Clinical Trials Register

Summary
EudraCT Number:	2012-000939-42
Sponsor's Protocol Code Number:	IP-N02
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-07-13
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2012-000939-42

A.3

Full title of the trial

A non-randomized, open-label, multi-centric dose-finding adaptive phase I/IIa study to assess safety, tolerability, pharmacokinetics and preliminary efficacy of repeated intravenous IPP-204106N administrations in adult patients with advanced solid tumors

A.3.1

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

Dose-finding adaptive phase I/IIa study to assess safety, tolerability, pharmacokinetics and preliminary efficacy of repeated intravenous IPP-204106N administrations in adult patients with advanced solid tumors

A.3.2

Name or abbreviated title of the trial where available

IP-N02

A.4.1

Sponsor's protocol code number

IP-N02

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	Elro Pharma
B.1.3.4	Country	France
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	Elro Pharma
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Elro Pharma
B.5.2	Functional name of contact point	Zimmer
B.5.3	Address:
B.5.3.1	Street Address	5, rue du Rhône
B.5.3.2	Town/ city	Mulhouse
B.5.3.3	Post code	68100
B.5.3.4	Country	France
B.5.4	Telephone number	33389661322
B.5.5	Fax number	33389327631
B.5.6	E-mail	robert.zimmer@immupharma.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	IPP-204106
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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	N6L
D.3.9.3	Other descriptive name	Nucant6L
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

Solid tumors

E.1.1.1

Medical condition in easily understood language

Cancer

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10065147
E.1.2	Term	Malignant solid tumor
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• The primary objective of the phase I part of the study is to determine the recommended optimal dose of intravenous IPP-204106N administered daily for at least 5 consecutive days (Days 1 to 5) with a wash-out period of 2 weeks, to adult patients with advanced solid tumors.
• The primary objective of the phase IIa part of the study is to search for early evidence of anti-tumor activity of IPP-204106N at the optimal dose, based on RECIST criteria or biomarkers analysis in adult patients with advanced solid tumors.

E.2.2

Secondary objectives of the trial

• To evaluate the overall safety of IPP-204106N.
• To determine the pharmacokinetic (PK) profile of IPP-204106N during the dose-escalation phase of the study.
• To evaluate the tumor response rate, duration of objective responses and stabilizations.
• To evaluate the tumor growth rate (GR).
• To evaluate the time to progression (TTP) and progression-free survival (PFS) of IPP-204106N at the recommended dose.
• To identify genomic and proteomic tumor biomarkers.
• To evaluate the early metabolic effects of IPP-204106N as measured by serial fluorine 18 fluorodeoxyglucose positron emission tomography - computed tomography (18FDG PET-CT) (descriptive analysis) at both time points during the treatment cycle and to evaluate the correlation between the early 18FDG PET-CT response and standard RECIST 1.1 or biomarker analysis and the correlation between the early 18FDG PET-CT response and TTP and PFS at the recommended dose.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent obtained prior to initiation of any study-specific procedures for study participation and signed informed consent for tumor biopsy and 18FDG PET-CT complementary study. Informed consent for tumor biopsy is mandatory for patients included in the phase IIa part of the study. Informed consent for 18FDG PET-CT study concerns phase I and IIa patients but is not mandatory.
2. Man or woman at least 18 years of age.
3. Histological or cytological confirmed advanced solid tumor, non eligible for curative local treatment or active palliation with systemic therapy.
4. Patients with measurable or evaluable disease (by tumor measurements or by tumor biomarker) with a proof of disease progression. At least one measurable lesion is mandatory for the phase IIa portion of the study.
5. Patients currently under treatment with N6L or patients who have taken part in the Phase I part of the study are eligible for the phase IIa part, according to the investigator’s judgment, irrespective of their tumor status.
6.Tumor biopsy available at study entry for patients included in the phase IIa part of the study and if possible for phase I patients.
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
8. Life expectancy more than 3 months according to the investigator’s judgment.
9. Recovery from any acute toxicity related to prior therapy. Toxicity should be ≤grade 1 according to NCI-CTCAE criteria or returned to baseline excluding alopecia.
10.Adequate hematological counts: neutrophils ≥1.5 x 10^9/L, platelets ≥ 100 x 10^9/L, hemoglobin ≥ 9 g/dL.
11. Adequate renal function: serum creatinine ≤1.5 × upper limit of normal range (ULN).
12. Adequate hepatic function:
• Serum bilirubin ≤1.5 × ULN (except for isolated hyperbilirubinemia attributed to Gilbert’s syndrome).
• Alkaline phosphatase (or ≤ 5 x ULN in case of liver or bone metastases), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) ≤2.5 × ULN (or ≤5 × ULN in case of liver metastases).
13. All women of child-bearing potential must use adequate contraception throughout the duration of the study, or their partner must be surgically sterilized. The pre-study pregnancy test must be negative for women with reproductive potential. Women who have been surgically sterilized or are at least two years post-menopausal may be enrolled and do not need birth control.

E.4

Principal exclusion criteria

1. Hematological malignancy (including lymphomas).
2. Any of the following within the 6 months prior to study drug administration: severe/unstable angina, myocardial infarction, coronary artery bypass graft, symptomatic congestive heart failure, stroke, including transient ischemic attack, or pulmonary embolism.
3. Ongoing cardiac arrhythmias of NCI-CTCAE grade ≥2.
4. Active uncontrolled infections.
5. Uncontrolled hypertension.
6. Radiotherapy or chemotherapy within 4 weeks before study treatment (6 weeks for nitrosoureas or mitomycin).
7. Pregnancy or breastfeeding.
8. Participation to another therapeutic clinical trial within the last 4 weeks except studies including treatment with N6L.
9. History of severe allergic reactions.
10. Documented or suspected allergy to any nucleolin antagonist.
11. Documented allergy to excipient (mannitol or chondroitin sulfate) product
12. Documented allergy to Aspirin

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is a composite (combined) toxicity/pharmacokinetic criterion defined as:
• Toxicity assessed during cycle 1: number of patients experiencing a dose limiting toxicity (DLT) according to the NCI-CTCAE (v 4.0, May 2009), defined as:
o Hematological drug-related toxicity: grade 4 neutropenia ≥7 days, grade 4 thrombocytopenia, grade 3 thrombocytopenia with hemorrhage/bleeding, and febrile neutropenia.
o Nausea, vomiting or diarrhea grade ≥3 despite optimal treatment.
o Any other drug-related biological or clinical grade ≥3 toxicity.
• Plasma exposure assessed during cycle 1 (on day 1): number of patients reaching targeted plasma drug exposure, i.e. plasma N6L concentration ≥5 µM for at least two hours. This concentration corresponds to active concentration in vitro in human tumor cell lines.
Phase IIa portion of the study
• Disease control rate, defined as objective responses plus stable disease

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline, Day 1, Day 2, Day 3, Day 4, Day 5, Day 12/15

E.5.2

Secondary end point(s)

• Overall safety of IPP-204106N: AE, SAE, vital signs, laboratory hematological and biochemical assessments.
• Pharmacokinetic profile of IPP-204106N during the dose-escalation phase.
• Anti-tumor activity of IPP-204106N: tumor objective responses according to RECIST criteria (version 1.1), duration of objective responses and stabilizations.
• Tumor growth rate
• Time to progression and progression-free survival at the recommended dose.
• Identification of genomic and proteomic tumor biomarkers.
• Early metabolic effects of IPP-204106N as measured by serial 18FDG PET-CT (descriptive analysis) at both time points during the treatment cycle and evaluation of the correlation between the early 18FDG PET-CT response and standard RECIST 1.1 or biomarker analysis and the correlation between the early 18FDG PET-CT response and TTP and PFS at the recommended dose.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline, Day 1, Day 2, Day 3, Day 4, Day 5, Day 12/15

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

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

dose -finding adaptive phase I/IIa

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

Dose finding bayesian adaptive Phase I

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

Dose finding bayesian adaptive Phase I

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.8.4.1

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

LVLS

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	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.1.2.1	Number of subjects for this age range:	30
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	10
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	15
F.4.2	For a multinational trial
F.4.2.1	In the EEA	40
F.4.2.2	In the whole clinical trial	40

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-07-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-04-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-03-11

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