Clinical Trials Register

Summary
EudraCT Number:	2010-018851-88
Sponsor's Protocol Code Number:	IPR/23
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-08-11
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

UK - MHRA

A.2

EudraCT number

2010-018851-88

A.3

Full title of the trial

NGR016: Randomized phase II study evaluating two doses of NGR-hTNF administered either as single agent or in combination with doxorubicin in patients with advanced soft-tissue sarcoma (STS)

A.3.1

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

Randomized study of NGR-hTNF given alone or in combination with doxorubicin in sarcoma patients

A.3.2

Name or abbreviated title of the trial where available

NGR016

A.4.1

Sponsor's protocol code number

IPR/23

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	MOLMED
B.1.3.4	Country	Italy
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	MOLMED
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	MOLMED S.p.A.
B.5.2	Functional name of contact point	Clinical development
B.5.3	Address:
B.5.3.1	Street Address	Centro direzionale Milano 2, Palazzo Canova
B.5.3.2	Town/ city	Segrate, Milano
B.5.3.3	Post code	20090
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390221277234
B.5.5	Fax number	+390221277239
B.5.6	E-mail	clinical.operations@molmed.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	NGR-hTNF
D.3.2	Product code	MM102
D.3.4	Pharmaceutical form	Concentrate 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	Other antineoplastic agents
D.3.9.2	Current sponsor code	MM102
D.3.10	Strength
D.3.10.1	Concentration unit	µg/µl microgram(s)/microlitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	180 to 200
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)	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	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.IMP: 2
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.2.5	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.3.4	Pharmaceutical form	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	DOXORUBICIN
D.3.9.1	CAS number	23214-92-8
D.3.9.4	EV Substance Code	SUB06391MIG
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	2
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	antracyclin

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

Locally advanced or metastatic Soft-tissue sarcoma in patients untreated or previously treated with one or more prior systemic
regimen.

E.1.1.1

Medical condition in easily understood language

Sarcoma patients

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	HLGT
E.1.2	Classification code	10041299
E.1.2	Term	Soft tissue sarcomas
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 the effect on progression-free survival
(PFS) of two NGR-hTNF doses administered either
as single agent or in combination with doxorubicin.

E.2.2

Secondary objectives of the trial

To determine the safety/toxicity profile of two NGRhTNF
doses given either as single agent or in
combination with doxorubicin.
To evaluate the effect on response rate (according to
RECIST criteria), disease control rate, and overall
survival.
To evaluate the effect on metabolic response rate (as
measured by FDG-PET).
To exploratively evaluate tumor response by
centralized review of changes in tumor density on CT
scan and/or perfusion/diffusion MRI.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients >=18 years

- Histologically-proven, locally advanced, or metastatic STS (excluding extraosseus Ewing sarcoma)

- Patients not amenable to surgery, radiotherapy, or combined-modality therapy with curative intent

- Patients untreated or previously treated with one or more systemic regimen

- ECOG Performance status 0-2 (Appendix A)

- At least one untreated (not previously irradiated) target lesion that could be measured in one dimension, according to RECIST criteria

- A life expectancy of 12 weeks or more

- Adequate baseline bone marrow, hepatic and renal function, defined as follows:
Neutrophils > 1.5 x 10^9/L and platelets > 100 x 10^9/L; Bilirubin < 1.5 x ULN;
AST and/or ALT < 2.5 x ULN in absence of liver metastasis or < 5 x ULN in presence of liver metastasis;
Serum creatinine < 1.5 x ULN;
Creatinine clearance (estimated according to Cockcroft-Gault formula, Appendix A) >= 50 ml/min

- Patients may have had prior treatment providing the following conditions are met before treatment start:
Surgery and radiation therapy: wash-out period of 14 days; Systemic therapy: wash-out period of 21 days

- Patients must give written informed consent

E.4

Principal exclusion criteria

- Patients may not receive any other investigational agents while on study

- Patients with myocardial infarction within the last six months, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication

- LVEF < 55% (only for patients candidate for doxorubicin treatment)

- Uncontrolled hypertension

- Prolonged QTc interval (congenital or acquired) > 450 ms

- History or evidence upon physical examination of CNS disease unless adequately treated (e.g., primary brain tumour, any brain metastasis, seizure not controlled with standard medical therapy) or history of stroke

- Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol

- Known hypersensitivity/allergic reaction to human albumin preparations or to any of the excipients

- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol

- Pregnancy or lactation. Patients - both males and females - with reproductive potential (i.e. menopausal for less than 1-year and not surgically sterilized) must practice effective contraceptive measures throughout the study. Women of childbearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to registration

E.5 End points

E.5.1

Primary end point(s)

The primary study endpoint is the Progression-Free Survival of 2 doses of NGR-hTNF administrated either alone or in combination with doxorubicin.

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 6 weeks

E.5.2

Secondary end point(s)

- On an ongoing basis: to determine the safety profile of two doses of NGR-hTNF given either alone or in combination with doxorubicin.

- Every 12 weeks after progression disease:to evaluate overall survival

Approximately every 6 weeks:
- To evaluate the effect on response rate (according to RECIST criteria), disease control rate, and overall survival.

- To evaluate the effect on metabolic response rate (as measured by FDG-PET).

- To exploratively evaluate tumor response by centralized review of changes in tumor density on CT scan and/or perfusion/diffusion MRI.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

Antitumor activity

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

same IMP used at different dosage, alone or in combination with doxorubicin

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 study completion is defined as the date of the close-out visit of the last center, on the condition that all the data have been validated and reassessed the study documents

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

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	30
F.4.2	For a multinational trial
F.4.2.1	In the EEA	96
F.4.2.2	In the whole clinical trial	96

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

2011-09-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-05-09

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