Clinical Trials Register

Summary
EudraCT Number:	2017-002985-28
Sponsor's Protocol Code Number:	MS100070-0306
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-05-24
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

Denmark - DHMA

A.2

EudraCT number

2017-002985-28

A.3

Full title of the trial

Open-label, Phase I/II study to evaluate pharmacokinetics, pharmacodynamics, safety, and anticancer activity of avelumab in pediatric subjects from birth to less than 18 years of age with refractory or relapsed solid tumors and lymphoma

A.3.1

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

Phase I/II study of avelumab in pediatric cancer subjects

A.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

MS100070-0306

A.5.4

Other Identifiers

Name:

IND number

Number:

IND 136751

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/071/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merck KGaA
B.1.3.4	Country	Germany
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	Merck KGaA
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck KGaA
B.5.2	Functional name of contact point	Communication Center
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496151725200
B.5.5	Fax number	+496151722000
B.5.6	E-mail	service@merckgroup.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	Yes
D.2.1.1.1	Trade name	BAVENCIO
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Serono Europe Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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/3/16/1798 and EU/3/16/1798
D.3 Description of the IMP
D.3.1	Product name	BAVENCIO
D.3.2	Product code	MSB0010718C
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	AVELUMAB
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	MSB0010718C
D.3.9.3	Other descriptive name	Anti PD-L1
D.3.9.4	EV Substance Code	SUB180078
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	20
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.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 (including central nervous system tumors) and lymphoma

E.1.1.1

Medical condition in easily understood language

Solid tumors (including central nervous system tumors) and lymphoma

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065143
E.1.2	Term	Malignant solid tumour
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10025632
E.1.2	Term	Malignant lymphoma
E.1.2	System Organ Class	100000004864

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

Phase I
- To evaluate the safety and tolerability of avelumab
- To determine the RP2D of avelumab in pediatric subjects 0 to < 18 years of age with solid tumors and lymphoma
Phase II
- To assess antitumor activity of avelumab by determining the ORR according to RECIST 1.1 and as adjudicated by the Investigator in 2 expansion cohorts in specified tumor types in pediatric subjects treated with avelumab

E.2.2

Secondary objectives of the trial

Phase I
-To assess antitumor activity of avelumab by determining the ORR according to RECIST 1.1 and as adjudicated by the Investigator in pediatric subjects with solid tumors and lymphoma treated with avelumab
Phase II
-To evaluate the safety and tolerability of avelumab
Phase I and Phase II
-To assess PFS based on Investigator assessments, DOR, TTR, and OS
-To characterize the PK of avelumab
-To assess the immunogenicity of avelumab
-To evaluate PD-L1 expression; tumor-infiltrating T-cell activity; T-cell population; and T-cell, B-cell, and NK-cell numbers in tumor tissue at Baseline and at confirmed progression (if tumor tissue is obtained)
-To measure changes in vaccination-related antibody concentrations (diphtheria, tetanus, and pneumococcal conjugate)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male or female subjects 0 to < 18 years of age at the time of first treatment dose with histologically or cytologically confirmed solid malignant tumors or lymphoma; confirmed progression on or refractory to standard therapy or no standard therapy available; availability of archival formalinfixed, paraffin-embedded block containing tumor tissue, or slides, or a fresh/recent tumor biopsy prior to avelumab treatment; adequate bone marrow, kidney, and liver function.

E.4

Principal exclusion criteria

Prior therapy with any antibody or drug targeting T-cell coregulatory proteins; concurrent anticancer treatment or immunosuppressive agents; prior organ transplantation; significant acute or chronic infections; other significant diseases or conditions that might impair the subject’s tolerance of trial treatment.

E.5 End points

E.5.1

Primary end point(s)

Phase I
1.Occurrence and severity of TEAEs ≥ Grade 3 according to NCI-CTCAE v4.03
2.DLTs to determine the RP2D
Phase II
3.Confirmed BOR according to RECIST 1.1 and as adjudicated by the Investigator

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I
1.Time from the first trial drug administration to the last drug administration date + 30 days or the earliest date of subsequent anticancer drug therapy minus 1 day, whichever occurs first, unless otherwise stated.
2.Time from the first trial drug administration to completion of the first 2 cycles of treatment.
Phase II
3.Time from rom the first trial administration date until confirmed disease progression.

E.5.2

Secondary end point(s)

Phase I
1.Confirmed BOR according to RECIST 1.1 and as adjudicated by the Investigator
Phase I and Phase II
2.Occurrence and severity of TEAEs, AEs of special interest, and treatment-related AEs, and incidence of laboratory abnormalities, as graded by NCI-CTCAE v4.03
3.DORper RECIST 1.1 and as adjudicated by the Investigator
4.TTR,per RECIST 1.1 and as adjudicated by the Investigator
5.PFS per RECIST 1.1 and as adjudicated by the Investigator
6.OS
7.Vital signs (including blood pressure and heart rate)
8.Single- and multiple-dose PK profiles of avelumab (ie, Cmax, AUC, t1/2, and Ctrough, as data permit)
9.Immunogenicity as measured by avelumab ADA, including NAbs
10.Assessment of tumor PD-L1 expression; tumor-infiltrating T-cell activity; T-cell population; and T-cell, B-cell, and NK-cell numbers at Baseline and at confirmed progression (if tumor tissue is obtained)
11.Vaccination-related antibody concentrations.

E.5.2.1

Timepoint(s) of evaluation of this end point

1.From 1st administration until progression
2.From 1st administration to the last administration date + 30d or date of subsequent anticancer drug therapy -1d
3.From 1st occurrence of CR or PR to either PD or death
4.From the date of 1st dose to the 1st documentation of CR or PR
5.From 1st administration to either 1st observation of PD or death within 12W of the last tumor assessment
6.From the 1st administration to death
7.At screening, every 2W during treatment period, EoT, Safety FU (30d after last tx)
8.At W1,W3,W5,W9,W13,W15,W25,W37,W49 and every 6 cycle thereafter, EoT,Safety FU (30d after last tx)
9.At W1, W3,W5,W9, W13, W25,W37,W49 and every 6 cycle thereafter, EoT and at Safety FU (30 d after last tx)
10.Baseline and at confirmed progression
11.At W1, W13 and EoT

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability and immunogenicity of avelumab

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

Evaluation of avelumab in pediatric subjects

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

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Information not present in EudraCT

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Belgium

Canada

Denmark

Korea, Republic of

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

The end of the trial will be defined as 1 year after the last subject completes his/her End of Treatment Visit.

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:

148

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

Minor subjects

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

148

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)

After a subject has completed the trial or has withdrawn early,usual treatment will be administered, if required,in accordance with the trial site’s standard of care and generally accepted medical practice and depending on the subject’s individual medical needs.The Sponsor will not provide any additional care to subjects after they leave the trial because such care should not differ from what is normally expected for subjects with cancer unless it differs from local laws and regulations.

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

2018-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-05-31

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