Clinical Trials Register

Summary
EudraCT Number:	2018-001529-24
Sponsor's Protocol Code Number:	MS201944-0170
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-07-26
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2018-001529-24

A.3

Full title of the trial

A Phase IIa, single-arm, multi center study to investigate the clinical activity and safety of
avelumab in combination with cetuximab plus gemcitabine and cisplatin in participants with advanced squamous non-small-cell lung cancer

IIa fázisú, egykarú, multicentrikus vizsgálat az avelumab klinikai aktivitásának és biztonságosságának értékelésére az avelumab készítménnyel kombinációban alkalmazott cetuximab plusz gemcitabin és ciszplatin kezelésben részesülő, előrehaladott, nem kissejtes tüdő laphámcarcinomában szenvedő betegek esetében

A.3.1

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

Phase IIa Study of avelumab and cetuximab plus gemcitabine and cisplatin in participants with squamous NSCLC

A.4.1

Sponsor's protocol code number

MS201944-0170

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	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 Centre Merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 20
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	Avelumab
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Avelumab
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.3.9.2	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.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.2.1.1.1	Trade name	Erbitux
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck KGaA
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Erbitux
D.3.2	Product code	EMD271786
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	CETUXIMAB
D.3.9.1	CAS number	205923-56-4
D.3.9.2	Current sponsor code	EMD271786
D.3.9.4	EV Substance Code	SUB01178MIG
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	5
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

Non Small Cell Lung Cancer

Nem kissejtes tüdőrák

E.1.1.1

Medical condition in easily understood language

Non Small Cell Lung Cancer

Nem kissejtes tüdőrák

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	10029514
E.1.2	Term	Non-small cell lung cancer NOS
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

To evaluate efficacy by means of confirmed best overall response (BOR) rate of the combination of cetuximab and avelumab plus doublet chemotherapy, defined as the proportion of participants having achieved confirmed complete response (CR) or partial response (PR) as BOR

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of the combination of cetuximab and avelumab plus doublet chemotherapy
To evaluate the progression-free survival (PFS) time
To assess the duration of response

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are 18 years or older, at the time of signing the informed consent

Type of Participant and Disease Characteristics
2. Histologically-confirmed Stage IV metastatic or recurrent (Stage IV) NSCLC of squamous histology as per the 7th International Association for the Study of Lung Cancer and the American Joint Committee on Cancer classifications.
3. Availability of formalin-fixed paraffin-embedded (FFPE) block containing tumor tissue or a minimum of 15 (preferably 25) unstained tumor slides (cut within 1 week) suitable for PD-L1 expression and EGFR expression/amplification assessments, from a recently obtained (within 6 months) biopsy or a fresh baseline tumor biopsy collected from a non-irradiated area.
4. At least 1 measurable lesion per RECIST v1.1 criteria. A lesion that has been irradiated can be used as a measurable lesion providing that disease has progressed at that site
5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at study entry.
6. Adequate hematological function defined by white blood cell (WBC) count ≥ 2.5 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused).
7. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 2.5 × ULN except for participants with documented metastatic disease to the liver for whom AST and ALT levels ≤ 5 × ULN are acceptable. Patients with documented Gilbert disease are allowed if total bilirubin is less than 3 × ULN.
8. Adequate renal function defined by an estimated creatinine clearance > 60 mL/minute according to the Cockcroft-Gault formula. or by 24-hour urine collection for creatinine clearance or according to local institutional standard method.
9. Estimated life expectancy of at least 3 months.

Sex
10. Are male or female.
A male participant must agree to use and to have their female partners use a highly effective contraception (i.e, methods with a failure rate of less than 1% per year) as detailed in Appendix 3 of this protocol 30 days before the first dose of study intervention (as appropriate), during the study intervention period and for at least 60 days after the last dose of study intervention and refrain from donating sperm during this period.
A female is eligible if she is not pregnant (i.e, after a confirmed menstrual period and a negative serum pregnancy test), not breastfeeding, and at least one of the following conditions applies:
a. Is not a woman of childbearing potential (WOCBP), as defined in Appendix 3
OR
b. Is a WOCBP who agrees to use a highly effective contraceptive method (i.e, has a failure rate of less than 1% per year), as listed in Appendix 3, 30 days before the start of the first dose of study intervention (as appropriate), during the study intervention period and for at least 60 days after the last dose of study intervention

E.4

Principal exclusion criteria

1. Participants whose tumor disease harbors an activating EGFR mutation or ALK rearrangement. Participants with tumors of unknown EGFR or ALK status will require testing only in never smokers.
2. All participants with brain metastases, except those meeting the following criteria:
a. Brain metastases that have been treated locally and are clinically stable for at least 4 weeks prior to treatment start.
b. No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable).
c. Participants must be either off steroids or on a stable or decreasing dose of < 10mg daily prednisone (or equivalent).
3. Previous malignant disease (other than NSCLC) within the last 5 years (except adequately
treated non-melanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum,
breast, or prostate) unless a complete remission without further recurrence was achieved at
least 2 years prior to study entry and the participant was deemed to have been cured with no
additional therapy required or anticipated to be required.
4. Active infection requiring systemic therapy.
5. Known history of human immunodeficiency virus or known acquired immunodeficiency syndrome.
6. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test positive).
7. Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent:
a. Participants with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
b. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
8. Interstitial parenchymal lung disease.
9. Pregnancy or lactation.
10. Known alcohol or drug abuse as determined by the Investigator.
11. History of uncontrolled intercurrent illness including but not limited to:
a. Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg or lower)
b. Uncontrolled active infection.
c. Uncontrolled diabetes (for example, hemoglobin A1c ≥ 8%).
12. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
13. Known history of inflammatory colitis, inflammatory bowel disease, pneumonitis, pulmonary
fibrosis.
14. Any psychiatric condition that would prohibit the understanding or rendering of informed consent or that would limit compliance with study requirements.

E.5 End points

E.5.1

Primary end point(s)

Confirmed BOR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) assessed by Investigator

E.5.1.1

Timepoint(s) of evaluation of this end point

From the first dose of study intervention until planned final assessment at 17 months

E.5.2

Secondary end point(s)

Occurrence of treatment-emergent adverse events (TEAEs) and treatment-related adverse events (AEs), treatment-related Grade ≥ 3 AEs, and immune-related AEs, according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0)
PFS time according to RECIST v1.1 by Investigator assessment
Duration of response (DOR) assessed from confirmed CR or PR until progression of disease (PD), death, or last tumor assessment

E.5.2.1

Timepoint(s) of evaluation of this end point

From the first dose of study intervention until planned final assessment at 17 months

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

Yes

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

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

Single arm phase 2 trial

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.8.2.4

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

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

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 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

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.1.3

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

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

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

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)

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.

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

2018-08-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-28

P. End of Trial
P.	End of Trial Status	Ongoing

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