinetiche di NOX-A12 da solo (solo gruppo pilota) e in associazione a VD.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Male or female, aged ≥ 18 years
2.Diagnosis of relapsed multiple myeloma for which
bortezomib/dexamethasone would be given as standard of care.
3.Bortezomib-naïve or bortezomib-sensitive patient (i.e. best response
of PR or better, sus-tained for at least 6 months), who did not receive
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bortezomib during the last line of therapy for MM prior to this study.
4.Progressive disease according to International Myeloma Working
Group criteria.
5.Pre-study WHO Performance Status ≤ 2 and modified CIRS score of
less than 7
6.Signed and dated, written informed consent.
7.Men and women of reproductive potential must agree to follow
accepted contraception methods during treatment and for 3 months
after completion of treatment.
8.Acceptable liver function: Bilirubin ≤ 1.5 x upper limit of normal (ULN),
AST (SGOT) and ALT (SGPT) ≤ 2.5 ULN at screening.
9.Acceptable hematology and hemostasis status: Platelet count ≥ 75 x
109/L, ANC > 0.75x109/L.
10.Acceptable renal function: Serum creatinine ≤1.5 ULN and/or
calculated creatinine clearance ≥ 50 mL/min (calculated according to
Cockroft & Gault formula).
11.No clinically significant abnormalities of liver volume, liver
hemodynamics or elasticity, measured by abdominal ultrasound.

1. Maschio o femmina, di età ≥ anni 18.
2. Diagnosi di mieloma multiplo recidivo per la quale il bortezomib o il desametasone sarebbe somministrato come standard di cura.
3. Pazienti mai trattati precedentemente con bortezomib o sensibili al bortezomib (ovvero risposta migliore di PR o superiore, mantenuta per almeno 6 mesi) che non hanno ricevuto bortezomib durante l'ultima linea di terapia per MM prima del presente studio.
4. Malattia progressiva secondo i criteri dell'International Myeloma Working Group.
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: bilirubina ≤ 1,5 volte il limite superiore rispetto al valore normale (ULN), AST (SGOT) e ALT (SGPT) ≤ 2,5 ULN al momento dello screening.
9. Ematologia e stato emostasi accettabili: conta piastrinica ≥ 75 x 109/l, ANC> 0,75x109/l.
10. Funzionalità renale accettabile: creatinina sierica ≤ 1,5 ULN e/o clearance creatinina calcolata ≥ 50 ml/min (calcolato in base alla formula di Cockroft e Gault).
11. Nessuna anormalità clinicamente significativa del volume del fegato, dell'emodinamica epatica o dell'elasticità, misurate mediante ecografia addominale.

E.4

Principal exclusion criteria

1.The patient has a history of, or is clinically suspicious for, cancerrelated Central Nervous System disease.
2.Prior allogeneic stem cell transplant (alloSCT) or patients who are
considered to be candidates for alloSCT as assessed by their treating
physician.
3.Patient has a history of other active malignancies within 3 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 confined and
surgically resected with curative intent.
4.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.
5.Female patient is pregnant or breast-feeding.
6.Known infection with HIV, active Hepatitis B or Hepatitis C.
7.The patient has a history of prior toxicity from bortezomib or
dexamethasone that resulted in permanent discontinuation of respective
treatments.
8.Clinical evidence of a current significant (grade 2 or higher) or
progressive neuropathy.
9.Treatment with any other investigational agent, or participation in
another clinical trial within 30 days prior to study drug administration.
10.Uncontrolled hypertension (defined as systolic blood pressure [BP] >
160 mm Hg or diastolic BP > 100 mm Hg).
11.Myocardial infarction or unstable angina within the past 6 months
prior to study drug administration.
12.Evidence of bleeding diathesis (greater than normal risk of bleeding)
or coagulopathy (in the absence of therapeutic anticoagulation).
13.Systemic illnesses or other severe concurrent disease or 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
treatments.
14.Known or suspected of not being able to comply with the trial
protocol.
15.Having been previously enrolled in this clinical trial.

1. Soggetti che hanno una storia di o sono clinicamente sospettati di essere affetti da malattie del Sistema Nervoso Centrale associate a cancro.
2. Precedente trapianto allogenico di cellule staminali (alloSTC) o pazienti che sono considerati candidati ad alloST secondo valutazione del loro medico curante.
3. Pazienti che hanno una storia di altre neoplasie attive nei 3 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.
4. 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.
5. Soggetti femminili in stato di gravidanza o in allattamento.
6. Infezione nota da HIV, epatite B o epatite C attive.
7. Pazienti che presentano una storia di precedente tossicità da bortezomib o desametasone che ha provocato l'interruzione permanente dei rispettivi trattamenti.
8. Evidenza clinica di una neuropatia corrente significativa (grado 2 o superiore) o progressiva.
9. Trattamento con altri farmaci sperimentali o partecipazione a un altro studio clinico nei 30 giorni precedenti alla somministrazione del farmaco oggetto dello studio.
10. Ipertensione non controllata (definita come pressione sistolica (BP)> 160 mmHg o pressione diastolica> 100 mmHg).
11. Infarto miocardico o angina instabile negli ultimi 6 mesi precedenti alla somministrazione del farmaco oggetto dello studio.
12. Evidenza di diatesi emorragica (superiore al normale rischio di sanguinamento) o coagulopatia (in assenza di terapia anticoagulante).
13. 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.
14. Pazienti che è noto o si sospetta non siano in grado di rispettare il protocollo della sperimentazione.
15. 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 ECGs
• laboratory parameters (CBC, platelets, differential WBC count, serum
chemistry, coagulation parameters, urinalysis)
• immunogenicity
Efficacy
Assessment of the overall tumor response - as measured by serum free
light chain, serum and urinary M-protein, clonal plasma cell counts in
blood and bone marrow, plasmacytoma size measurements and
prescence of bone lesions.

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, esame delle urine)
• immunogenicità

Efficacia
La valutazione della risposta tumorale complessiva - come misurata da catena libera leggera su siero, proteina-M su siero e su urine, conte cellulari plasmatiche clonali nel sangue e nel midollo osseo, valutazione dell'estensione del plasmocitoma e presenza di lesioni nel midollo.

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 4 and cycle 8.

Sicurezza - durante il periodi di trattamento e per 30 giorni dopo l'ultima dose

Efficacia - alla fin dei Cicli 4 e 8

E.5.2

Secondary end point(s)

• mobilisation of CD34+ cells, plasma cells and myeloma cells
• immunophenotyping of CD34+ cells, plasma cells and myeloma cells
• survival free of disease
• pharmacokinetic analysis of SDF-1 in plasma
• pharmacokinetic analysis of NOX-A12 in plasma

- mobilitazione delle cellule CD34+, delle plasmacellule e delle cellule del mieloma
- immunofenotipo delle cellule CD34+, delle plasmacellule e delle e delle cellule del mieloma
- sopravvivenza libera da malattia
- 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

Characteristation of blood circulating cells - Pilot group - Day1,2 and 4
post dose. All patients - Day 1 and 2 Cycle 1 and 4.

SDF-1 and NOX-A12 pharmacokinetic analysis - pilot group Day 1,2 and 4
post dose. With VD - Day1,4,8,11 and 21 of Cycle 1 and 4.

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 di SDF-1 e di NOX-A12 - Gruppo pilota Giorni 1, 2 e 4 post dose. Con VD - Giorni 1, 4, 8, 11 e 21 dei Cicli 1 e 4.

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

End of Trial will be the date of the Last Patient Last Visit in the follow up period for the expansion part of the trial.

LVLS del periodo di follow up per la parte 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 upto 8 cycles of NOX-A12 treatment prior to
the receipt of VD, patients will continue under normal local tratment
practices. Patients who have experienced a response will be followed
for the duration of their response, but may recieve any care - including
transplantation - which may be available to them locally.

A seguito del completamento del trattamento fino a 8 cicli con NOX-A12 prima di ricevere VD, 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	2015-09-30

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