Clinical Trials Register

Summary
EudraCT Number:	2020-001776-15
Sponsor's Protocol Code Number:	MS202202-0002
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-08-07
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

Czechia - SUKL

A.2

EudraCT number

2020-001776-15

A.3

Full title of the trial

A Phase II single-arm study to investigate tepotinib
combined with cetuximab in RAS/BRAF wild-type
left-sided metastatic colorectal cancer (mCRC)
patients having acquired resistance to anti-EGFR
antibody targeting therapy due to MET
amplification

Jednoramenná studie fáze II k vyhodnocení přípravku tepotinib v kombinaci s cetuximabem u pacientů s levostranným metastazujícím kolorektálním karcinomem s RAS/BRAF divokého typu (mCRC), kteří mají získanou rezistenci vůči cílené terapii proti protilátkám anti-EGFR v důsledku amplifikace MET.

A.3.1

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

Phase II single-arm study of tepotinib combined
with cetuximab

A.4.1

Sponsor's protocol code number

MS202202-0002

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 Healthcare 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 Healthcare 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 Str. 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	+496151725200
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	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	Tepotinib
D.3.2	Product code	MSC2156119J
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tepotinib
D.3.9.2	Current sponsor code	MSC2156119J
D.3.9.4	EV Substance Code	SUB189535
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
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.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 Europe B.V.
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	Cetuximab
D.3.2	Product code	MSB0010442D
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	MSB0010442D
D.3.9.4	EV Substance Code	SUB01178MIG
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	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

left-sided metastatic colorectal cancer (mCRC)

E.1.1.1

Medical condition in easily understood language

metastatic colorectal 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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10052362
E.1.2	Term	Metastatic colorectal cancer
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

Safety Run-in:
To confirm the recommended Phase II dose (RP2D) of tepotinib when used in combination with cetuximab
Overall Study:
To evaluate the preliminary efficacy of tepotinib (RP2D) in combination with cetuximab in terms of tumor response

E.2.2

Secondary objectives of the trial

Overall Study:
1) To further evaluate the efficacy of the combination of tepotinib (RP2D) and cetuximab in terms of:
- a)duration of response (DoR)
- b) progression-free survival (PFS)
- c)overall survival (OS)
2) To evaluate the safety and tolerability of tepotinib in combination with cetuximab
3) To characterize the immunogenicity of cetuximab

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age
1. Are ≥ 18 years of age (or having reached the age of majority according to local laws and regulations, if the age of majority is > 18 years of age) at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Advanced (locally advanced or metastatic) left sided CRC with RAS/BRAF wild-type at study entry confirmed prior to enrollment, with previous anti-EGFR therapy and acquired resistance on the most recent anti-EGFR monoclonal antibody therapy (panitumumab or cetuximab) by radiological documentation of disease progression according to RECIST Version 1.1.
3. MET amplification detected by a positive liquid biopsy and/or tissue with appropriate regulatory status (collected after disease progression of the previous anti-EGFR therapy).
4. Measurable disease by Investigator in accordance with RECIST Version 1.1.
5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
6. Life expectancy > 3 months.
7. Participants having at least one systemic treatment for mCRC including 1 anti-EGFR monoclonal antibody therapy as the most recent line of therapy for mCRC before study treatment and must have shown a radiologically confirmed by RECIST Version 1.1 complete response (CR) or partial response (PR), both for at least 4 months or stable disease (SD) for at least 6 months to that therapy prior to disease progression.
a. For Cohort A in sites outside of US, participants must only have had one prior systemic treatment for mCRC.
b. For Cohort B in sites in the US only, participants must have had at least two prior systemic treatments for mCRC.
8. Less than 2 months between the last administration of the most recent EGFR containing regimen and first dosing in this study.
9. Adequate hematological function in the absence of transfusions in 7 days before testing defined by white blood cell count ≥ 3 × 109/L with absolute neutrophil count, ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 8.5 g/dL.
10. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), AST ≤ 3 × ULN, and ALT ≤ 3 × ULN. For participants with liver metastases: total bilirubin ≤ 1.5 × ULN, AST/ALT ≤ 5 × ULN.
11. Adequate renal function defined by an estimated glomerular filtration rate > 30 mL/min according to the 4-component Modification of Diet in Renal Disease (MDRD) equation. (GFR [mL/min/1.73 m2] = 175 × serum creatinine (Scr)-1.154 × age 0.203 × 1.212 [if African American] × 0.742 [if female]).

Sex
12. Are male or female
Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.

Informed Consent
13. Capable of giving signed informed consent

E.4

Principal exclusion criteria

Medical Conditions
1. Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS metastases. Also excluded are participants with carcinomatous meningitis.
2. Participants who have brain metastasis as the only measurable lesion.
Prior/Concomitant Therapy
3. Prior chemotherapy, biological therapy, radiation therapy, hormonal therapy for anti-cancer purposes, targeted therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study intervention, except for the anti-EGFR containing regimen including associated chemotherapy if applicable, which may be continued until enrollment of the participant in the study.
Prior/Concurrent Clinical Study Experience
4. Any unresolved toxicity Grade 2 or more according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, from previous anticancer therapy excluding neuropathy, alopecia and rash.
Other Exclusions
5. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE v 5.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more occurrences of partially controlled asthma).
6. Discontinuation of the most recent cetuximab or panitumumab containing therapy due to an adverse event.
7. Prior treatment with other agents targeting the HGF/MET pathway.
8. Impaired cardiac function:
a. Left ventricular ejection fraction < 45% defined by echocardiography (a screening assessment not required for participants without a history of congestive heart failure unless
clinically indicated)
b. Serious arrhythmia
c. Unstable angina pectoris
d. New York Heart Association heart failure Class III and IV
e. Myocardial infarction within the last 12 months prior to study entry
f. Symptomatic pericardial effusion
9. Hypertension uncontrolled by standard therapies (not stabilized to < 150/90 mmHg).
10. Past or current history of neoplasm other than mCRC, except for curatively treated nonmelanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and
with no evidence of disease for at least 5 years.
11. Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the test products.
12. Major surgery within 28 days prior to Day 1 of study intervention.
13. Known infection with human immunodeficiency virus, or an active infection with hepatitis B or hepatitis C virus.
14. Substance abuse, active infection, or other acute or chronic medical or psychiatric condition or laboratory abnormalities that might increase the risk associated with study participation at the discretion of Investigators.
15. IMP use in another study within 3 weeks of the first dose of study intervention.

E.5 End points

E.5.1

Primary end point(s)

Safety Run-in:
Occurrence of dose limiting toxicities (DLTs)

Overall Study:
Objective response (OR, confirmed complete response [CR] or partial response [PR]) determined according to RECIST Version 1.1 assessed by the Investigators

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety Run-In:
Overall Study: Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15 and subsequently every 4 cycles until study closure or disease progression

E.5.2

Secondary end point(s)

Overall Study:
1)
a) DoR (months) according to RECIST Version 1.1 assessed by the Investigators.
b) PFS (months) according to RECIST Version 1.1 assessed by the Investigators.
c) OS (months) assessed by the Investigators.

2)
- Occurrence of Adverse Events (AE) and treatment related
AEs
- Occurrence of clinically significant changes in vital
signs, laboratory parameters and 12-lead electrocardiogram (ECG) findings

3)
Immunogenicity of cetuximab as measured by antidrug antibody (ADA) assays on Day 1 Cycle 1 and End of Treatment Visit

E.5.2.1

Timepoint(s) of evaluation of this end point

Survival Follow -Up and End of Treatment Visits

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

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

biomarker research, Immunogenicity Assessments

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

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

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

Czech Republic

France

Italy

Russian Federation

Spain

Turkey

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

The end of the study is defined as the date when the last participant has completed the last visit in the Survival Follow-up.

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

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.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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)

None

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

2020-10-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-09-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2021-11-25

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