Clinical Trials Register

Summary
EudraCT Number:	2013-005387-25
Sponsor's Protocol Code Number:	noprofit1616
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-01-07
Trial 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

2013-005387-25

A.3

Full title of the trial

Phase 2a Study of an Immunotherapeutic Vaccine, DPX-Survivac, Alone or with Low dose Cyclophosphamide in Primary Glioblastoma Patients Receiving Standard of Care Therapy

A.3.1

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

A.4.1

Sponsor's protocol code number

noprofit1616

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	Sapienza, University of Rome
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Sapienza, University of Rome
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sapienza, University of Rome
B.5.2	Functional name of contact point	Marianna Nuti
B.5.3	Address:
B.5.3.1	Street Address	Viale Regina Elena 324
B.5.3.2	Town/ city	Rome
B.5.3.3	Post code	00161
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390649973029
B.5.5	Fax number	+390649973029
B.5.6	E-mail	marianna.nuti@uniroma1.it

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	Yes
D.2.1.1.1	Trade name	DPX-SURVIVAC
D.2.1.1.2	Name of the Marketing Authorisation holder	Biotec Services International Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	DPX-Survivac
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	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DPX-SURVIVAC
D.3.9.3	Other descriptive name	SURVIVAC
D.3.9.4	EV Substance Code	SUB31461
D.3.10	Strength
D.3.10.1	Concentration unit	ml millilitre(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.1 to 0.5
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)	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	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

Glioblastoma is the most common primary brain tumour in humans with
the most severe prognosis. Standard treatments consist primarily of
surgery in order to debulk thetumoral mass, as well as
radiochemotherapy to induce optimal local tumor control. However the
median overall survival (OS)is about 15 months, with 88% of patients
dead within 3 years

il glioblastoma è il tumore cerebrale più diffuso, associato ad una
prognosi infausta. I trattamenti standard sono rappresentati dalla
chirurgia che permette di eradicare la massa tumorale e la radiochemioterapia
per il controllo della crescita tumorale. La sopravvivenza
media è di circa 15 mesi, con l'88% di decessi entro i 3 anni.

E.1.1.1

Medical condition in easily understood language

Glioblastoma is a malignant brain tumor, invasive, fast-growing and poor
prognosis. Glioblastoma can be of primitive type or manifest as the
processing of other brain tumors (secondary type).

il glioblastoma è un tumore maligno del cervello, invasivo, a rapida
crescita e prognosi infausta. può essere di tipo primitivo o manifestarsi
come trasformazione di altri tumori cerebrali.

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	18.0
E.1.2	Level	HLT
E.1.2	Classification code	10045172
E.1.2	Term	Tumour vaccine therapies
E.1.2	System Organ Class	100000004865

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

The rationale of this study is to investigate the efficiency of survivin vaccines (with adjuvant ) to stimulate specific anti tumor immunity and decrease immunosuppression in GBM patients and potentially affect overall survivall and to assess the need of the addition of cyclophoshamide for the optimal immune activation.
Primary endpoint is the activation of the immune response in vaccinated patients.
A 2-fold increase of specific T cells activation will be considered positive.

E.2.2

Secondary objectives of the trial

Increase of OS and PFS (secondary endpoints) in GBM patients treated with gold standard after the administration of Depovax alone or in association with a metronomic dose of Cyclophosphamide.
To assess the safety profile of subcutaneous administration of DPX Survivac alone or with low dose oral cyclophosphamide

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Primary or recurrent histologically confirmed GBM after surgery
2.Total or subtotal (at least 90%) resection of tumour mass, confirmed by assessment of neurosurgeon and postoperative magnetic resonance imaging (MRI) within 48 hours
3.Ages 18 to 70 years old
4.Postoperative Karnofsky Performance Status (KPS) ≥70
5.A life expectancy > 6 months
6.Adequate hematologic, renal and hepatic function
7.Fertile subjects must use acceptable birth control from screening until the last study visit or early termination. Acceptable methods of birth control include: spermicide with condom, diaphragm, or cervical cap, IUD (intrauterine device), hormonal contraception, vasectomy, and abstinence. (Plan B or the rhythm method are not considered reliable methods.)
8.Willing and able to provide written informed
9.Ability to comply with protocol requirements

E.4

Principal exclusion criteria

1.Past or ongoing documented autoimmune diseases
2.HIV, syphilis, active HBV and HCV infection
3.Any medical disorder that would impair the ability to receive study treatment
4.Other active of in the past five years malignancies
5.Any unresolved chronic toxicity greater than Grade 2 (NCI-CTCAE version 4.03) from previous anticancer therapy (except alopecia)
6.Pregnant or breast feeding patients
7.Documented immune deficiency
8.Lymphodemia in the region to be vaccinated
9. Mandatory treatment with corticosteroids or salicylates in inflammatory dose

E.5 End points

E.5.1

Primary end point(s)

The activation of the immune response in vaccinated patients as primary endpoint will be considered postive with a value corresponding to a 2-fold increase of specific T cells activation.

The parameters evaluated will be:
•Specific populations of CD4+ and CD8+ T Lymphocytes activated by survivin (primary endpoint)
•Modulation of immunosuppressive cellular populations (Tregs, TAM-M2, MDSC)
•Epitope spreading phenomenon vaccine-induced (against tumor lysate or others TAAs)
•Immunogenic death, evaluated by specific markers such as Calreticulin, HSP70,90 and HMGB1.
Immune system will be investigated for the following readout:
1. Determine if standard therapies performed in conjunction with vaccination increase immune activation;
2. Define if standard treatments with or without survivin vaccination can be effective in reducing immunosuppression (Tregs);
3. Identify biological markers to monitor response to therapy and disease progression;
4. Define the optimal vaccination schedule according to the immunological status of patient.

E.5.1.1

Timepoint(s) of evaluation of this end point

A venous blood sample (50ml) will be collected from all patients before the following steps:
1.At enrolment(study day 0)
2.At the beginning of vaccine treatment.(study day 21)
3.At the study day 42 (last dose of priming phase)
4.At the study day 119
5.At the study day 168
6.At the study day 224
7.At 2 weeks post the last vaccine injection (study day 280)

E.5.2

Secondary end point(s)

Increase of OS and PFS (secondary endpoints) in GBM patients treated with gold standard (Stupp, NEJM 2005) after the administration of Depovax alone or in association with a metronomic dose of Cyclophosphamide.
To assess the safety profile of subcutaneous administration of DPX Survivac alone or with low dose oral cyclophosphamide

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoints of evaluation of OS (overall survival) and PFS (progression
free survival) will be investigated during the follow up at the time:
- one month after treatment end.
- three months after treatment end.
- six months after treatment end.
- nine months after treatment end.
- twelve months after treatment end.

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

E.6.7

Pharmacodynamic

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

Yes

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

Yes

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.5

The trial involves multiple Member States

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 trial includes patients affected by primary and recurrent GBM.Patients will not be deprived of today's best care available.GBM patients are often young adults with no co-morbidity and have no possibility of care and very limited time to progression and overall survival.The psicological impact of utilizing vaccines to induce self
activation of their own immune system is strong together with the
knowledge that this is carried out with no important side effects and
optimal quality of life

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 months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

patients will be evaluated after treatment by clinical and instrumental
controls.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Sapienza, university of Rome
G.4.3.4	Network Country	Italy

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-05-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-13

P. End of Trial
P.	End of Trial Status	Ongoing

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