Clinical Trials Register

Summary
EudraCT Number:	2014-003277-42
Sponsor's Protocol Code Number:	MCLA-128-CL01
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2019-12-13
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

Germany - PEI

A.2

EudraCT number

2014-003277-42

A.3

Full title of the trial

A Phase I/II Study of MCLA-128, a full length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients with Solid Tumors (eNRGY)

A.3.1

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

A study of the investigational drug MCLA-128 which is an antibody that is
specific to both HER2 and HER3 receptors that are associated with solid
tumors

A.4.1

Sponsor's protocol code number

MCLA-128-CL01

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	Merus N.V.
B.1.3.4	Country	Netherlands
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	Merus N.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merus N.V
B.5.2	Functional name of contact point	MCLA-128-CL01 Project Physician
B.5.3	Address:
B.5.3.1	Street Address	Uppsalalaan 17, 3rd and 4th floor
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3584 CT
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+1617586 9488
B.5.6	E-mail	E.Wasserman@merus.nl

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	Zenocutuzumab
D.3.2	Product code	MCLA-128
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	Zenocutuzumab
D.3.9.1	CAS number	1969309-56-5
D.3.9.2	Current sponsor code	MCLA-128
D.3.9.3	Other descriptive name	A bispecific humanized full length IgG1 antibody with enhanced ADCC
D.3.9.4	EV Substance Code	SUB169257
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

E.1.1.1

Medical condition in easily understood language

Solid tumors

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	10049280
E.1.2	Term	Solid tumour
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

Part 1:
- Determination of MTD/MRD and tolerability
Part 2: Groups A - E:
- To characterize the safety and tolerability of MCLA-128
- To explore the relationships between the anti-tumor activity of MCLA-128 and disease-related biomarkers
Part 2: Groups F, G, H (NRG1 fusion)
- To assess the magnitude of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed locally
- To assess durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed locally

E.2.2

Secondary objectives of the trial

Part1:
- safety and tolerability of MCLA-128
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Evaluation of anti-tumor response and CBR
Part 2 Groups A - E:
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Evaluation of PFS and overall survival, duration of response
Part 2: Groups F, G, H (NRG1 fusion)
- To assess the magnitude of anti-tumor activity of MCLA-128 in patients
with NRG1 fusions as assessed centrally
- To assess the clinical benefit rate (CBR) of MCLA-128 in patients with
NRG1 fusions as assessed locally and centrally
- To assess durability of anti-tumor activity of MCLA-128 in patients with
NRG1 fusions as assessed centrally
- To assess time to onset of response in patients with NRG1 fusions as assessed locally and centrally
- To characterize the safety and tolerability of MCLA-128
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Evaluation of progression-free survival and overall survival

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Age ≥18 yrs
2.≥1 measurable lesion, RECIST v1.1 or evaluable disease for a limited number of patients in group H
3.ECOG 0, 1 or 2
4.life expectancy ≥12 wks
5. Toxicities incurred as a result of previous anti-cancer therapy resolved to ≤Grade 1 except for alopecia, Grade 2 sensory neurotoxicity, or any other toxicity that in the opinion of the investigator does not affect the assessment of adverse events related to the study drug
6.Treatment with anti-cancer or investigational product within set intervals before first dose of IMP:
a.>14d or >5 half-lives prior to study entry, whichever is shorter.
b.>14d for radiotherapy. Note: A less than 1-week wash-out period is permitted only for palliative radiation to non-CNS disease with Sponsor approval.
7.Recovery from prior surgery/other procedure/ complication to ≤ Grade 2 or to baseline condition that in opinion of the investigator does not affect the assessment of adverse events related to the study drug;
8.Screening Lab values:
a.Absolute neutrophil count ≥1.5 x 10^9/L without colony stimulating factor support for at least 7 days prior to Screening;
b.Platelets ≥75 x 10^9/L without transfusion support for at least 7 days prior to Screening;
c.Hemoglobin ≥8 g/dL or ≥5 mmol/L;
d.ALT, AST ≤3 x ULN and total bilirubin ≤1.5 x ULN (for exceptions please refer to protocol)
e.Estimated glomerular filtration rate (GFR) of >30 mL/min based on the Cockroft-Gault formula;
9.Able to provide at baseline a mandatory tumor biopsy sample, preferably a block. If safe/feasible, a fresh FFPE biopsy sample is preferred; archival tissue is acceptable (preferably not more than 2
years old
Note 1: For patients who received afatinib or other HER-targeting agents, a biopsy collected after the last line of treatment is strongly preferred to assess for mechanisms of acquired resistance
Note 2: For patients with a locally confirmed NRG1 gene fusion, when archival tissue is not available and collection of a fresh biopsy is not safe or feasible during the screening period, these patients will be allowed to enroll in the MCLA128-CL01 trial provided they meet all other inclusion/exclusion criteria.
10.Negative pregnancy test at Screening and ≤7 days of D1
Note: Women with amenorrhea associated with prior treatment with antineoplastic medications are still considered as being of child-bearing potential.
11.Sexually active male and female patients of childbearing potential must agree to use one of the highly effective methods of birth control during entire study and 6 months after final administration of MCLA-128
12.Give written informed consent
13.Capable of understanding protocol requirements, is willing and able to comply with study procedures and has signed the main informed consent document. For any optional biopsy sampling (tissue and/or blood) and long-term sample storage, additional consent is required
14. Patients must have received prior standard therapy appropriate for their tumor type and stage of disease;
15. Histologic or cytologic diagnosis of locally-advanced unresectable or metastatic solid tumor malignancy with a documented NRG1 gene fusion, identified through molecular assays such as PCR, next generation sequencing-based assays [DNA or RNA], as routinely performed ast CLIA
or other similarly-certified laboratories. The following tumor types are included:
o Group F: NSCLC
o Group G: pancreatic adenocarcinoma
o Group H: any other solid tumor
NOTE: Patients harboring fusions that are predicted to be non-functional, i.e.., lack of EGF-domain, will not be included in the study. For equivocal cases, including those with NRG1 as the upstream partner, the Sponsor will manually review genomic results and may request collateral testing, approve, or deny the case.

E.4

Principal exclusion criteria

1. Pregnant or lactating;
2. Presence of an active uncontrolled infection or an unexplained fever greater than 38.5°C during Screening up to the first scheduled day of dosing. At the discretion of the Investigator, patients with tumor fever or a clinically insignificant minor infection may be enrolled (i.e. mild upper respiratory infection);
3. Known hypersensitivity to any of the components of MCLA-128 or history of severe hypersensitivity reactions to human or humanized monoclonal antibodies, including therapeutic antibodies;
4. Patients with the following infectious diseases are excluded:
a. known HIV
b. active Hepatitis B infection (HBsAg positive) without receiving antiviral treatment
Note:
• Patients with active hepatitis B (HBsAg positive) must receive antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral agents, starting at least ≥ 7 days before the initiation of the study
treatment.
• Patients with antecedents of Hepatitis B (anti-HBc positive, HBsAg and HBV-DNA negative) are eligible.
c. positive test for Hepatitis C ribonucleic acid (HCV RNA)
Note:
• Patients in whom HCV infection resolved spontaneously (positive HCV antibodies without detectable HCV-RNA) or those that achieved a sustained response after antiviral treatment and show absence of
detectable HCV RNA ≥ 6 months (with the use of IFN-free regimens) or ≥ 12 months (with the use of IFN-based regimens) after cessation of antiviral treatment are eligible;
NOTE: Patients without known or suspected HIV, Hepatitis B or Hepatitis C infection do not require specific viral testing during the screening period.
5. Known symptomatic or unstable brain metastases. Patients with asymptomatic brain metastases are eligible to participate if the metastases have been radiographically and clinically stable for at least
one month. If on steroids for this indication, the patient must be on a stable dose for at least one month.
6. Patients with leptomeningeal metastases
7. Previous or concurrent malignancy (excluding non-basal cell carcinoma of skin or carcinoma in situ of the uterine cervix) unless the tumor was treated with curative or palliative intent and in the opinion of the investigator, with sponsor agreement, the previous or concurrent malignancy condition doesn't affect the assessment of safety and efficacy of the study drug;
8. Presence of LVEF <50% on the screening echocardiogram; or history or presence of any significant cardiovascular disease, including unstable angina or myocardial infarction within 12 months prior to screening, congestive heart failure (NYHA Class III or IV), or ventricular arrhythmia requiring medication;
9. Presence of any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate or participate in the study, or interfere with the interpretation of the results.

E.5 End points

E.5.1

Primary end point(s)

Part 1:
• Evaluation of adverse events (AEs) and dose limiting toxicities (DLT).
Part 2: Groups A - E:
• Frequency and nature of AEs
• Overall response rate (ORR), DOR, CBR (defined as the proportion of patients in whom a CR or PR is observed, or SD of a minimum duration of 12 weeks) per RECIST v1.1 as per local Investigator's assessment. The relationship between anti-tumor activity and biomarkers including expression of HER2, HER3, and heregulin will be explored, and serum biomarkers such as CA-125 (ovarian, endometrial) and CA 19-9 (gastric)
Part 2: Groups F, G, H (NRG1 fusion):
• Overall response rate (ORR) per RECIST v1.1 as per local Investigator's assessment
• Duration of response per RECIST v1.1 as per local Investigator's assessment

E.5.1.1

Timepoint(s) of evaluation of this end point

Part 1:
- Continuous assessment of AEs
Part 2 A-E:
- Continuous assessment of AEs
- Every 8 weeks until end of treatment (ORR, DOR, CBR)
- Pre-dose Cycle 1 Day, Cycle 2 D1. Every 2 cycles therafter (biomarkers)
Part 2 F,G,H:
- Every 8 weeks until end of treatment

E.5.2

Secondary end point(s)

Part 1:
1 Frequency and nature of AEs/serious adverse events (SAEs)
2 Assessment of PK variables, including total exposure, maximum concentration (Cmax) clearance, volume of distribution (V), volume of distribution at steady state (Vss), half-life (t1/2), AUC0-t (area under the concentration versus time curve from time zero to time t), AUC0-∞
(area under the concentration versus time curve), tmax (time to reach maximum concentration)
3 Incidence and serum titers of anti-drug antibodies against MCLA-128
4 Anti-tumor activity and clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and survival; CBR is defined as the proportion of patients in whom a complete response (CR) or partial
response (PR) or stable disease (SD) is observed (where SD duration is a minimum of 12 weeks).
Part 2: Groups A - E:
5 Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-∞, tmax
6 Population PK analysis
7 Incidence and serum titers of anti-drug antibodies against MCLA-128
Part 2: Groups F, G, H (NRG1 fusion):
8 Overall response rate per RECIST v1.1 as per central review.
9 CBR (defined as the proportion of patients with a CR or PR, or an SD of a minimum duration of 24 weeks) per RECIST v1.1 as per local Investigator's assessment.
10 CBR per RECIST v1.1 as per central review.
11 Duration of response per RECIST v1.1 as per central review.
12 Time to response per RECIST v1.1. as per local Investigator's assessment.
13 Time to response per RECIST v1.1 as per central review.
14 Frequency and nature of AEs
15 Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-∞, tmax
16 Population PK analysis
17 Incidence and serum titers of anti-drug antibodies against MCLA-128

E.5.2.1

Timepoint(s) of evaluation of this end point

Part 1:
1 Continuous AEs assessment
2 Pre-dose C1D1, EOI; 2,4,24h post EOI, pre-dose & EOI on D15.Cycles 2&3:pre-dose & EOI D1,15. C4 & every 2 cycles thereafter pre-dose D1
3 D1 pre-dose C1,2,3,&4. Every fourth cycle thereafter & EOT & Final visit
4 Every 8 wks til EOT
Part 2 A-E:
5,6 Pre-dose C1D1, EOI; 2,4,24 h post EOI, pre-dose & EOI on D15.C2&3:pre-dose & EOI D1,15. C4 & every2 cycles thereafter pre-dose D1 7 D1 pre-dose for C1,2,3,&4. Every fourth cycle thereafter & EOT & Final visit
Part 2 F, G, H:
8-13 Every 8 wks til EoT
14 Continuous AEs assessment
15 16 Pre-dose C1D1, EOI; 2,4,24 h post EOI, pre-dose & EOI on D15.Cycles 2&3:pre-dose & EOI D1,15. C4,6,8 pre-dose D1
17 D1 pre-dose for C1,2,3,4&8

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

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

Yes

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

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Part 2 is parallel design, Part 1 is not

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

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

Singapore

Taiwan

Austria

Belgium

Canada

Denmark

France

Germany

Israel

Italy

Japan

Korea, Republic of

Netherlands

Norway

Spain

Sweden

United Kingdom

United States

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

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:

172

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

286

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

258

F.4.2.2

In the whole clinical trial

458

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)

Patients may remain on treatment until disease progression, death, unacceptable toxicity or discontinuation for any other reason.
Continuing treatment beyond progression for either arm is only to be considered under special circumstances when it is believed that the
patient may clinically benefit by continued treatment beyond progression. If it is judged by the Investigator in consultation with the Sponsor to be in the best interest of the patient, patients may continue dosing.

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

2020-08-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-18

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
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