Clinical Trials Register

Summary
EudraCT Number:	2017-001828-22
Sponsor's Protocol Code Number:	101
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:
Date on which this record was first entered in the EudraCT database:	2018-05-23
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

2017-001828-22

A.3

Full title of the trial

A Multicenter Phase 2/3 Trial of the Efficacy and Safety of
Intracerebroventricular Radioimmunotherapy using 131I-burtomab for
Neuroblastoma Central Nervous System/Leptomeningeal Metastases

A.3.1

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

A clinical trial in several sites where pediatric patients with Neuroblastoma
are treated with injections of 131I-burtomab (the study drug). The
tolerability and efficacy of the drug will be tested.

A.4.1

Sponsor's protocol code number

101

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03275402

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/322/2020

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Y-mAbs Therapeutics A/S
B.1.3.4	Country	Denmark
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	Y-mAbs Therapeutics A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	KLIFO A/S
B.5.2	Functional name of contact point	Vice President, Clinical
B.5.3	Address:
B.5.3.1	Street Address	Smedeland 36
B.5.3.2	Town/ city	Glostrup
B.5.3.3	Post code	2600
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4544222935
B.5.6	E-mail	Klas.Raadberg@klifo.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/17/1839
D.3 Description of the IMP
D.3.1	Product name	131I-omburtamab
D.3.2	Product code	131I-murine 8H9
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Intracerebroventricular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	omburtamab
D.3.9.1	CAS number	1895083-75-6
D.3.9.2	Current sponsor code	131I-OMBURTAMAB
D.3.9.3	Other descriptive name	OMBURTAMAB
D.3.9.4	EV Substance Code	SUB188981
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.3 to 1.4
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	Yes
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

Treatment of pediatric neuroblastoma patients with CNS relapse as
evidenced by CNS/LM metastases

E.1.1.1

Medical condition in easily understood language

Treatment of pediatric neuroblastoma patients with CNS relapse as
evidenced by CNS/LM metastases

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 overall survival (OS) rate at 3 years

E.2.2

Secondary objectives of the trial

1. To evaluate CNS/LM progression-free survival (CNS/LM PFS) at 6 and
12 months.
2. To evaluate Overall Survival (OS) at 12 months.
3. To evaluate the objective response rate (ORR) at 6 months.
4. To evaluate dosimetry of 131I-omburtamab
5. To evaluate the pharmacokinetics of 131I-omburtamab
6. To evaluate safety of 131I-omburtamab
7. To evaluate the immunogenicity of 131I-omburtamab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients must have a histologically confirmed diagnosis of
neuroblastmona with relapse in the CNS or LM.
2. Patients need to have progressed in CNS/LM through induction
therapy or have relapsed in CNS/LM following induction. CNS/LM
progression/ relapse is defined as LM disease or metastatic deposits in
the CNS parenchyma, (excluding skull bone-based metastases)
3. Stable systemic disease not requiring chemo/ immunotherapy as
judged by the investigator
4. Ventriculoperitoneal (VP) shunts (only shunts with programmable
valves can be accepted) is allowed however should be closed (or
adjusted to highest pressure setting) during Investigational Medicinal
Product (IMP) infusion. It is recommended that the VP shunt remains
closed for approximately 5 hours after treatment and then readjusted.
The shunt readjustment times are at the discretion of the treating
physician. Closure of VP shunt is done at the discretion of the treating
physician and the VP shunt should at any time based on patient safety
evaluation be reopened at the assessment of the treating physician.
Patients with ventriculo-atrial or ventriculo-pleural shunts are not
eligible.
5. Patients must be between the ages of birth and 18 years at the time of
screening
6. Patients must have a life expectancy of at least 3 months as judged by
the investigator.
7. Acceptable hematological status defined as:
• Hemoglobin ≥8 g/dL
• White blood cell count ≥1000/μL
• Absolute neutrophil count ≥500/μL
• Platelet count ≥50,000/μL
8. Acceptable liver function defined as:
• (ALT) and /or AST ≤ 5 times UNL
• Bilirubin ≤3 x UNL
In case either AST or ALT ≥3 x ULN, bilirubin must be ≤ 2 UNL
9. Acceptable kidney function defined as:
• eGFR >60 mL/min/1.73 m2 calculated by the 2009 revised Bedside
Schwartz Equation (Appendix 3).
10. Written informed consent from legal guardian(s) and/or child must
be obtained in accordance with local regulations. Pediatric patients must
provide assent as required by local regulations

E.4

Principal exclusion criteria

1. Patients with primary neuroblastoma (NB) in CNS
2. Patients must not have obstructive or symptomatic communicating
hydrocephalus as determined by Ommaya patency/CSF flow study.
3. Patients must not have worsening of neurologic function, according to
the assessment by investigator, within 3 weeks prior to first dose of
131I-omburtamab.
4. Patients must not have an uncontrolled life-threatening infection.
5. Patients must not have received cranial or spinal irradiation less than
3 weeks prior to first dose of 131I-omburtamab in this trial
6. Patients must not have received systemic chemo/ immunotherapy
(corticosteroids not included) less than 3 weeks prior to enrolment in
this trial.
7. Patients must not have received any B7-H3 treatment prior to
enrolment in this trial.
8. Patients must not have severe major non-hematologic organ toxicity;
specifically, any renal, cardiac, hepatic, pulmonary, and gastrointestinal
system toxicity must fall below Grade 3 prior to enrolment in this trial.
Patients with stable neurological deficits (due to brain tumor) are not
excluded. Patients with Grade 3 or lower hearing loss are not excluded.
9. Patients must not be pregnant or breast-feeding
10. Female patients of child-bearing potential (i.e. having experienced
menarche) and male partners to female patients who do not agree to the
use of effective contraception during treatment and for a period of 12
months after the last 131I-omburtamab dose. Effective contraception for
women is defined as intrauterine devices or hormonal
contraceptives(contraceptive pills, implants, transdermal patches,
hormonal vaginal devices, or injections with prolonged release).
Effective contraception for male partners is defined as use of condoms.
To be exempt from the requirement to use contraception after 131Iomburtamab
treatment, one of the criteria described in section 9.2.11 of
this protocol must be met.
11. Fertile male patients who do not agree to the use of condoms during treatment and for a period of 12 months after the last 131I-omburtamab
dose. For a sterilized male patient to be exempt from the requirement to
use contraception after 131I-omburtamab treatment, he must have
undergone surgical sterilization (vasectomy).

E.5 End points

E.5.1

Primary end point(s)

Overall survival (OS) rate at 3 years after the first treatment dose of
131I-omburtamab

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 3 years after 131I-omburtamab treatment

E.5.2

Secondary end point(s)

1. CNS/LM PFS at 6 and 12 months.
2. OS at 12 months.
3. ORR assessed as a combination of partial response and complete
response as defined by the Response Assessment in Neuro-Oncology
group criteria for brain metastasis( Lin et al, 2015) or leptomeningeal
metastases as defined by ENANO-ESMO criteria( Le Rhun et al, 2017).
ORR will be assessed at 6 months after the first treatment dose of
131Iomburtamab.
4. ORR according to CSF cytology. Response is defined as a complete
response when CSF converts from positive at baseline to negative after
treatment with 131I-omburtamab.
5. Whole-body, organ, blood, and CSF radiation dosimetry.
6. Pharmacokinetic analysis of activity in blood and CSF including
derivation of best-fit uptake and/or clearance parameters (half-times,
maximum value) of time-activity concentration curves and of I-131
residence times (i.e., cumulated activity) concentrations (in μCi-h/g).
7. The frequency, type, and duration of treatment-emergent severe
adverse events and serious adverse events, including clinically
significant laboratory abnormalities. All adverse events will be graded
according to CTCAE, version 4.0.
8. Performance assessment to monitor gross changes in neurological
function is performed at week 26 and subsequently every 6 months
during trial period.
9. The rate of ADA occurrence assessed three weeks after the first and
second treatment dose of 131I-omburtamab.

E.5.2.1

Timepoint(s) of evaluation of this end point

Short-term follow-up at 26 weeks after treatment and with long-term
follow-up for up to 3 years following treatment

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

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

dosimetry

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)

Yes

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

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

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

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Denmark

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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 (EOT) will occur when all patients have been followed until
the visit at 3 years, or death whichever comes first.

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

Yes

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients could be between the ages of birth and 18 years and therefore
informed consent from legal guardian(s) and/or child must be obtained
in accordance with local regulation. Pediatric patients must provide
assent as required by local regulations

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)

Any treatment deemed safe and justified by the investigator can be
administered according to clinical practice and at the discretion of the
investigator

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

2018-01-23

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status

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