Clinical Trials Register

Summary
EudraCT Number:	2012-003618-15
Sponsor's Protocol Code Number:	IRFMN-GBM-6272
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:	2013-07-19
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

2012-003618-15

A.3

Full title of the trial

Multicenter, randomized, non-comparative, open-label phase II trial on the efficacy of Ortataxel and Fotemustine in recurrent glioblastoma

Studio clinico multicentrico, italiano, randomizzato, non-comparativo, in aperto, di fase II per valutare l’efficacia di Ortataxel e Fotemustina nel trattamento della recidiva di glioblastoma

A.3.1

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

Italian study on the efficacy of Ortataxel in recurrent Glioblastoma

Studio italiano volto a valutare l'efficacia del farmaco Ortataxel nel trattamento del glioblastoma recidivato

A.4.1

Sponsor's protocol code number

IRFMN-GBM-6272

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	IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri"
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	Spectrum Pharmaceuticals
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Istituto di Ricerche Farmacologiche "Mario Negri"
B.5.2	Functional name of contact point	unità coordin. conduz. e monitor.
B.5.3	Address:
B.5.3.1	Street Address	via La Masa
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20156
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390239014650
B.5.5	Fax number	00390233200231
B.5.6	E-mail	elena.biagioli@marionegri.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	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.3.2	Product code	Ortataxel
D.3.4	Pharmaceutical form	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	Ortataxel
D.3.9.1	CAS number	186348-23-2
D.3.9.3	Other descriptive name	Ortataxel
D.3.9.4	EV Substance Code	SUB36059
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
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	Yes
D.3.11.13.1	Other medicinal product type	antineoplastic agent
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Muphoran
D.2.1.1.2	Name of the Marketing Authorisation holder	Italfarmaco
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.2	Product code	Fotemustine
D.3.4	Pharmaceutical form	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	FOTEMUSTINE
D.3.9.1	CAS number	92118-27-9
D.3.9.4	EV Substance Code	SUB07809MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
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	Yes
D.3.11.13.1	Other medicinal product type	antineoplastic agent

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 in recurrence/progression after surgery (or biopsy), radiotherapy and chemotherapy with temozolomide

Glioblastoma in recidiva o progressione dopo chirurgia (o biopsia), radioterapia e chemioterapia con Temozolomide

E.1.1.1

Medical condition in easily understood language

Glioblastoma in recurrence/progression

Glioblastoma in recidiva o progressione

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of Ortataxel in terms of PFS-6, defined as the percentage of patients who are alive and progression free at 6 months after the randomization. Fotemustine will act as a calibration arm

Valutare l’efficacia di Ortataxel in termini di PFS-6, definita come la percentuale di pazienti che sono vivi e liberi da progressione dopo 6 mesi dalla data di randomizzazione. Il braccio con Fotemustina servirà da braccio di “calibrazione”.

E.2.2

Secondary objectives of the trial

To evaluate:
- percentage of survival patients after 9 months from the randomization.
- percentage of patients who are judged by the Investigators to have an objective response as determined by the RANO criteria.
- the treatment compliance.
- the safety profile.

- percentuale di pazienti che sono vivi a 9 mesi dalla data di randomizzazione.
- percentuale di pazienti che hanno risposta oggettiva secondo quanto determinato dai criteri RANO.
- La compliance al trattamento in studio
- Il profilo di sicurezza.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically confirmed GBM.
- GBM in recurrence/progression after surgery, standard radiotherapy and chemotherapy with Temozolomide.
- Imaging confirmation of first tumor progression or regrowth as defined by the RANO criteria.
- No more than one prior line of chemotherapy (Temozolomide).
- Recovery from the toxic effects of prior therapy.
- Patients who have undergone recent surgery for recurrent or progressive tumor are eligible provided that:
a) Surgery must have confirmed the recurrence.
b) A minimum of 14 days must have elapsed from the day of surgery to randomization. For core or needle biopsy, a minimum of 7 days must have elapsed prior to randomization.
c) Craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization.
- Age ≥ 18 years.
- Willingness and ability to provide written informed consent and to comply with the study protocol as judged by the investigator.
- Karnofsky-PS ≥ 60%.
- Stable or decreasing dose of corticosteroids within 5 days prior to randomization.

- Pazienti con glioblastoma
- Glioblastoma in recidiva o progressione confermato istologicamente alla prima recidiva dopo chirurgia, trattamento standard con radioterapia e Temozolamide.
- Conferma radiologica di progressione o recidiva in accordo ai criteri RANO.
- Non più di una precedente linea di chemioterapia (Temozolamide).
- Completa risoluzione di tutti gli effetti tossici delle terapie precedenti.
- Pazienti che hanno subito recentemente una chirurgia per recidiva o progressione del tumore sono eligibili se la chirurgia ha confermato la recidiva e sono trascorsi almeno 14 giorni dalla data di chirurgia alla data di randomizzazione. In seguito ad agobiopsia o agoaspirato sono sufficienti 7 giorni.
- Capacità di comprendere e rilasciare il consenso informato scritto per la partecipazione allo studio.
- Età ≥ 18 anni.
- Karnofsky-PS ≥ 60%.
- Dose di corticosteroidi stabile o in diminuzione nei 5 giorni precedenti la randomizzazione

E.4

Principal exclusion criteria

- Patients unable to undergo brain MRI scans with gadolinium (iv).
- Pre-existing peripheral neuropathy, grade ≥ 2.
- History of intracranial abscess within 6 months prior to randomization.
- Anticipation of need for major surgical procedure during the course of the trial.
- Treatment with enzyme inducing antiepileptic agents was not allowed. However, patients whose anticonvulsant was changed to a non-enzymeinducing antiepileptic drug were eligible for entry after a 1-week ‘‘washout’’ period.

- Pazienti che non possono essere sottoposti a risonanza magnetica (MRI) con gadolinio (via endovenosa) come mezzo di contrasto.
- Pre-esistente neuoropatia periferica di grado ≥ 2.
- Ascesso intracranico nei 6 mesi precedenti la randomizzazione. Procedura chirurgica maggiore programmata.
- Trattamento con agenti antiepilettici induttori enzimatici. Tuttavia, pazienti passati ad una terapia anticonvulsivante con un agente antiepilettico non induttore enzimatico sono eligibili dopo una settimana di “washout”

E.5 End points

E.5.1

Primary end point(s)

6-months progression-free survival (PFS-6), defined as the percentage of patients who are alive and progression free at 6 months after the randomization

PFS-6, definita come la percentuale di pazienti che sono vivi e liberi da progressione dopo 6 mesi dalla data di randomizzazione

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

E.5.2

Secondary end point(s)

PFS
OS-9
ORR
Dose-intensity
Percentage of patients with dose and/or time modifications
Percentage of premature withdrawals
Incidence, nature, severity and seriousness of AEs
Maximum toxicity grade experienced by each patient for each specific toxicity
Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity
Patients with at least a SAE
Patients with at least a serious adverse drug reaction (SADR)
Patients with at least a suspect unexpected serious adverse reaction (SUSAR).

PFS
OS-9
ORR
Dose di farmaco effettivamente somministrato per unità di tempo
Percentuale di pazienti che hanno avuto una modifica di dose e/o tempi
Percentuale di pazienti che si sono ritirati dallo studio
Incidenza, natura, severità e serietà di un AE
Massimo grado di tossicità avuta da ciascun paziente per ciascuna tossicità
Percentuale di pazienti con tossicità di grado 3-4
Pazienti con almeno un SAE
Pazienti con almeno un SADR
Pazienti con almeno un SUSAR

E.5.2.1

Timepoint(s) of evaluation of this end point

9 months

9 mesi

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

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

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

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

LVLS, at least 9 months after randomization

Ultima visita dell'ultimo paziente, almeno 9 mesi dopo la randomizzazione

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

100

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 treated as expected by the normal clinical practice

I pazienti verranno seguiti in base a quanto previsto dalla normale pratica clinica

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

2013-09-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-24

P. End of Trial
P.	End of Trial Status	Completed

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