Conditions: Breast Cancer Metastatic
Keywords: Bispecific Antibody immunoglobulin gamma-1(IgG1), Human Epidermal Growth Factor Receptor (HER)2, HER3 MCLA-128 Antibodies, bispecific Immunologic Factors Cytokines combination Trastuzumab with and without Vinorelbine zenocutuzumab
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 105
Healthy volunteers: no

Brief summary:
A Phase 2, open-label, multicenter international study will be performed to evaluate the efficacy of MCLA-128-based combinations. Three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2.

MCLA-128 (zenocutuzumab) is given in combinations in two metastatic breast cancer (MBC) populations, Human Epidermal Growth Factor Receptor (HER) 2-positive/amplified (Cohort 1) and Estrogen Receptor-positive/low HER2 expression (Cohort2).

Two combinations treatments will be evaluated in Cohort 1, the doublet and triplet. Initially zenocutuzumab is given in combination with trastuzumab in the doublet. After the safety of the doublet has been assessed in 4-6 patients, MCLA-128 is given in combination with trastuzumab and vinorelbine in the triplet, in parallel to the efficacy expansion of the doublet.

The doublet and triplet combinations are both evaluated in two steps with an initial safety run-in followed by a cohort efficacy expansion. In total up to 40 patients evaluable for efficacy are included in both the doublet and triplet.

In Cohort 2 zenocutuzumab is administered in combination with the same previous endocrine therapy on which progressive disease is radiologically documented. A total of up to 40 patients evaluable for efficacy are included in the Cohort 2.

Detailed description:
Study Design Phase 2, open-label, multicenter international study to evaluate the efficacy of MCLA-128 (zenocutuzumab)-based combinations in 2 metastatic breast cancer populations, Human Epidermal Growth Factor Receptor (HER)2-positive/amplified (Cohort 1) and estrogen receptor-positive/low-HER2 expression (Cohort 2). Three combination treatments were evaluated, 2 in Cohort 1 and 1 in Cohort 2.

Cohort 1: To be eligible, patients had to have HER2-positive/amplified metastatic breast cancer, with confirmed HER2 overexpression by Immunohistochemistry (IHC) with a score of 3+ or of 2+ combined with positive Fluorescence in Situ Hybridization (FISH), have received up to 5 lines of HER2-directed therapy in the metastatic setting, and have progressed on the most recent line per Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1, and have been previously treated with trastuzumab, pertuzumab and an HER2 Antibody-Drug Conjugates (ADC) in any sequence and any setting.

Initially zenocutuzumab was administered with trastuzumab (doublet combination). Safety was reviewed by an Independent Data Monitoring Committee (IDMC). If the safety of the doublet was approved, the triplet combination of zenocutuzumab plus trastuzumab and vinorelbine was to be evaluated in parallel with the doublet combination.

The doublet and triplet Cohort 1 combinations were each evaluated in 2 steps with an initial safety run-in period in 4 to 6 patients who were reviewed by the IDMC before deciding to expand the cohort. The triplet combination go/no-go decision was made by the IDMC after evaluation of the doublet safety run-in patients (based on Adverse Avents \[AEs\], Serious Adverse Events \[SAEs\], relationship to study drug, and other clinically relevant parameters \[eg, laboratory parameters\], available pharmacokinetics, immunogenicity, and cytokine data). If the triplet combination was considered safe, the expansion of the doublet and triplet combinations was performed in parallel. Patients were included in the triplet or doublet in a 3:1 ratio, taking into account previous exposure to vinorelbine.

After the safety run-in, if Cohort 1 doublet and Cohort 1 triplet combination therapies were considered tolerable by the IDMC, they were each to be expanded to a total of up to 40 patients evaluable for efficacy. If the doublet combination regimen was not well tolerated, Cohort 1 was to be closed. If the triplet combination was not well tolerated but the doublet was acceptable, the doublet expansion was to be continued.

Cohort 2: To be eligible, patients had to have estrogen receptor-positive and low-HER2 expression metastatic breast cancer (IHC 1+, or IHC 2+ combined with negative FISH), and radiologic or photographic evidence of disease progression on the last line of prior endocrine therapy (administered for ≥12 weeks) that included an aromatase inhibitor (AI) or fulvestrant. Patients who had received up to 3 prior endocrine therapies in the metastatic setting and had progressed on a Cyclin-Dependent Kinase (CDK) inhibitor (in any line) were eligible.

Zenocutuzumab was administered in combination with the same previous endocrine therapy on which progressive disease was radiologically/photographically documented. Up to 40 patients evaluable for efficacy were included.

Arms:
arm 1: zenocutuzumab + trastuzumab arm 2: zenocutuzumab + trastuzumab + vinorelbine arm 3: zenocutuzumab + endocrine therapy

Interventions: intervention 1: Zenocutuzumab intervention 2: Trastuzumab intervention 3: Vinorelbine intervention 4: Endocrine therapy
Intervention descriptions: intervention 1: full length immunoglobulin gamma-1 (IgG1) bispecific antibody targeting Human Epidermal Growth Factor Receptor (HER)2 and HER3 intervention 2: humanised IgG1 monoclonal antibody intervention 3: antineoplastic drug of vinca alkaloid family intervention 4: same endocrine therapy is administered as the last line of endocrine therapy

Protocol document:
Prot_000.pdf: 
Protocol MCLA-128-CL02  
Version 5.0, 11 April 2022 
 
 
 
PROPERTY OF MERUS N.V.  
 CONFIDENTIAL  
Page 1 of 127 
 
 
Phase 2 study of MCLA-128-based combinations in metastatic 
breast cancer (MBC): MCLA-128/trastuzumab/chemotherapy in 
HER2-positive MBC and MCLA-128/endocrine therapy in estrogen 
receptor positive and low HER2 expression MBC 
 
STUDY CODE: 
MCLA-128-CL02 
VERSION: 
5.0 
DATE: 
11 April 2022 
EUDRACT NUMBER: 
2017-002821-39 
IND: 
131752 
SPONSOR: 
Merus N.V., Yalelaan 62, 3584 CM Utrecht, The Netherlands 
 
Tel:  + 31 85 016 2500 
 
 
The information contained in this document, especially unpublished data, is confidential 
communication from Merus N.V. (Merus). Acceptance of this document constitutes the agreement 
of the recipient that this information will not be disclosed to others without written authorization 
from Merus, except to the extent necessary for Ethics Committee/Institutional Review Board 
procedures and to obtain written informed consent from those persons to whom test drug may be 
administered.


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KEY STUDY CONTACTS 
Sponsor Medical Expert 
Ernesto Wasserman, MD 
Senior Vice President, Clinical Development 
Merus N.V. 
Yalelaan 62, 3584 CM Utrecht, The Netherlands  
Mobile: +1 617 586 9488 / +31 6 11288794 
E-mail: e.wasserman@merus.nl 
 
CRO Medical Monitor 
Mohamed Bekradda, MD 
Oncology Therapeutic Development (OTD) SARL 
100 rue Martre, 92110 Clichy, France  
Tel: +33 1 47 15 01 05 / Mobile: +33 6 07 18 67 81 
Fax: +33 1 45 19 06 59 
E-mail: mohamed.bekradda@oncotd.com  
 
CRO Clinical Operations Director 
Fabrice Bourdel, MSc 
Oncology Therapeutic Development (OTD) SARL  
100 rue Martre, 92110 Clichy, France  
Tel: +33 1 47 15 01 03 / Mobile: +33 6 07 18 77 84  
Fax: +33 1 45 19 06 59 
E-mail: fabrice.bourdel@oncotd.com 
 
 
 
 
 
 


Protocol MCLA-128-CL02  
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SPONSOR SIGNATURE PAGE 
Phase 2 study of MCLA-128-based combinations in metastatic breast cancer (MBC): MCLA-
128/trastuzumab/chemotherapy in HER2-positive MBC and MCLA-128/endocrine therapy in 
estrogen receptor positive and low HER2 expression MBC 
MCLA-128-CL02, Version 4.0, 30 April 2021 
 
I, the undersigned, have read this protocol and agree that it contains all the necessary information 
required for the conduct of the study. 
 
 
Ernesto Wasserman, MD 
Sponsor Project Physician, Merus N.V. 
 
Viktoriya Stalbovskaya, PhD 
VP Biometrics, Merus N.V. 
 
Jim Ford, MSc 
Sr. Director Clinical Trials, Merus N.V. 
 
Sharon Bowen 
Senior Director Regulatory Affairs 
 
Anastasia Vliet 
Clinical Study Manager/Clinical Operations Manager 
 
Electronic signature page is attached 
 
 
 
 
 


Protocol MCLA-128-CL02  
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
I confirm that I have read the study protocol MCLA-128-CL02, entitled “Phase 2 study of MCLA-128-
based combinations in metastatic breast cancer (MBC): MCLA-128/trastuzumab/chemotherapy in 
HER2-positive MBC and MCLA-128/endocrine therapy in estrogen receptor positive and low HER2 
expression MBC”, Version 4.0, 30 April 2021.  
The information it contains is consistent with the current risk-benefit evaluation of the investigational 
product. 
I understand it, and I agree to conduct the study according to this protocol, GCP principles as described 
in CPMP/ICH/135/95 and 21 CFR Parts 50, 54, 56, and 312, and applicable local requirements, and will 
comply with the protocol requirements, subject to scientific, ethical and safety considerations.  
I understand that I must keep confidential the information contained in the study documents that I 
have been or will be provided with. 
I understand that, should the decision be made by the Sponsor to terminate prematurely or suspend 
the study at any time for any reason, such a decision will be communicated to me in writing. Should I 
decide to withdraw from participating in the study I will communicate immediately such a decision in 
writing to the Sponsor. 
Furthermore, by the present, I am committed to enroll the first patient in this study within a month. 
 
 
NAME & QUALIFICATION: 
__________________________________ 
INSTITUTION & LOCATION: 
__________________________________ 
 
__________________________________ 
 
__________________________________ 
 
Signature  
__________________________________ 
Date 
__________________________________ 
 
 


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SUMMARY OF PROPOSED CHANGES AND RATIONALE  
 
Section / Page 
Throughout the document Version Number and Version Date. 
Rationale 
Administrative changes to clearly document new version. 
 
Section / Page 
Section in Protocol Synopsis: Study duration 
Rationale 
The initial anticipated “Completion of the data analysis” date of October 2019 has been 
exceeded due to a handful of patients who still benefit from the study drug. Protocol Version 
5.0 provides a new expected date. 
  
Section / Page 
Section 3.2: Study duration 
Rationale 
Update to reduce the study procedures. 
Since the Development International Birth Date of 13 January 2015, until the cutoff date 12 
January 2022, a total of 363 cancer patients had been treated with MCLA-128 in 2 Clinical 
Trials. So far, the safety profile including identified (IRRs) and potential risks (Diarrhea and 
decreased cardiac ejection fraction) associated with MCLA-128 is considered acceptable with 
the implementation of appropriate risk management measures including directed exclusion 
criteria, premedication, symptomatic treatment, and targeted monitoring.  
With this consideration, the Sponsor proposes for the remaining patients who have been on 
treatment for at least 24 months in this study, to reduce the study procedures in order to 
decrease their burden, but to offer the opportunity to continually derive benefit from the 
Study drug. The Sponsor will continue to  monitor  Safety and efficacy, either via an 
alternative “post-study or Expanded access” program or via the implementation of Protocol 
Version 5.0. This will allow an expedited analysis of study results, while maintaining an 
appropriate level of safety surveillance. 
 
Section / Page 
Summary of study procedures  
Rationale 
The replacement of columns Study treatment period, End of Treatment 
Visit and Follow-Up period, to reduce the study procedures for the patients remaining on the 
study.  
Patients transferring into the alternative program will follow a similar treatment plan. 
 
Section / Page 
Section 8.2: Laboratory Assessments 
Rationale 
Updated for clarity  
 
Section / Page 
Section 8.8.2: LVEF (by ECHO or MUGA) and 12-lead electrocardiogram (ECG) + Appendix 3 
Rationale 
Updated from every 4 cycles (3 months) to every 6 months due to the current Safety Profile 
and the focus on the appropriate level of safety surveillance. 
 
Section / Page 
Section 9.1: Tumor Assessments 
Rationale 
Updated from every 6 weeks to every 12 weeks to reduce the patient’s burden, but still 
allows the possibility to have a Tumor Assessment done in between in case of symptomatic 
deterioration signs or signs of disease progression. 
 
Section / Page 
Efficacy assessments central review: Protocol synopsis and section 9.1.1. 
Rationale 
Enough independent central analysis of patient imaging has been completed and additional 
assessment of imaging for those patients currently on treatment for at least 24 months is no 
longer required.  Therefore, central review of imaging by an independent radiologist(s) for 
all patients on-study is no longer applicable as of Protocol Version 5.0. 
The Sponsor relies on the local Investigator assessment and continued focus will be on the 
appropriate level of safety surveillance. 


Protocol MCLA-128-CL02  
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Section / Page 
Protocol synopsis Biomarkers; section 11 
Rationale 
Enough biomarker data has been accumulated from all patients treated on the trial. 
Therefore the additional data from the few patients who have been on treatment for 24 
months is not needed as per Protocol Version 5.0. 
 
 
 


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PROTOCOL SYNOPSIS 
TITLE: Phase II study of MCLA-128-based combinations in metastatic breast cancer (MBC): MCLA-
128/trastuzumab/chemotherapy in HER2-positive MBC and MCLA-128/endocrine therapy in estrogen 
receptor positive and low-HER2 expression MBC 
INVESTIGATIONAL PRODUCT: MCLA-128 
SPONSOR: Merus N.V., Yalelaan 62, 3584 CM Utrecht, The Netherlands 
OBJECTIVES 
Cohort 1 (HER2-positive/amplified MBC): MCLA-128 + trastuzumab ± vinorelbine  
Primary objective: 
• 
Evaluate efficacy of MCLA-128 combined with trastuzumab ± vinorelbine in terms of clinical benefit 
rate (CBR) at 24 weeks based on RECIST 1.1 (per investigator review) in HER2-positive/amplified MBC 
patients who have progressed on prior HER2-directed therapy that included trastuzumab, pertuzumab, 
and an HER2 antibody drug conjugate (ADC) in any sequence and in any setting 
Secondary objectives: 
• 
Evaluate CBR at 24 weeks based on RECIST 1.1 per central review 
• 
Evaluate progression-free survival (PFS; per investigator and central review) 
• 
Evaluate overall response rate (ORR) based on RECIST 1.1 (per investigator and central review) 
• 
Evaluate duration of response (DoR) based on RECIST v1.1 (per investigator and central review) 
• 
Evaluate overall survival (OS) 
• 
Evaluate safety and tolerability of MCLA-128 in combination with trastuzumab ± vinorelbine  
• 
Characterize pharmacokinetics (PK) of MCLA-128 in combination with trastuzumab ± vinorelbine 
• 
Characterize immunogenicity of MCLA-128 in combination with trastuzumab 
Exploratory objective: 
• 
Evaluate potential correlations between biomarkers in tumor or blood samples and antitumor activity 
(including HER2, HER3, HER2:HER3 dimers, heregulin and other potential biomarkers) 
Cohort 2 (estrogen receptor [ER]-positive/low HER2 expression MBC): MCLA-128 + endocrine therapy 
Primary objective: 
• 
Evaluate efficacy of MCLA-128 combined with endocrine therapy in terms of CBR at 24 weeks based on 
RECIST 1.1 (per investigator review) in ER-positive and low HER2 expression MBC patients who have 
previously progressed on the same endocrine therapy 
Secondary objectives:  
• 
Evaluate CBR at 24 weeks based on RECIST 1.1 per central review 
• 
Evaluate PFS (per investigator and central review) 
• 
Evaluate ORR based on RECIST 1.1 (per investigator and central review) 
• 
Evaluate DoR based on RECIST 1.1 (per investigator and central review) 
• 
Evaluate OS 
• 
Evaluate safety and tolerability of MCLA-128 combined with endocrine therapy 
• 
Characterize PK of MCLA-128 combined with endocrine therapy 
• 
Characterize immunogenicity of MCLA-128 combined with endocrine therapy 
Exploratory objective: 
• 
Evaluate potential correlations between biomarkers in tumor or blood samples and antitumor activity 
(including HER2, HER3, HER2:HER3 dimers, heregulin and other potential biomarkers). 
STUDY DESIGN 
A phase 2, open-label, multicenter international study will be performed to evaluate the efficacy of MCLA-
128-based combinations in two metastatic breast cancer (MBC) populations, HER2-positive/amplified 
(Cohort 1) and ER-positive/low HER2 expression (Cohort 2). Three combination treatments will be 
evaluated, two in Cohort 1 and one in Cohort 2, in 20-30 sites in 7 countries in Europe and the USA. 


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Cohort 1: Patients with HER2-positive/amplified MBC, having confirmed HER2 overexpression by 
immunohistochemistry (IHC) 3+ or IHC 2+ combined with positive fluorescence in situ hybridization (FISH), 
who have been treated with up to a maximum of 5 lines of HER2-directed therapy in the metastatic setting 
and have progressed on the most recent line as per RECIST v1.1, are eligible. Patients must have been 
treated previously with trastuzumab, pertuzumab and an HER2 ADC in any sequence and in any setting. For 
enrollment, HER2 status will be based on medical records, and eligibility will be confirmed subsequently as 
soon as possible, by central lab review. Patients found to be ineligible retrospectively will not be evaluable 
for the primary objective and may be replaced. Documented imaging proof of disease progression on the 
last prior line of therapy should be made available when possible. 
Initially MCLA-128 will be administered with trastuzumab (doublet combination). Safety will be reviewed by 
an Independent Data Monitoring Committee (IDMC). After the safety of the doublet has been assessed, 
MCLA-128 + trastuzumab + vinorelbine (triplet combination) will be evaluated in parallel with the doublet 
combination (see figure below). 
The doublet and triplet Cohort 1 combinations will both be evaluated in two steps with an initial safety run-
in in 4 to 6 patients who will be reviewed by the IDMC, followed by a cohort efficacy expansion, as 
described below. The triplet combination go/no-go decision will be made by the IDMC after evaluation of 
the doublet safety run-in patients. If the triplet combination is considered safe, the expansion of the 
doublet and triplet combinations will be performed in parallel. Patients with be included with a 3:1 ratio for 
triplet or doublet respectively, favoring the triplet combination and taking into account previous exposure 
to vinorelbine. 
Study design for Cohort 1 combination therapies (doublet and triplet) 
 
Safety run-in: After 4-6 patients have received at least 2 complete cycles (6 weeks) of MCLA-128 + 
trastuzumab, a safety review will be performed by the IDMC. If the doublet combination is considered safe, 
the safety run-in for the triplet combination will be initiated in the next 4 to 6 successive eligible patients. 
Safety of the triplet will be evaluated by the IDMC after these 4-6 patients have received at least 2 complete 
cycles (6 weeks) of MCLA-128 + trastuzumab + vinorelbine. 
Based on the observed safety in the first 4-6 patients (adverse events [AEs], serious adverse events [SAEs], 
relationship to study drug, and other clinically relevant parameters [e.g. laboratory parameters], available 
PK, immunogenicity, and cytokine data) the IDMC, investigators and Sponsor will decide on a potential 
additional run-in period for each combination (i.e. doublet and triplet).  
Expansion: After the safety run-in, each Cohort 1 combination therapy considered tolerable by the IDMC 
will be expanded to a total of up to 40 patients evaluable for efficacy.  
If the doublet combination regimen is not tolerated, Cohort 1 will be closed. If the triplet combination is not 
well tolerated but the doublet is acceptable, the doublet expansion will be continued.  
Cohort 2: Patients with ER-positive and low HER2 expression MBC (IHC 1+, or IHC 2+ combined with 
negative FISH) who have radiologic or photographic evidence of disease progression on the last line of prior 
endocrine therapy (administered for at least 12 weeks) that included an aromatase inhibitor or fulvestrant. 
Patients who have received up to 3 prior endocrine therapies in the metastatic setting and have progressed 
on a cyclin-dependent kinase inhibitor (in any line) are eligible. For enrollment, HER2 and HR status and 
radiologic/photographic documentation of prior progression will be based on medical records. Eligibility will 
be confirmed as soon as possible for HER2/HR status by central lab review and for prior disease progression 
by central imaging review. Patients found to be ineligible retrospectively will not be evaluable for the 
primary objective and may be replaced. 


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MCLA-128 will be administered in combination with the same previous endocrine therapy on which 
progressive disease is radiologically/photographically documented. A total of up to 40 patients evaluable for 
efficacy will be included. 
 
Study design for Cohort 2 combination therapies  
 
An Independent Data Monitoring Committee (IDMC), composed of at least 2 physicians expert in the 
domain of early clinical development in MBC, will review safety and efficacy throughout the study and 
decide on the addition of extra patients in the expansion parts, opening of the triple combination cohorts, 
and any ad hoc safety decisions. The principal investigators, the Sponsor’s medical expert(s) and other 
representatives may be called upon to assist as observers. 
STUDY POPULATION 
Inclusion criteria 
Patients must fulfill all of the following requirements to enter the study: 
1. Signed informed consent before initiation of any study procedures. 
2. Women with histologically or cytologically confirmed breast cancer with evidence of metastatic or 
locally advanced disease not amenable to any local therapy with curative intent: 
2.1 Cohort 1 (MCLA-128 + trastuzumab ± vinorelbine) 
a. Documented HER2 overexpression/amplification, defined as immunohistochemistry (IHC) 3+ 
positive, or IHC 2+ combined with positive fluorescence in situ hybridization (FISH), based on local 
analysis on the most recent tumor biopsy (preferably metastatic, otherwise primary), either fresh 
or archival collected within 24 months before screening. 
b. Documented disease progression (by investigator assessment) on up to a maximum of 5 lines of 
HER2-directed therapy administered in the metastatic setting, and have progressed on the most 
recent line. Trastuzumab, pertuzumab and an HER2 antibody drug conjugate (e.g. T-DM1) must 
have been previously administered in any sequence and in any setting.  
2.2 Cohort 2 (MCLA-128 + endocrine therapy) 
a. Documented hormone receptor positive status (estrogen receptor positive [ER+] and/or 
progesterone receptor positive [PR+]), defined as ≥ 1% positive stained cells by local standards, 
based on local analysis on the most recent tumor biopsy. 
b. Documented low-level HER2 expression, defined as IHC HER2 1+, or IHC HER2 2+ combined with 
negative FISH, based on local analysis on a fresh tumor biopsy or an archival biopsy collected 
within 24 months before screening (preferably metastatic, otherwise primary). 
c. No more than 3 lines of prior endocrine therapy (aromatase inhibitor or fulvestrant) for 
metastatic disease, with radiologic or photographic evidence of disease progression on the last 
line, after at least 12 weeks of therapy. 
d. Progression on a cyclin-dependent kinase inhibitor.  
e. No more than two previous chemotherapy regimens for advanced/metastatic disease. 
Note: Pre/peri-menopausal women can be enrolled if amenable to be treated with the LHRH agonist 
goserelin. Such patients must have commenced treatment with goserelin or an alternative LHRH agonist 
at least 4 weeks prior to study entry, and patients who received an alternative LHRH agonist prior to 
study entry must switch to goserelin for the duration of the trial. 
3. In Cohort 1, patients must have at least one lesion with measurable disease as defined by RECIST 
version 1.1. In Cohort 2, patients must have at least one lesion with measurable disease as defined by 
RECIST version 1.1. Patients with bone-only disease are eligible, even in the absence of measurable 


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disease. Patients with bone-only disease must have lytic or mixed lesions (lytic + sclerotic). For Cohort 
2, imaging documenting progression on the last line of hormone therapy must be available for central 
review. 
4. Age ≥ 18 years at signature of informed consent. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
6. Life expectancy of ≥ 12 weeks, as per investigator. 
7. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multiple gated acquisition 
scan (MUGA). 
8. Adequate organ function: 
a. Absolute neutrophil count (ANC) ≥ 1.5 X 109/L 
b. Hemoglobin ≥ 9 g/dL 
c. Platelets ≥ 100 x 109/L 
d. Serum calcium within normal ranges (or corrected with supplements) 
e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x upper limit of 
normal (ULN) and total bilirubin ≤ 1.5 x ULN (in cases of liver involvement, ALT/AST ≤ 5 x ULN 
and total bilirubin within normal ranges will be allowed) 
f. 
Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min calculated according to the 
Cockroft and Gault formula or MDRD formula for patients aged > 65 years (Appendix 19.2) 
g. Serum albumin > 3.0 g/dL 
Exclusion Criteria 
The presence of any of the following criteria excludes a patient from participating in the study: 
1. Central nervous system metastases that are untreated or symptomatic, or require radiation, surgery, or 
continued steroid therapy to control symptoms within 14 days of study entry. 
2. Known leptomeningeal involvement. 
3. Advanced/metastatic, symptomatic, visceral spread, with a risk of life-threatening complications in the 
short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], 
pulmonary lymphangitis, and over 50% liver involvement). 
4. Participation in another interventional clinical trial or treatment with any investigational drug within 4 
weeks prior to study entry. 
5. Any systemic anticancer therapy within 3 weeks of the first dose of study treatment. For cytotoxic 
agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, or anticancer 
immunotherapies, a washout period of 6 weeks is required. For patients in Cohort 2, this does not 
apply to the most recently received hormone therapy. 
6. Major surgery or radiotherapy within 3 weeks of the first dose of study treatment. Patients who 
received prior radiotherapy to ≥ 25% of bone marrow are not eligible, irrespective of when it was 
received. 
7. Persistent grade > 1 clinically significant toxicities related to prior antineoplastic therapies (except for 
alopecia); stable sensory neuropathy ≤ grade 1 NCI-CTCAE v. 4.03 is allowed. 
8. History of hypersensitivity reaction or any toxicity attributed to trastuzumab, murine proteins, or any of 
the excipients that warranted permanent cessation of these agents (applicable for Cohort 1 only). 
9. Previous exposure to vinorelbine (applicable for Cohort 1 triplet combination only). 
10. Exposure to the following cumulative anthracycline doses: 
a. Doxorubicin or liposomal doxorubicin > 360 mg/m² 
b. Epirubicin > 720 mg/m² 
c. Mitoxantrone > 120 mg/m² and idarubicin > 90 mg/m² 
d. Other anthracycline at a dose equivalent to > 360 mg/m² doxorubicin 
e. For patients having received > 1 anthracycline, the cumulative dose must not exceed the 
equivalent of 360 mg/m² doxorubicin 


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11. Chronic use of high-dose oral corticosteroid therapy (>10 mg of prednisone equivalent a day). 
12. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable angina. 
13. History of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or serious 
cardiac arrhythmia requiring treatment (except atrial fibrillation, paroxysmal supraventricular 
tachycardia). 
14. History of myocardial infarction within 6 months of study entry. 
15. History of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in 
situ cervical carcinoma) within 3 years of study entry. 
16. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy. 
17. Current serious illness or medical conditions including, but not limited to uncontrolled active infection, 
clinically significant pulmonary, metabolic or psychiatric disorders. 
18. Known HIV, HBV, or HCV infection. 
19. Pregnant or lactating women; women of childbearing potential must use effective contraception 
methods (patient and/or partner, e.g., surgical sterilization, a reliable barrier method) prior to study 
entry, for the duration of study participation, and for 7 months after the last dose of MCLA-
128/trastuzumab. See Section 8.10. 
20. Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites or 
other visceral locations). 
21. Patients with bone-only disease with blastic-only metastasis.    
INVESTIGATIONAL AND COMPANION THERAPIES 
MCLA-128: 750 mg intravenous flat dose over 2 hours, Day 1 every 3 weeks (q3w). 
Premedication with paracetamol/acetaminophen, antihistamines and corticosteroids (as per standard 
practices) is mandatory for every MCLA-128 infusion. 
Trastuzumab: 8 mg/kg intravenous loading dose over 90 minutes on Day 1 Cycle 1, then from Cycle 2, 6 
mg/kg will be administered intravenously over 30-90 minutes, on Day 1 of each cycle, q3w. For safety run-in 
patients, trastuzumab administration will be delayed to Day 2 in Cycle 1. 
Vinorelbine: 25 mg/m² intravenously over 10 minutes, Days 1 and 8, every 3 weeks. For safety run-in 
patients, vinorelbine administration will be delayed to Days 2 and 9 in Cycle 1. 
Endocrine therapy: Patients will receive the same dose and regimen as that administered under the last line 
of endocrine therapy prior to study entry on which the patient progressed.  
TREATMENT REGIMENS 
For all combinations a cycle is considered 3 weeks (including Cohort 2 which may include q4w fulvestrant 
dosing). A 6-hour observation period will be implemented following infusion start for the initial MCLA-128 
and/or trastuzumab administration, and 2 hours for all subsequent administrations. 
Cohort 1 doublet combination: 
• 
Safety run-in (4-6 patients): for Cycle 1, MCLA-128 will be administered on Day 1, and trastuzumab on 
Day 2. From Cycle 2, trastuzumab will be administered on Day 1, 30 minutes after the completion of the 
MCLA-128 administration.   
• 
Expansion: for all cycles, MCLA-128 will be administered on Day 1 followed by trastuzumab 30-minutes 
after the end of the MCLA-128 infusion.  
Cohort 1 Doublet treatment administration 


Protocol MCLA-128-CL02  
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Safety Run-In 
 
* Followed by a 6-hour observation period from infusion start, for the 
initial administration and 2 hours for all subsequent administrations. 
For Cycle 2, trastuzumab must be infused over 90 min 
Expansion 
 
* Followed by a 6-hour observation period from infusion start, for the 
initial administration and 2 hours for all subsequent administrations. 
For Cycle 2, trastuzumab must be infused over 90 min 
Cohort 1 triplet combination: 
• 
Safety run-in (4-6 patients): for Cycle 1, MCLA-128 will be administered on Day 1 followed 30 minutes 
later by trastuzumab, and vinorelbine will be administered on Days 2 and 9. From Cycle 2, vinorelbine 
will be administered on Day 1, 30 minutes after trastuzumab, and on Day 8. 
• 
Expansion: for all cycles, MCLA-128 will be administered on Day 1 followed 30 minutes later by 
trastuzumab, followed by vinorelbine 30 minutes after the end of the trastuzumab infusion.  
Cohort 1 Triplet treatment administration 
Safety Run-In 
* Followed by a 6-hour observation period from infusion start, for the 
initial administration and 2 hours for all subsequent administrations. 
For Cycle 2, trastuzumab must be infused over 90 min 
Expansion 
* Followed by a 6-hour observation period from infusion start, for the initial 
administration and 2 hours for all subsequent administrations. 
For Cycle 2, trastuzumab must be infused over 90 min 
 
For both the doublet and the triplet combinations, if an individual patient does not tolerate all drugs on the 
same day, the safety run-in Cycle 1 dosing schedule will be maintained for that patient. 
Cohort 2: All patients will receive MCLA-128 administration on Day 1 q3w. For endocrine therapy patients 
will receive the same dose and regimen as that administered under the last line of endocrine therapy prior 
to study entry and on which the patient progressed. Fulvestrant will be administered on Days 1, 15, 29 and 
once every 28 days thereafter, or aromatase inhibitor therapy (letrozole, anastrazole and exemestane) will 
be administered daily from Day 1.  
Treatment administration for Cohort 2 (all cycles) 
 
A 6-hour observation period will be implemented following infusion start for 
the initial MCLA-128 administration, and 2 hours for all subsequent 
administrations. 
* Same endocrine therapy under which the patient progressed prior to study 
entry. Can be administered before, during, or immediately after the MCLA-128 
infusion. 


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Treatment assignment: for Cohort 1, if the triplet combination is considered safe, the expansion of the 
doublet and triplet combinations will be performed in parallel. Patients with be included with a 3:1 ratio for 
triplet or doublet respectively, favoring the triplet combination and taking into account previous exposure 
to vinorelbine; for Cohort 2, no specific treatment assignment is required. 
Treatment adaptation 
• 
No dose reductions are permitted for MCLA-128, trastuzumab, or endocrine therapy agents. 
• 
The vinorelbine dose will be decreased or interrupted in cases of decreased neutrophil counts or 
elevated bilirubin levels, according to the SPC, and discontinued if grade ≥ 2 neurotoxicity (NCI-CTCAE v. 
4.03) occurs.  
• 
MCLA-128 infusion will be interrupted in the event of an infusion-related reaction (IRR) and must be 
stopped definitively for severe IRRs. For mild to moderate events the infusion can be resumed at a 50% 
infusion rate and infusion duration extended to 4 hours. 
• 
MCLA-128 and trastuzumab administration can be delayed for a maximum of 6 weeks between 
infusions to manage AEs, specifically for clinically significant LVEF decreases, signs of congestive heart 
failure or persistent grade 2 or grade 3-4 diarrhea. 
• 
Hormone therapy drugs will be administered according to the SPC of each drug. 
Treatment duration 
Study treatment will be administered until confirmed progressive disease (as per RECIST 1.1), unacceptable 
toxicity, withdrawal of consent, patient non-compliance, investigator decision (e.g. clinical deterioration), 
treatment interruption > 6 consecutive weeks, withdrawal of any study drug. Patients will be followed up 
for safety for at least 35 ± 5 days following the last study drug administration and until 
recovery/stabilization of related toxicities, and for disease progression and survival status for 12 months. 
PROPHYLACTIC AND CONCOMITANT MEDICATION  
Permitted 
• 
Administration of paracetamol/acetaminophen, antihistamines and corticosteroids is mandatory with 
every MCLA-128 administration. In the event of an IRR or hypersensitivity, the patient will be managed 
according to local clinical practice, as clinically indicated. 
• 
All medication necessary for the wellbeing of the patient and which is not expected to interfere with 
evaluation of the study drug, including supportive treatment of symptoms and AEs or standard 
treatment of concomitant conditions may be given at the investigator’s discretion. 
• 
Goserelin in pre/peri-menopausal women who started an LHRH agonist >4 weeks prior to study entry. 
Prohibited  
• 
Concomitant chronic oral corticosteroids (>10 mg/day prednisone equivalent), TNF-alpha inhibitors, 
anti-T-cell antibodies (due to risk of immunosuppression). 
• 
Any investigational drugs during the study or 4 weeks prior to the first dose of study treatment. 
• 
Systemic anticancer therapy (other than the last endocrine therapy in Cohort 2) or yellow fever vaccine 
(Cohort 1) during the study or within 3 weeks of the first dose of study treatment. 
SAFETY / TOLERABILITY ASSESSMENTS 
• 
AEs (CTCAE version 4.03), SAEs 
• 
Lab parameters: hematology, biochemistry, coagulation, urinalysis, cytokines 
• 
ECG, MUGA/ECHO 
• 
Medical history, vital signs, performance status and physical exam  
• 
Concomitant medications  
• 
Dose modifications (reductions, interruptions, delays), discontinuation due to toxicity 
EFFICACY ASSESSMENTS 
Tumor assessment will be based on CT/MRI with contrast per RECIST 1.1, every 6 weeks after treatment 
start. With the implementation of Protocol version 5.0 this will be every 12 weeks. Objective responses 


Protocol MCLA-128-CL02  
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must be confirmed at least 4 weeks after first observation. Central review of imaging by an independent 
radiologist(s) will be performed for all patients (screening and on-study).  
 
Enough independent central analysis of patient imaging has been completed and additional assessment of 
imaging for those patients currently on treatment for at least 24 months is no longer required.  Therefore, 
central review of imaging by an independent radiologist(s) for all patients on-study is no longer applicable 
as of Protocol Version 5.0. 
 
Bone scans will be performed as clinically indicated for patients with bone metastases at baseline or 
suspected lesions on study. 
Tumor markers (CA15-3, CEA, CA27-29) will be assessed on Day 1 every cycle. 
BIOMARKERS 
Candidate exploratory biomarkers will be evaluated in tumor tissue (screening, optional after 12 weeks and 
End of Treatment [EOT]) and blood (pre-dose on Day 1 every 4 cycles and EOT). 
Enough biomarker data has been accumulated from all patients treated on the trial. Therefore the 
additional data from the few patients who have been on treatment for 24 months is not needed as per 
Protocol Version 5.0. 
 
Tumor: HER2, HER3, HER2:HER3 dimerization, downstream signaling proteins (eg PIK3CA), heregulin, 
phosphorylation of HER2, HER3 and proteins in the MAPK and AKT signaling pathway, expression of 
inhibitors such as PTEN, mutations in cancer-related genes including HER2 and HER3 signaling, heregulin-
gene fusions. 
Blood: Fc receptor polymorphism, plasma circulating tumor DNA mutations, exploratory serum biomarkers 
(e.g. soluble HER2, heregulin). 
PHARMACOKINETICS 
PK sampling is no longer applicable as of Protocol Version 4.0. 
For Protocol Versions 1.0, 2.0 and 3.0, blood samples will be collected to measure serum MCLA-128 and 
trastuzumab exposure. No PK sampling will be performed for vinorelbine, fulvestrant or aromatase 
inhibitors.  
PK sampling will be performed at the following time points: 
Cohort 1 doublet and triplet combinations: MCLA-128 
• 
Cycle 1: Day 1, pre-dose, EOI, and at 2, 4, and 22 hours post EOI, then at any time on Day 8 (or Day 9 
for safety run-in triplet patients) 
• 
Cycle 2: Day 1, pre-dose, EOI (run-in and expansion), and at 2, 4, and 22 hours post EOI, then at any 
time on Day 8 (run-in only) 
• 
Cycles 3 and 5: Day 1, pre-dose and EOI  
• 
Every 4 cycles thereafter: pre-dose  
Cohort 1 doublet combination: trastuzumab 
• 
Cycle 1 Day 1: pre-dose and EOI (expansion only) 
• 
Cycle 1 Day 2: pre-dose and EOI (run-in only) 
• 
Cycle 2 Day 1: pre-dose and EOI (run-in and expansion) 
Cohort 1 triplet combination: trastuzumab 
• 
Cycles 1 and 2, Day 1: pre-dose and EOI (run-in and expansion) 
Cohort 2 MCLA-128/endocrine therapy combination: MCLA-128 
• 
Cycle 1: Day 1, pre-dose, EOI, and at 2, 4, and 22 hours post EOI, then at any time on Day 8; 
• 
Cycle 2, 3, 5: Day 1, pre-dose, EOI  
• 
Every 4 cycles thereafter: pre-dose 


Protocol MCLA-128-CL02  
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IMMUNOGENICITY 
Anti-MCLA-128 antibody sampling is no longer applicable as of Protocol Version 4.0. 
For Protocol Versions 1.0, 2.0 and 3.0, blood samples (5 mL) will be collected in all patients to assess serum 
titers of anti-MCLA-128 antibodies pre-dose on Day 1 pre-dose for Cycles 1, 3, 5, every 4 cycles thereafter, 
and EOT. 
CYTOKINES 
Blood samples will be collected to analyze a serum cytokine panel (TNFα, IFNγ, IL-1β, IL-6, IL-8, IL-10) in the 
safety run-in patients of Cohort 1 only as follows (no cytokine evaluation is planned in Cohort 2): 
Cohort 1 doublet combination (run-in only): 
• 
Cycle 1: Day 1, pre-dose, 2, 4, and 22 hours post end of infusion (EOI) of MCLA-128 
• 
Cycle 1: Day 2, pre-dose, 2 hours post-EOI of trastuzumab 
• 
Cycle 2: Day 1, pre-dose, 2, 4, and 22 hours post-EOI of MCLA-128 
Cohort 1 triplet combination (run-in only): 
• 
Cycles 1 and 2: Day 1, pre-dose, 2, 4, and 22 hours post-EOI of MCLA-128 
STATISTICAL CONSIDERATIONS 
Sample size 
Cohort 1 safety run-in: 4 to 6 evaluable patients in the safety run-in will have power to detect an AE with a 
true incidence of 33% is 80 to 90%. 
Cohort 1 efficacy expansion: 40 evaluable patients in the doublet or triplet combination will have adequate 
precision to exclude 30% (lower limit of 90% CI > 30%). The threshold for the CBR rate at 24 weeks is 
defined based on the assumption that PFS follows an exponential distribution with a median of 5 months 
(clinically relevant) and 3.5 months (not clinically relevant).  
Cohort 2: 40 evaluable patients with observed CBR of at least 45% will provide enough precision to exclude 
30% (lower limit of 90% CI>30%). The threshold for CBR at 24 weeks is defined based on the assumption 
that PFS follows an exponential distribution with a median of 5 months (clinically relevant) and 3.5 months 
(not clinically relevant). 
The final number of patients will depend on the safety and efficacy outcomes during the study. Up to ~130 
patients are anticipated, allowing for a total of 40 patients in each of the three planned combination 
regimens and a ~10% rate of non-evaluable patients. 
Definitions 
All efficacy endpoints will be defined and analyzed based on tumor assessment by RECIST 1.1. 
CBR: the proportion of patients with a best overall response of CR, PR or SD ≥ 24 weeks. 
ORR: the proportion of patients with best overall response of CR or PR.  
PFS: the time from treatment start until radiologic progression or death due to any cause. 
PFS ratio: the ratio of PFS with the previous regimen to PFS on study treatment. 
DoR: the time from response (CR or PR) until progression or death due to underlying cancer. 
OS: the time from treatment start until death due to any cause. 
Endpoints 
Primary  
Cohorts 1 and 2: CBR per investigator radiologic review at 24 weeks  
Key secondary  
Cohort 1: CBR at 24 weeks per central review, and ORR, PFS, and DoR per investigator and central review 
Cohort 2: CBR at 24 weeks per central review, and PFS per investigator and central review 
Other secondary (both cohorts): 
Safety: Incidence, severity and relationship of AEs, laboratory abnormalities, SAEs, ECG and LVEF 
measurements and vital signs 


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Tolerability: discontinuations due to AEs, dose modifications due to AEs, immunogenicity, and cytokine 
assessments 
Other efficacy: DoR (Cohort 2), PFS ratio (Cohort 2), ORR (Cohort 2), and OS (Cohorts 1 and 2) 
Pharmacokinetics: Cmax, C0h, AUC, CL, Vss, tmax and t1/2 for MCLA-128, and CEOI and C0h for trastuzumab. 
Analysis populations  
Treated population: patients who receive at least one dose of MCLA-128. 
Evaluable for efficacy: patients who receive at least 2 complete cycles (6 weeks) of treatment and have 
undergone baseline assessment and one on-study tumor assessment, or who discontinue early due to 
disease progression. 
Analyses 
Patient disposition and demographics will be analyzed in the treated population, efficacy will be analyzed in 
the evaluable for efficacy population, and safety will be analyzed in the treated population. 
Quantitative variables will be summarized using descriptive statistics. Continuous variables will be 
presented as N, mean and/or median, standard deviation, range. Categorical variables will be presented 
using frequencies and percentage. 
Criteria for success primary endpoint for Cohorts 1 and 2: A median PFS of 5 months is assumed as relevant, 
with the activity threshold for CBR at 24 weeks set to 45%. 
CBR and ORR will be summarized with accompanying 90% exact binomial CI.  
For PFS, OS and DoR the survival function will be estimated using the Kaplan-Meier product limit method; 
probability estimates and 90% CI will be provided at specified time points; median duration and 90% CI will 
also be provided. DoR will be estimated for responders only. The number and proportion of any patients 
with a PFS ratio ≥ 1.3 will be tabulated for Cohort 2 with 90% exact CI. 
AEs will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA®) preferred term and by 
organ class according to incidence and severity. Severity of AEs will be based on CTCAE 4.03.  
PK, immunogenicity, cytokines and biomarkers will be analyzed centrally and reported separately. 
STUDY DURATION 
First patient in: November 2017 
Completion of data analyses: June 2024 


Protocol MCLA-128-CL02  
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Summary of study procedures for all patients 
 
Protocol 
Section 
Screening 
STUDY TREATMENT 
PERIOD 
1 Cycle = 21 days 
STUDY 
TREATMENT 
PERIOD 
AS PER 
PROTOCOL 
VERSION 5.0 
END OF 
TREATMENT 
VISIT (EOT) 
FOLLOW-UP 
PERIOD 
END OF 
TREATMENT 
VISIT (EOT) &  
FOLLOW-UP 
VISIT 
AS PER 
PROTOCOL 
VERSION 5.0 
STUDY PROCEDURES (all 
patients) 
 
≤28 days 
before 
treatment 
Day 1 of
each 
cycle 
As indicated  
on-study 
1 Cycle = 21 days 
35±5 days 
from last dosing 
Every 
3 months 
35±5 days 
from last dosing 
General Assessments 
 
 
 
 
 
 
 
 
Informed consent 
15.3 
X 
 
 
 
 
 
 
Patient enrollment form 
 
X 
 
 
 
 
 
 
Eligibility criteria 
4 
X 
 
 
 
 
 
 
Demographics, medical history 
- 
X 
 
 
 
 
 
 
Diagnosis and prior treatment 
- 
X 
 
 
 
 
 
 
Baseline symptoms and 
complaints 
8 
X 
 
 
 
 
 
 
Concomitant medication 
6.2 
 
Continuous 
X 
 
 
 
Laboratory Tests 
 
 
 
 
 
 
 
 
Serum pregnancy test (other 
than for patients with proven 
menopause or surgically sterile) 
8.10 
X 
≤7 days 
before 
treatment 
 
 
 
X 
 
X 
Urine pregnancy test (a serum 
test must be carried out to 
confirm a positive result) 
8.10 
 
X 
 
X 
 
Up to 7 months 
after last MCLA-
128/trastuzumab 
treatment 
 
Urinalysis (dipstick) 
8.2 
X 
As clinically indicated 
 
X 
 
 
Tumor Assessments 
 
 
 
 
 
 
 
 
CT/MRI scans of chest, abdomen, 
pelvis, and brain 
9.1 
X 
 
X 
every 6 weeks 
after start of 
X 
every 4 cycles 
(12 weeks). In 
If previous 
imaging 
For patients who 
discontinue for 
reasons other 
For patients 
who 
discontinue for 


Protocol MCLA-128-CL02  
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Page 18 of 127 
 
Protocol 
Section 
Screening 
STUDY TREATMENT 
PERIOD 
1 Cycle = 21 days 
STUDY 
TREATMENT 
PERIOD 
AS PER 
PROTOCOL 
VERSION 5.0 
END OF 
TREATMENT 
VISIT (EOT) 
FOLLOW-UP 
PERIOD 
END OF 
TREATMENT 
VISIT (EOT) &  
FOLLOW-UP 
VISIT 
AS PER 
PROTOCOL 
VERSION 5.0 
STUDY PROCEDURES (all 
patients) 
 
≤28 days 
before 
treatment 
Day 1 of
each 
cycle 
As indicated  
on-study 
1 Cycle = 21 days 
35±5 days 
from last dosing 
Every 
3 months 
35±5 days 
from last dosing 
any clinically indicated sites of 
disease and bone lesions as 
appropriate throughout 
treatment; clinical evaluation of 
superficial disease 
* Follow-up brain scans should 
only be conducted if lesions are 
present at baseline 
study 
treatment until 
progression 
case of 
symptomatic 
deterioration 
signs or signs of 
PD in between 
the 
assessments an 
unscheduled 
assessment 
must be 
performed. 
assessment is >6 
weeks prior 
than progression, 
as clinically 
indicated 
reasons other 
than 
progression, as 
clinically 
indicated 
Radionuclide bone scan, whole 
body 
9.1 
X 
 as close as 
possible 
and ≤9 
weeks 
before 
starting 
study 
treatment 
 
As clinically 
indicated to 
assess baseline 
or suspected 
new bone 
metastases 
As clinically 
indicated to 
assess baseline or
suspected new 
bone metastases
 
As clinically 
indicated to 
assess suspected 
new bone 
metastases for 
patients who 
discontinue for 
reasons other 
than progression 
 
As clinically 
indicated to 
assess 
suspected new 
bone 
metastases for 
patients who 
discontinue for 
reasons other 
than 
progression 
 
 
 


Protocol MCLA-128-CL02  
Version 5.0, 11 April 2022 
 
 
 
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Tumor markers (CA15-3, CEA, 
CA27-29) 
(as far as possible, measures 
should be made in the same 
laboratory)  
9.2 
X 
within 7 
days before
treatment  
X 
 
 
X 
For patients with 
elevated levels at 
screening who 
discontinue for 
reasons other 
than progression 
For patients 
with elevated 
levels at 
screening who 
discontinue for 
reasons other 
than 
progression. 
Other Clinical Assessments 
 
 
 
 
 
 
 
 
Adverse events 
8 
 
Continuous 
X 
 
Related cardiac 
events up to 1 
year 
X 
Serious adverse events 
8 
 
Continuous 
X 
 
Suspected only, up 
to 1 year 
X 
LVEF (by ECHO or MUGA) and 12-
lead electrocardiogram (ECG) 
8.8.2 
X 
As close as
possible 
to and 
within 4 
weeks 
prior to 
Day 1 
Cycle 1. 
 
X 
Pre-dose Day 1, 
every 4 cycles  
(C5, C9, etc) 
unless 
performed <7 
days, and as 
clinically 
indicated 
LVEF/ECG every 6
months and at any
time during the 
study if clinically 
indicated. 
X  
if >6 weeks since 
last assessment 
All patients will 
undergo LVEF/ECG 
every 6 months for 
1 year after the last 
MCLA-128 dose. 
Patients who 
discontinue due to 
decrease in LVEF 
and/or possible 
CHF should 
continue LVEF 
assessments as 
clinically indicated 
(≤18 weeks 
between 
assessments), until 
initiation of a new 
anticancer therapy, 
LVEF values return 
to ≥50% or for 1 
year, whichever is 
first. 
X 
Pharmacokinetics 
10 
 
 
Protocol 
Versions 1.0, 
 
 
 
 


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2.0 and 3.0 
only:  
Cycles 1, 2, 3, 5, 
then every 4 
cycles  
Immunogenicity assessment 
13 
 
 
Protocol 
Versions 1.0, 
2.0 and 3.0 
only:  
Pre-dose Day 1 
Cycles 1, 3, 5 
then every 4 
cycles (C9, C13, 
etc)  
 
Protocol Versions 
1.0, 2.0 and 3.0 
only:  
X 
 
 
Fresh tumor OR archival sample 
within 24 months prior to 
screening (for HER2 status, 
exploratory biomarkers, and HR 
status as appropriate)* 
11.1.1 
X 
 
Optional sample 
12 weeks after 
start of study 
treatment 
 
Optional 
(preferably from 
site of 
progression) 
 
Optional 
(preferably from 
site of 
progression) 
Liquid biopsy (for exploratory 
biomarkers) 
11.1.2 
 
 
Pre-dose Day 1 
Cycle 1, then 
every 4 cycles 
(C5, C9, etc) 
 
X 
 
 
Other investigations as clinically 
indicated  
- 
X 
X 
X 
x 
X 
X 
X 
*For Cohort 2 patients with bone-only disease, primary tumor tissue will be used (unless it is determined that testing for HER2 expression in a bone biopsy is possible) 
 
 
 
 
 


Protocol MCLA-128-CL02  
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Summary of study procedures and timings specific to Cohort 1 patients (doublet and triplet combinations) 
 
Protocol 
Section 
Screening 
STUDY TREATMENT PERIOD  
1 Cycle = 21 days 
STUDY 
TREATMENT 
PERIOD  
AS PER PROTOCOL
VERSION 5.0 
 
END OF 
TREATMENT VISIT
END OF 
TREATMENT 
VISIT (EOT) &  
FOLLOW-UP VISIT 
AS PER PROTOCOL
VERSION 5.0 
STUDY PROCEDURES (Cohort 1) 
 
≤7 days before 
treatment  
Days 1, 2, 8 and 9 of each cycle as specified 
1 Cycle = 21 days 
35±5 days  
from last dosing 
35±5 days 
from last dosing 
Clinical Assessments 
 
 
 
 
 
 
Physical examination, ECOG PS, height 
(screening only) and weight, vital signs  
Appendix 
19.1 
X 
Doublet: Days 1 and 8 of Cycle 1 and Day 1 of 
each subsequent cycle 
Triplet safety run-in: Days 1,2 and 9 of Cycle 
1 and Days 1 and 8 of each subsequent cycle 
Triplet expansion: Days 1 and 8 of each cycle 
 
X 
X 
Cytokine panel 
12 
 
Doublet safety run-in: Days 1 and 2 of Cycle 
1 and Day 1 of Cycle 2 
Triplet safety run-in: Day 1 of Cycles 1 and 2 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
Complete blood count (CBC)  
8.2 
X 
Doublet: Days 1 and 8 of Cycle 1 and Day 1 of 
each subsequent cycle 
Triplet safety run-in: Days 1 and 9 of Cycle 1 
and Days 1 and 8 of each subsequent cycle  
Triplet expansion: Days 1 and 8 of each cycle 
Days 1 and 8 of 
each cycle 
X 
X 
Serum chemistries 
8.2 
X 
Doublet: Days 1 and 8 of Cycle 1 and Day 1 of 
each subsequent cycle 
Triplet safety run-in: Days 1 and 9 of Cycle 1 
and Days 1 and 8 of each subsequent cycle 
Triplet expansion: Days 1 and 8 of each cycle 
Days 1 and 8 of 
each cycle 
X 
X 
Study Treatment 
 
 
 
 
 
 
MCLA-128 premedication (immediately 
prior to MCLA-128) 
5.3.1.1 
 
Day 1 of each cycle 
X 
 
 
MCLA-128 (intravenous) 
5.3.1.1 
 
Day 1 of each cycle 
X 
 
 
Trastuzumab (intravenous; 30 min after 
MCLA-128 when given on the same day) 
5.3.1.2 
 
Doublet safety run-in: Day 2 of Cycle 1 and 
Day 1 of each subsequent cycle 
X 
 
 


Protocol MCLA-128-CL02  
Version 5.0, 11 April 2022 
 
 
 
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Protocol 
Section 
Screening 
STUDY TREATMENT PERIOD  
1 Cycle = 21 days 
STUDY 
TREATMENT 
PERIOD  
AS PER PROTOCOL
VERSION 5.0 
 
END OF 
TREATMENT VISIT
END OF 
TREATMENT 
VISIT (EOT) &  
FOLLOW-UP VISIT 
AS PER PROTOCOL
VERSION 5.0 
STUDY PROCEDURES (Cohort 1) 
 
≤7 days before 
treatment  
Days 1, 2, 8 and 9 of each cycle as specified 
1 Cycle = 21 days 
35±5 days  
from last dosing 
35±5 days 
from last dosing 
Doublet expansion and all triplet: Day 1 of 
each cycle 
Vinorelbine (intravenous; 30 min after 
trastuzumab when given on the same day) 
 
5.3.1.3 
 
Triplet safety run-in: Days 2 and 9 of Cycle 1, 
then Days 1 and 8 of each subsequent cycle 
Triplet expansion: Days 1 and 8 of each cycle 
X 
 
 
 
 


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Summary of study procedures and timings specific to Cohort 2 patients (MCLA-128 + endocrine therapy combination) 
 
Protocol 
Section 
Screening 
STUDY TREATMENT PERIOD  
1 Cycle = 21 days 
STUDY TREATMENT 
PERIOD  
AS PER PROTOCOL 
VERSION 5.0 
 
 
END OF TREATMENT
VISIT 
END OF TREATMENT 
VISIT (EOT) &  
FOLLOW-UP VISIT 
AS PER PROTOCOL 
VERSION 5.0 
STUDY PROCEDURES (Cohort 2) 
 
≤7 days before    
treatment  
Day 1 of each 
cycle  
Day 8 of Cycle 1 
only 
1 Cycle = 21 days  
35±5 days  
from last dosing 
35±5 days 
from last dosing 
Clinical Assessments 
 
 
 
 
 
 
 
Physical examination, ECOG PS, height 
(screening only) and weight, vital signs  
Appendix 
19.1 
X 
X 
X 
 
X 
X 
DEXA scan (bone mineral density) 
- 
X 
Up to 6 months 
prior to Day 1 
Cycle1 
X 
Every 12 months since last evaluation 
X 
Every 12 months 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
Complete blood count (CBC) 
8.2 
X 
X 
X 
Day 1 of each cycle 
X 
X 
Serum chemistries 
8.2 
X 
X 
X 
Day 1 of each cycle 
X 
X 
Study Treatment 
 
 
 
 
 
 
 
MCLA-128 premedication (immediately 
prior to MCLA-128) 
5.3.1.1 
 
X 
 
X 
 
 
MCLA-128 (intravenous) 
5.3.1.1 
 
X 
 
X 
 
 
Endocrine therapy (as per last prior line 
immediately before study entry) 
5.3.1.4 
 
Same dose and regimen on which the 
patient most recently progressed 
X 
 
 
 
 


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TABLE OF CONTENTS 
KEY STUDY CONTACTS 
2 
SPONSOR SIGNATURE PAGE 
3 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
4 
PROTOCOL SYNOPSIS 
7 
TABLE OF CONTENTS 
24 
ABBREVIATIONS 
29 
1 
BACKGROUND 
32 
1.1 
Metastatic Breast Cancer and Current Therapeutic Options 
32 
1.1.1 
HER2-Positive Breast Cancer 
32 
1.1.2 
Hormone Receptor Positive Breast Cancer 
34 
1.2 
Development of MCLA-128 
36 
1.2.1 
Description of MCLA-128 
36 
1.2.2 
Preclinical Studies 
36 
1.2.3 
MCLA-128 Clinical Experience 
38 
1.3 
Rationale for the Current Study 
41 
1.3.1 
Preclinical Studies for MCLA-128 + Trastuzumab in HER2-Positive MBC 
41 
1.3.2 
Preclinical Studies for MCLA-128 + Endocrine Therapy in Hormone Receptor-
Positive/HER2-Negative MBC 
41 
1.3.3 
Rationale for MCLA-128 Combination Therapy Study Design 
43 
2 
STUDY OBJECTIVES 
44 
2.1 
Cohort 1: MCLA-128 + Trastuzumab ± Vinorelbine in HER2-Positive/Amplified MBC 
44 
2.2 
Cohort 2: MCLA-128 + Endocrine Therapy in Estrogen Receptor [ER]-Positive/Low HER2 
Expression MBC 
44 
3 
STUDY DESIGN AND DURATION 
45 
3.1 
Study Design 
45 
3.2 
Study Duration 
46 
4 
SELECTION OF PATIENTS 
47 
4.1 
Number of Patients 
47 
4.2 
Inclusion Criteria 
47 
4.3 
Exclusion Criteria 
48 
5 
STUDY TREATMENT 
50 


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5.1 
Formulations and Storage 
50 
5.1.1 
MCLA-128 
50 
5.1.2 
Trastuzumab 
50 
5.1.3 
Vinorelbine 
50 
5.1.4 
Endocrine Therapy 
50 
5.2 
Preparation for Administration 
50 
5.2.1 
MCLA-128 
50 
5.2.2 
Companion Study Drugs 
51 
5.3 
Study Drugs Administration 
51 
5.3.1 
Study Drugs 
51 
5.3.2 
Combination Treatment Schedules 
52 
5.3.3 
Dose Adaptation 
55 
5.4 
Treatment Withdrawal 
57 
5.5 
Packaging and Labeling 
58 
5.5.1 
MCLA-128 
58 
5.5.2 
Companion Study Drugs 
58 
5.6 
Supplies and Accountability 
58 
5.7 
Compliance 
59 
6 
PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS 
59 
6.1 
Medical Conditions 
59 
6.2 
Medications 
59 
7 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS 
61 
7.1 
Screening, Eligibility and Enrolment Procedures 
69 
7.2 
Evaluations On-Study 
70 
7.3 
End of Treatment Visit and Follow-Up 
70 
8 
SAFETY ASSESSMENTS 
70 
8.1 
Clinical Safety 
70 
8.2 
Laboratory Measurements 
71 
8.3 
Definitions (21 CFR§312.32) 
71 
8.4 
Documentation 
73 
8.5 
Grade and Severity 
74 
8.6 
Relationship to Study Treatment 
74 


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8.7 
SAE Reporting Requirements 
75 
8.8 
AEs of Special Interest 
75 
8.8.1 
Infusion-related reactions 
75 
8.8.2 
Cardiotoxicity 
76 
8.8.3 
Diarrhea 
76 
8.9 
Period of Observation 
76 
8.10 
Patients of Reproductive Potential 
77 
8.11 
Misuse and Overdose 
78 
8.12 
Independent Data Monitoring Committee 
78 
9 
EFFICACY ASSESSMENTS 
78 
9.1 
RECIST Tumor Measurement and Analysis 
78 
9.1.1 
Central review 
79 
9.1.2 
Imaging Technique 
80 
9.1.3 
Evaluation of Lesions 
80 
9.1.4 
Definition of Best Overall Tumor Response 
81 
9.2 
Tumor Markers 
82 
10 
PHARMACOKINETICS ASSESSMENTS 
83 
11 
PHARMACODYNAMICS ASSESSMENTS 
84 
11.1 
Sample collection 
84 
11.1.1 
Tumor sample 
85 
11.1.2 
Liquid Biopsy 
85 
11.2 
Analyses 
86 
11.2.1 
Tumor HER2 and Hormone Receptor Status 
86 
11.2.2 
Exploratory Biomarker Analyses 
86 
12 
CYTOKINE ASSESSMENTS 
87 
13 
IMMUNOGENICITY ASSESSMENTS 
87 
14 
STATISTICAL CONSIDERATIONS 
88 
14.1 
Sample Size 
88 
14.2 
Study Endpoints 
88 
14.2.1 
Definitions 
88 
14.2.2 
Endpoints 
89 
14.3 
Analysis Populations 
89 


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14.4 
Statistical Analyses 
89 
14.4.1 
Analysis of the Primary Efficacy Endpoint 
90 
14.4.2 
Analysis of Other Efficacy Endpoints 
90 
14.4.3 
Analysis of the Safety Endpoints 
90 
14.4.4 
Analyses of PK, Immunogenicity, Cytokines and Biomarkers 
91 
14.5 
Interim Analysis 
91 
15 
ETHICAL AND LEGAL ASPECTS 
91 
15.1 
Ethical Conduct 
91 
15.2 
Delegation of Investigator Duties 
91 
15.3 
Patient Information and Informed Consent 
92 
15.4 
Confidentiality 
92 
15.5 
Approval of the Clinical Study Protocol and Amendments 
92 
15.6 
Ongoing Information for IEC/ IRB and Health Authorities 
93 
15.7 
Study Closure 
93 
15.8 
Record Retention 
93 
15.9 
Liability and Insurance 
93 
15.10 Financial Disclosure 
94 
16 
STUDY MONITORING AND AUDITING 
94 
16.1 
Monitoring and Source Data Verification 
94 
16.2 
On-Site Audits/Inspections 
94 
17 
Documentation and use of study findings 
95 
17.1 
Documentation of Study Findings 
95 
17.2 
Confidentiality, Use of Study Findings and Publication Policy 
95 
18 
REFERENCES 
97 
19 
APPENDICES 
105 
19.1 
Appendix 1: ECOG Performance Status 
105 
19.2 
Appendix 2: Calculation of renal clearance 
106 
19.3 
Appendix 3: Algorithm for MCLA-128 (MCLA) and trastuzumab (T) treatment with 
symptomatic LVEF decline 
107 
19.4 
Appendix 4: New Response Evaluation Criteria in Solid Tumors - Revised RECIST Guidelines 
(Version 1.1) 
108 
19.5 
Appendix 5: Summary of Product Characteristics (SPC)/Package Insert 
127 
List of Tables 


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Table 5-1: Composition of MCLA-128 for Intravenous Infusion, 20 mg/mL 
50 
Table 7-1: Study procedures for all patients 
62 
Table 7-2: Study procedures and timings specific to Cohort 1 patients (doublet and triplet 
combinations) 
66 
Table 7-3: Study procedures and timings specific to Cohort 2 patients (MCLA-128 + endocrine 
therapy combination) 
Error! Bookmark not defined. 
Table 8-1: Hematology and chemistry sampling 
71 
Table 9-1: Tumor imaging assessments 
79 
Table 9-2: Evaluation of response in target lesions 
80 
Table 9-3: Evaluation of non-target lesions 
80 
Table 9-4: Overall response in patients with target (+/- non-target) disease 
81 
Table 9-5: Best overall response 
81 
Table 10-1: MCLA-128 PK blood sampling (Cohort 1, doublet and triplet) 
83 
Table 10-2: Trastuzumab PK blood sampling (Cohort 1) 
83 
Table 10-3: MCLA-128 PK blood sampling (Cohort 2) 
84 
Table 11-1: Tumor biomarker sampling 
85 
Table 11-2: Liquid biopsy biomarker sampling 
85 
Table 12-1: Cytokine blood sampling (Cohort 1 doublet safety run-in) 
87 
Table 12-2: Cytokine blood sampling (Cohort 1 triplet safety run-in) 
87 
 
List of Figures 
Figure 3-1: Study design for Cohort 1 combination therapies (doublet and triplet) 
45 
Figure 3-2: Study design for Cohort 2 combination therapies 
46 
Figure 5-1: Doublet combination treatment administration in safety run-in patients 
53 
Figure 5-2: Doublet combination treatment administration in expansion patients 
53 
Figure 5-3: Triplet combination treatment administration in safety run-in patients 
54 
Figure 5-4: Triplet combination treatment administration in expansion patients 
54 
Figure 5-5: Cohort 2 treatment administration in all patients 
55 
 
 
 
 


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ABBREVIATIONS 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody-Dependent Cell-Mediated Cytotoxicity 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
AUC 
Area Under The Curve 
CBR 
Clinical Benefit Rate 
CEOI 
Concentration at the end of the infusion 
CHF 
Congestive Heart Failure 
CHO 
Chinese Hamster Ovary 
CL 
Clearance 
Cmax 
Maximum Drug Concentration 
CR  
Complete Response 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria For Adverse Events 
ctDNA 
Circulating Tumor DNA 
DEXA 
Dual-Energy X-ray Absorptiometry 
EC20/50 
Concentration Corresponding to 20%/50% of Maximum Effect  
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGF 
Epidermal Growth Factor 
EGFR 
Epidermal Growth Factor Receptor 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EOI 
End of Infusion 
EOT 
End of Treatment 
ER 
Estrogen Receptor 
ET 
Endocrine Therapy 
Fab 
Fragment Antigen-Binding 
Fc 
Fragment Crystallizable 
FDA 
Food And Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
HER 
Human Epidermal Growth Factor Receptor 
FISH 
Fluorescence In Situ Hybridization 
HR 
Hazard Ratio 


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HRG 
Heregulin 
IC50 
Half Maximal Inhibitory Concentration 
ICH 
International Conference On Harmonization 
IDMC 
Independent Data Monitoring Committee  
IFN 
Interferon 
Ig 
Immunoglobulin 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IRB 
Independent Review Board 
IL 
Interleukin 
IM 
Intramuscular 
IRR 
Infusion Related Reactions 
IV 
Intravenous 
KD 
Dissociation Constant 
LDH 
Lactate Dehydrogenase 
LVEF 
Left Ventricular Ejection Fraction 
MBC 
Metastatic Breast Cancer 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple Gated Acquisition 
NFKB 
Nuclear Factor Kappa  
ORR 
Overall Response Rate 
OS 
Overall Survival 
OTD 
Oncology Therapeutic Development 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PO 
Per Os 
PR 
Partial Response 
PT 
Preferred Term 
QD 
Once Daily 
q3w 
Once Every 3 Weeks 
QTc 
Corrected QT Interval 
RP2D 
Recommended Phase 2 Dose 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria In Solid Tumors Guidelines 
RTK 
Receptor Tyrosine Kinase 


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SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
System, Organ, Class 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
t1/2 
Terminal half-Life 
Tmax 
Time Of Observed Maximum Serum Drug Concentration 
TNBC 
Triple Negative Breast Cancer 
TNF 
Tumor Necrosis Factor 
V 
Apparent Volume Of Distribution 
Vss 
Volume Of Distribution At Steady State 
WBC 
White Blood Cell 
 
 


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1 
BACKGROUND 
1.1 
Metastatic Breast Cancer and Current Therapeutic Options 
Breast cancer is a global disease, with a yearly incidence of over 1.67 million patients worldwide 
reported in 2012, accounting for over 25% of all cancers in women and ranking as the fifth cause of 
cancer death in women (522,000 deaths) (IARC/WHO). In the United States, over 250,000 women are 
expected to develop the disease in 2017, with over 40,010 deaths (Siegel et al., 2017).  
Approximately 5-10% of breast cancer patients are diagnosed with metastasis at initial presentation, 
and overall 20% will eventually develop metastasis (Chang et al., 2003). The development of 
metastases dramatically worsens the prognosis. About 90% of breast cancer mortality is due to 
metastases that are resistant to adjuvant therapies (Gonzalez-Angulo et al., 2007). Metastatic breast 
cancers (MBC) represent a heterogeneous population with a diverse clinical course. Median survival 
ranges from 15 to 27 months in stage IV breast cancer despite more aggressive disease management 
and recent more effective therapeutic agents (Andre et al., 2004; Giordano et al., 2004; Dawood et 
al., 2008), and overall survival (OS) rates vary significantly. This highly unpredictable clinical behavior 
reflects the biologic heterogeneity of the disease, which is classified based on the presence or the 
absence of hormone receptors for estrogen and/or progesterone, and the expression/amplification 
status of the human epidermal growth factor receptor 2 (HER2) protein/oncogene (Hammond et al., 
2010; Wolff et al., 2013).  
The primary goals of systemic treatment for MBC are prolongation of survival, alleviation of 
symptoms, and maintenance or improvement in quality of life, despite the toxicity associated with 
treatment (Osoba, 1995; Geels et al., 2000; Stockler et al., 2000). Systemic treatments for MBC include 
chemotherapy, endocrine therapy (ET), biological targeted therapy, and supportive therapy. For 
patients with advanced MBC, the choice of therapy is based on considerations related to patient 
characteristics and comorbidities, disease status, prior treatments, and biological characteristics of 
the tumor (NCCN, 2017.; Bernard-Marty et al., 2004).  
1.1.1 
HER2-Positive Breast Cancer 
Approximately 15% to 20% of breast cancer tumors overexpress HER2 (Slamon et al., 1987; Witton et 
al., 2003), a member of the HER superfamily composed of tyrosine kinase receptors regulating 
proliferation and survival of epithelial cells. The family includes four receptors: HER1 (epidermal 
growth factor receptor [EGFR]), HER2 [neu, C-erbB2], HER3 and HER4. HER2 is considered an orphan 
receptor as it has no known ligand, while the three other HER receptors have known ligands and form 
either homodimers or heterodimers upon ligand binding. HER2 can heterodimerize with any of the 
other receptors and is considered the preferred dimerization partner. Dimerization results in 
autophosphorylation of tyrosine residues within the receptor cytoplasmic domain and initiates signal 
transduction via the PI3K/AKT and RAS/MAPK pathways (Browne et al., 2009; Castaneda et al., 2010).  
HER2 overexpression/amplification in breast cancers is associated with a more aggressive clinical 
phenotype and historically portends poor prognosis (Slamon et al., 1987). Although HER2-
overexpression identifies patients who are likely to respond to therapy with trastuzumab, not all these 
patients retain benefit from treatment. Approximately 15% of patients relapse after therapy, 
indicating the presence of de novo or acquired resistance (Nahta and Esteva, 2006). Several resistance 
mechanisms have been proposed including (1) altered receptor-antibody interaction, (2) activation of 
downstream pathways via increased signaling from other HER family members or other receptors, or 
(3) constitutive activation of downstream elements.  


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1.1.1.1 
Anti-HER2 Antibodies in HER2-Positive MBC 
The humanized anti-HER2 antibody trastuzumab (Herceptin®) improves response rate, PFS and OS 
when added to chemotherapy for advanced HER2-positive breast cancers (Slamon et al., 2001). In 
early stage HER2-positive breast cancer, several pivotal trials have shown improvements in disease-
free survival and OS, and trastuzumab/chemotherapy combination has now become standard therapy 
for most such cases (O’Sullivan et al., 2015). Nonetheless approximately 30–50% of patients with naïve 
HER2-positive MBC do not achieve an objective response in the first-line setting indicating de novo 
resistance to trastuzumab, with both time to progression (TTP) and OS being short (7–17 months and 
22–38 months, respectively) (Slamon et al., 2001; Baselga et al., 2012b; Nielsen et al., 2013; Swain et 
al., 2013). This has motivated the development of alternative approaches to block HER2 signaling. 
Multiple lines of research have highlighted a central role for HER3 signaling as a key mechanism for de 
novo and acquired resistance to HER2 therapies in several tumor types leading to the development of 
compounds aimed at disrupting signaling through HER2:HER3 heterodimerization, the mechanism by 
which HER3 elicits signaling (Jiang et al., 2012). 
Pertuzumab is a fully humanized monoclonal antibody that binds to a different epitope of the HER2 
extracellular domain (subdomain II) than trastuzumab (subdomain IV), presumably preventing HER2 
from dimerizing with other HER family members (EGFR, HER3 and HER4), notably HER3. In 2012, 
results from the phase 3 CLEOPATRA study (Clinical Evaluation of Pertuzumab and Trastuzumab) led 
to FDA approval for pertuzumab in combination with trastuzumab and docetaxel for the treatment of 
patients with HER2-positive MBC who have not received prior anti-HER2 or chemotherapy for 
metastatic disease. The primary endpoint of centrally confirmed PFS was significantly longer with the 
addition of pertuzumab, improved by 6.3 months from a median of 12.4 to 18.5 months (hazard ratio 
[HR] of 0.62 for progression or death, 95% CI 0.51–0.75, p <0.001) (Baselga et al., 2012b). OS was also 
markedly prolonged with the addition of pertuzumab, with 15.7-month increase from 40.8 to 56.5 
months (HR 0.68, 95% CI 0.56–0.84, p <0.001) (Swain et al., 2015), confirming that this triple drug 
combination is a promising approach. 
1.1.1.2 
T-DM1 in HER2-Positive MBC 
Ado-trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate composed of trastuzumab 
linked to emtansine (DM1; a derivative of maytansine), a highly potent anti-microtubule cytotoxic 
agent. T-DM1 was granted FDA approval in 2013 for HER2-positive MBC progressing after trastuzumab 
and taxane therapy in the metastatic setting, or following early relapse on adjuvant trastuzumab-
based therapy. Approval was based on the EMILIA trial, a randomized, open-label, international phase 
3 trial comparing T-DM1 with lapatinib plus capecitabine in patients with HER2-positive MBC 
previously treated with trastuzumab and a taxane (Verma et al., 2012). Median PFS was significantly 
prolonged with T-DM1 compared with lapatinib plus capecitabine (9.6 versus 6.4 months; HR for 
progression or death from any cause 0.65, 95% CI 0.55–0.75, p <0.001). Median OS was also 
significantly improved with T-DM1 (30.9 versus 25.1 months; HR for death from any cause 0.68, 95% 
CI 0.55–0.85, p <0.001) and ORR was higher with T-DM1 (43.6% versus 30.8%, p <0.001). Based on 
this, T-DM1 is now the standard of care as second-line therapy for HER2-positive MBC. A second 
randomized, open-label, international phase 3 trial (TH3RESA) provided supportive data (Krop et al., 
2017). For patients progressing on trastuzumab-based therapy and T-DM1, treatment options include 
trastuzumab with another chemotherapy agent, or with combined capecitabine and lapatinib.  


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1.1.2 
Hormone Receptor Positive Breast Cancer  
Approximately 75% of breast cancers are considered estrogen and/or progesterone receptor positive 
(Nadji et al., 2005; Rugo, 2008). Such tumors are associated with better survival than those with low 
or no estrogen receptor expression (Yu et al., 2012). The hormone estrogen (17ß-estradiol E2) 
represents the primary stimulant in the growth and development of these tumors (Johnston and 
Dowsett, 2003). Thus, deprivation of estrogen signaling via ET has become the mainstay of treatment 
for early and metastatic estrogen receptor positive (ER+) disease in the absence of visceral crisis.  
1.1.2.1 
Endocrine Therapy 
A variety of ET options are available, including oophorectomy, gonadotropin-releasing hormone 
analogs, selective estrogen receptor modulators (SERMs; tamoxifen), selective estrogen receptor 
degraders (SERDs; fulvestrant) and aromatase inhibitors (AIs; letrozole, anastrozole and exemestane) 
(Buzdar and Hortobagyi, 1998; Lumachi et al., 2015). AIs block estrogen production by inhibiting 
aromatases in both peripheral tissues and the cancer, and are only effective for postmenopausal 
women in whom the major source of estrogen comes from the conversion of androgens to estrogens 
via aromatase enzyme activity in peripheral tissues such as adipose tissue and the breast. Tamoxifen 
was the first selective estrogen receptor modulator used clinically and is still widely prescribed in pre-
menopausal women. 
The use of hormone therapies targeting and downregulating estrogen receptor signaling is a mainstay 
of treatment for patients with ER+ breast cancers, and has substantially reduced the relapse rate for 
early-stage breast cancer (Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 2005). However 
about one-third of all hormone receptor-positive/HER2-negative patients diagnosed with early stage 
disease, experience disease recurrence (Baselga et al., 2012b), and in this setting single-agent AIs or 
tamoxifen show limited clinical benefit (Klijn et al., 2000; Baselga et al., 2012a). Resistance manifests 
as either relapse after treatment of primary hormone receptor-positive breast cancer or as disease 
progression in the metastatic setting (Larionov and Miller, 2009; Dalmau et al., 2014).  
ET resistance is complex and heterogeneous and may differ from patient to patient, between primary 
and acquired resistance and even between ET types. A wide range of distinct mechanisms implicated 
in ET resistance in breast cancer have been described including 1) ER mutations in the ligand-binding 
domain (Li et al., 2013; Merenbakh-Lamin et al., 2013; Segal and Dowsett, 2014), epigenetic changes 
(Parl, 2003; Fan et al., 2006) or reduced expression (Martínez-Galán et al., 2014), 2) crosstalk between 
the ER and EGFR/HER2 involving the PI3K-Akt-mTOR and MAPK pathways, with HER2 overexpression 
conferring ET resistance, even in the presence of hormone receptors (Lupien et al., 2010) with 
crosstalk resulting in estrogen receptor phosphorylation and activation (Campbell et al., 2001; Yamnik 
et al., 2009), 3) NFKB signaling and inflammation including overexpression in ET-resistant breast 
tumors (Gu et al., 2002; deGraffenried et al., 2004a; Zhu et al., 2006; Morrison et al., 2014), 4) cancer 
stem cell development may be resistant to ET due to low estrogen receptor expression, 5) prolonged 
estrogen deprivation can lead to estrogen hypersensitivity (Herynk et al., 2010), 6) epithelial-
mesenchymal transition with loss of estrogen receptor expression, and 7) inhibition of phagocytosis 
can re-sensitize resistant cells to tamoxifen (Clarke, 2011). 
1.1.2.2 
CDK4/6 Therapy 
A more recent strategy in treating ER+ breast cancer is to target cyclin-dependent kinases 4 and 6 
(CDK4/6), a key pathway involved in regulation of the G1/S transition of the cell cycle. Preclinical 


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models suggest a particular role for CDK4/6 inhibition in ER+ breast cancer cells, including estrogen-
sensitive and estrogen-resistant models. Cyclin D1 amplification is a common event in ER+ breast 
cancer, identified in 58% of hormone receptor-positive/HER2-negative breast cancer (Cancer Genome 
Atlas Network, 2012). Antiestrogen-induced growth arrest in ER+ breast cancer cells is accompanied 
by decreased cyclin D1 expression, whereas the emergence of ET resistance is associated with 
persistent cyclin D1 expression and retinoblastoma (Rb) phosphorylation (Watts et al., 1995; 
Thangavel et al., 2011). Evidence of a continued role for CDK4/6 inhibition in ET-resistant ER+ cells 
comes from in vitro evaluation of the CDK4/6 inhibitor palbociclib in a panel of molecularly 
characterized breast cancer cell lines that demonstrated the most activity in ER+ cancers including 
those with conditioned estrogen resistance (Finn et al., 2009).  
Anti-CDK4/6 agents inhibit the phosphorylation of the Rb tumor suppressor, which promotes Rb-E2F 
binding and prevents E2F-mediated oncogenic transcription. Compelling preclinical data indicate the 
efficacy of palbociclib in ER+ breast cancer cell lines (Fry et al., 2004; Toogood et al., 2005; Dean et al., 
2010). The phase 3 PALOMA-2 trial confirmed 10-month improved PFS in women with ER+ MBC 
treated with first-line letrozole plus palbociclib versus letrozole alone (24.8 vs 14.5 months, HR, 0.58; 
P <.000001) (Finn et al., 2016), i.e., in women who had not received ET for metastatic disease. The 
phase 3 PALOMA-3 trial demonstrated 5-month improved PFS in women with ER+ MBC who had 
progressed despite ET for metastatic disease, treated with palbociclib plus fulvestrant, versus 
fulvestrant alone (9.5 vs 4.6 months; HR, 0.46; P <.0001) (Cristofanilli et al., 2016). Thus palbociclib 
plus letrozole is the preferred first-line therapy in women with ER+ MBC, and palbociclib plus 
fulvestrant is effective therapy in patients with ER+ MBC not previously treated with palbociclib who 
have progressed on a nonsteroidal AI. 
The success of palbociclib spurred the development of other CDK4/6 inhibitors including ribociclib 
(Hortobagyi et al., 2016), which is now FDA approved in combination with fulvestrant, and 
abemaciclib, which has been granted an FDA breakthrough therapy designation, while FDA approval 
will be requested for abemaciclib in combination with fulvestrant, based on the MONARCH-2 study 
(Sledge et al., 2017). 
1.1.2.3 
mTOR Inhibition 
The PI3K-Akt-mTOR pathway is a key intracellular signaling pathway playing a significant role in cell 
growth and proliferation, and is implicated in resistance to ET, HER2-directed therapy, and cytotoxic 
chemotherapy. Furthermore, mTOR inhibitors such as everolimus synergized with letrozole in 
preclinical models (Mayer, 2013) and mTOR was described as a mechanism facilitating escape of long-
term estrogen deprivation (deGraffenried et al., 2004b). The addition of mTOR inhibitors to ET has 
been investigated in phase 2 and 3 trials, including patients with ER+/HER2-negative MBC.  
The phase 3 trial BOLERO-2 enrolled 724 patients with ER+ advanced breast cancer with recurrence 
during or within 12 months after adjuvant non-steroidal AIs or progression during or within 1 month 
after AI treatment (Baselga et al., 2012a). Patients were randomized to receive everolimus combined 
with exemestane versus exemestane plus placebo. The pre-planned interim analysis showed that 
median PFS was significantly better for everolimus plus exemestane compared to the control arm, for 
both investigator analyses (6.9 months versus 2.8 months; HR = 0.43, 95% CI 0.35-0.54, p <0.001) and 
central analyses (10.6 versus 4.1 months, HR = 0.36, 95% CI 0.27 to 0.47, p <0.001). After a median 18-
month follow-up, the addition of everolimus to exemestane was confirmed to significantly improve 
patient outcome over exemestane alone (median PFS 7.8 versus 3.2 months, HR = 0.45, 95% CI 0.38 


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to 0.54, p  <0.0001) (Yardley et al., 2013). Everolimus in combination with exemestane is approved by 
both the FDA and the EMA for hormone receptor-positive/HER2-negative advanced MBC patients 
after failure of a non-steroidal AI. 
1.2 
Development of MCLA-128 
1.2.1 
Description of MCLA-128  
MCLA-128 is a bispecific humanized full length IgG1 antibody with enhanced antibody-dependent cell-
mediated cytotoxicity (ADCC) activity targeting the receptor tyrosine kinases HER2 and HER3. It is 
produced by recombinant expression in the Chinese hamster ovary cell line, CHO-DG44.  
Molecular formula: 
C6479H9997N1725O2024S45 
Molecular mass: 
145.9 kDa 
Chemical name: 
Not yet issued 
INN:  
Not yet issued 
MCLA-128 is composed of two identical common light chains and two different heavy chains each 
containing a different fragment antigen-binding. The Fc regions of both heavy chains have been 
engineered in a complementary manner using CH3 engineering, to ensure efficient 
heterodimerization and bispecific antibody formation and to enhance ADCC activity following a 
reduction of fucosylation. MCLA-128 has a 1331 amino acid sequence containing four disulfide bonds 
and a molecular weight of 145.9 kDa. 
MCLA-128 acts via two independent mechanisms of action: 1) inhibition of HER3 pathway signaling by 
disruption of HER2:HER3 heterodimerization and 2) elimination of tumor cells via enhanced ADCC, 
and employs a ‘dock and block’ mechanism. Based on X-ray crystal structure, MCLA-128 docks to the 
HER2 domain I which orientates the HER3 binding arm to block the HER3 domain III (putative HRG 
domain), thus blocking oncogenic signaling via the HER2:HER3 heterodimer (Maussang-Detaille et al.). 
MCLA-128 does not compete with trastuzumab for binding to HER2 since it is binding to a different 
domain. 
MCLA-128 is formulated as a clear liquid solution for infusion at a target concentration of 20 mg/mL 
in 25 mM histidine, 220 mM trehalose and 0.16 mM polysorbate 20 at pH 6.0 in clear type I glass vials 
with an extractable volume of 5 mL or 18.8 mL. 
1.2.2 
Preclinical Studies  
1.2.2.1 
Pharmacology 
In vitro pharmacodynamic studies showed the mean KD values for MCLA-128 of 3.2 and 2.0 nM in BT-
474 and SK-BR-3 cells (HER2-amplified breast cancer cell lines also expressing HER3), respectively, and 
which were in the same range as for trastuzumab (3.7 and 1.3 nM respectively). Although KD values of 
the individual HER2 and HER3 Fabs of MCLA-128 showed a higher affinity for the HER3 Fab compared 
to HER2 Fab, the overall affinity of MCLA-128 was closest to the HER2 Fab and correlates with the 
overexpression of HER2 in the cell lines. MCLA-128 potently inhibited heregulin (HRG)-induced 
proliferation and morphologic changes of HER2-overexpressing breast cancer cell lines SK-BR-3 and 
BT-474. MCLA-128 has been shown to inhibit HRG-mediated proliferation in breast and gastric cell 
lines, at a notably lower half-maximal inhibitory concentration (IC50=35 pM) than combined 


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trastuzumab and pertuzumab, and fully inhibited HRG (3.75 nM)-induced HER2:HER3 dimerization 
with a higher potency than the anti-HER2 pertuzumab plus trastuzumab antibody combination. HRG 
binds to HER3, resulting in its dimerization with HER2 and subsequent induction of intracellular 
signaling (Peess et al., 2015). MCLA-128 selectively inhibits the formation of HRG-induced HER2:HER3 
dimers. 
In vivo, MCLA-128 was evaluated in a xenograft murine model with the breast cancer cell line JIMT-1 
leading to tumor volume reduction after 29 days with 60% survival (with four weekly doses of 25 or 
2.5 mg/kg MCLA-128), while no animals treated with trastuzumab and pertuzumab experienced a 
decrease in tumor volume and none survived. Both HER2:HER3 heterodimerization and HER3:PI3K 
formation was significantly inhibited in MCLA-128-treated tumor tissue. 
Breast cancer brain metastases are known to use an HRG-dependent survival mechanism (Momeny 
et al., 2015). In an orthotopic ST1360B murine brain metastatic breast cancer model, all mice treated 
with MCLA-128 (25 mg/kg twice weekly) survived for 21 days, compared to all vehicle animals which 
were sacrificed. 
1.2.2.2 
Pharmacokinetics 
The cynomolgus monkey was selected as the non-clinical toxicology species due to cross reactivity of 
the two Fab fragments in MCLA-128 towards both human and monkey HER2 and HER3, and lack of 
cross-reactivity of the HER2 binding arm to rodent HER2. 
Following a single intravenous dose of MCLA-128 in cynomolgus monkeys, systemic exposure was 
dose proportional across the range 10-100 mg/kg, with terminal elimination half-lives in the range 73-
210 hours. Half-life tended to increase with increasing dosage, suggesting a possible contribution from 
target-mediated clearance at lower dosages, with endogenous IgG clearance mechanisms being more 
predominant at higher dosages. The calculated volumes of distribution were in the range 68.3-121 
mL/kg, slightly higher than the plasma volume in monkeys, suggesting limited distribution outside the 
plasma compartment.  
Exposure following the first dose in the repeated dose toxicity study (five doses of MCLA-128, once 
weekly for 5 weeks) was dose-proportional and there was no sex difference in PK parameters. Most 
animals were continuously exposed to MCLA-128 during the treatment period, with a 3-fold 
accumulation (based on AUC) observed in females at 10 mg/kg/week, no accumulation at 30 
mg/kg/week, and only slight accumulation (1.4-1.7 fold) in low-dose males (10 mg/kg/week) and 
animals at 100 mg/kg/week. Few animals showed evidence of loss of exposure towards the end of the 
treatment period, which correlated with the presence of ADA.  
1.2.2.3 
Toxicology 
MCLA-128 was well tolerated following single and repeated dose (up to five weekly doses) intravenous 
administration in cynomolgus monkeys, with no treatment-related clinical, laboratory or pathological 
findings up to the highest dose tested (100 mg/kg).  
There was no evidence of cardiotoxicity or effects on thyroid function. The 1-month repeated dose 
toxicity study in cynomolgus monkeys, at IV doses up to 100 mg/kg, showed that MCLA-128 had no 
effect on the central or peripheral nervous systems, ECG intervals, blood pressure, or respiration rate. 
There was some evidence of an immune response to MCLA-128 in a few treated animals in the 
repeated dose toxicity study, but all treated animals were exposed to MCLA-128 for all of or the 


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majority of the treatment period, such that the formation of ADA in isolated animals was not 
considered to have compromised the safety evaluation. There were no treatment-related changes to 
hematologic, chemistry or urinalysis parameters. Overall, all changes observed were procedural in 
origin, or related to an immune response to MCLA-128 in individual monkeys in the treatment groups. 
There was no evidence of target organ toxicity in the clinical pathology investigations or terminal 
pathology data. 
MCLA-128 formulations showed good local tolerability, with no evidence of local irritation at injection 
sites in the cynomolgus monkey toxicity studies, and no hemolytic potential or plasma incompatibility 
in an in vitro hemocompatibility study conducted in human blood. A tissue cross-reactivity study 
conducted with human tissues showed no evidence of any non-specific or ‘off-target’ binding that was 
likely to be of clinical concern, most non-epithelial binding being cytoplasmic in nature, and thus 
unlikely to be relevant to the in vivo administration. 
There was no evidence of cytokine release after infusion of MCLA-128 in cynomolgus monkeys at 
doses up to 100 mg/kg. Since monkeys are known to be poor predictors of cytokine release in humans, 
in vitro cytokine release studies were performed. In vitro cytokine release studies conducted using 
whole human blood from healthy donors showed a very low potential for MCLA-128 to induce 
cytokine release, compared to reference antibodies such as Campath®. In this test system, both MCLA-
128 and trastuzumab showed little or no cytokine release However, since trastuzumab is known to 
induce a certain incidence of infusion reactions in clinical use, and there are likely to be low levels of 
HER2/HER3 expression in healthy donor blood (as used in the in vitro cytokine release assays), further 
cytokine release testing was performed as part of the ADCC effector function assays conducted with 
HER2 and HER3 expressing cell lines. In these studies, cytokines were determined in supernatants 
collected following co-incubation of human effector cells (PBMCs) with the HER2 and HER3 expressing 
SK-BR-3 cell line, with or without addition of MCLA-128 (and also trastuzumab as a comparator 
antibody). Based on the EC20 and EC50 values for the four cytokines that were significantly released 
upon incubation with the therapeutic antibodies (i.e. IFNγ, IL-6, IL-8 and TNFα), it can be concluded 
that MCLA-128 was 2.2 to 7.1 times more potent in inducing cytokine release than trastuzumab. 
Genotoxicity and carcinogenicity studies are not considered appropriate for this class of biological 
product. 
1.2.3 
MCLA-128 Clinical Experience 
At the time of protocol writing, MCLA-128 was under evaluation in an ongoing first-in-human phase 
1/2 study in adult patients with advanced solid tumors (MCLA-128-CL01). A summary of this open-
label dose-escalation study of single agent MCLA-128 followed by cohort expansion at the 
recommended phase 2 dose (RP2D) is summarized here. See the Investigator Brochure for further 
details. 
The primary objective of the dose escalation part of the study was to determine the maximum 
tolerated dose (MTD) in patients with advanced or metastatic epithelial tumors relapsed or refractory 
to at least 2 prior regimens of standard treatment or without any standard treatment available. 
Secondary objectives included safety/tolerability, PK, immunogenicity and efficacy.  
The phase 1 part of the study is complete with 9 dose levels investigated with MCLA-128 administered 
at 40, 80, and 160 mg in cohorts of 1 patient, then 240, 360, 480, 600, 750, and 900 mg (flat dose) 
once every 3 weeks (q3w) administered over 60-120 minutes intravenously (IV) in cohorts of 3 to 6 


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patients. No dose limiting toxicities were experienced up to and including 900 mg in the phase 1 part. 
The Data Review Committee selected 750 mg q3w as the RP2D as a 120-minute IV infusion based on 
the cumulative safety profile, available PK data and a PK simulation study.  
At the initiation of the current MCLA-128-CL02 study, safety, tolerability and efficacy were under 
evaluation at the RP2D in the phase 2 part in selected solid tumor expansion cohorts with advanced 
or metastatic relapsed or refractory epithelial HER2-expressing tumors; to date, cohorts have been 
opened for metastatic breast, gastric/gastroesophageal, ovarian, colorectal (cohort closed 
prematurely), non-small cell lung cancer and endometrial cancers. 
1.2.3.1 
Patients and Treatment 
As of 15 February 2017, a total of 47 patients were enrolled in the study, 28 in the phase 1 part and 
19 in the phase 2 part.  
In the phase 1 part, median age was 60 years (range 25-83), 61% of patients were male, and ECOG PS 
was 0/1 in 43%/57% of patients. The main tumor types were colorectal (8 patients), 
gastric/gastroesophageal (6 patients), and breast (3 patients). Patients had a median of 2 metastatic 
sites (0-14) and had received a median of 3 lines of prior metastatic therapy (range 1-7). 
Among the 19 patients enrolled in the phase 2 part (3 not yet treated at the data cut-off), ten had 
breast cancer, 6 gastric/gastroesophageal, 2 ovarian, and 1 colorectal cancer. Median age was 54 years 
(range 33-74), 32% of patients were male, and ECOG PS was 0/1 in 17%/83% of patients. Patients had 
a median of 2.5 metastatic sites (range 1-4) and had received a median of 5.5 prior lines of metastatic 
therapy (2-18). All 10 enrolled breast cancer patients had received 3-4 prior lines of anti-HER2 
therapies. 
A median of 2 cycles (range 1-28) were administered to the phase 1 patients and as of 15 Feb 2017, 
of the 19 enrolled phase 2 patients, 16 had been treated, receiving a median of 3 cycles (range 1-12), 
while the 9 treated MBC patients receiving a median of 5 cycles (range 2-12). 
1.2.3.2 
Safety  
In the phase 1 part, the most frequent related adverse events (AEs) were infusion-related reactions 
(IRRs; 10 patients, 36%), and gastrointestinal toxicity, notably nausea (8 patients, 29%), vomiting (7 
patients, 25%), diarrhea (5 patients, 18%), and stomatitis (4 patients, 14%). Asthenia/fatigue were 
reported in 4/2 patients (14%/7%) and skin disorders (rash/dermatitis/fissures/nail disorder) in 6 
patients (21%). All related AEs were grade 1-2 other than one grade 3 event (suspected related IRR). 
In the phase 2 part, the most frequent AEs were IRRs (4 patients, 25%), diarrhea (3 patients, 19%), and 
fatigue (2 patients, 13%). All but one were grade 1-2, with 1 patient experiencing a grade 4 suspected 
related hypersensitivity reaction (allergy) which had a fatal outcome. This 71-year-old gastric 
carcinoma patient experienced a grade 4 hypersensitivity reaction (life-threatening). At baseline she 
had 56% LVEF and severe aortic valve and mitral valve stenosis with no clinical manifestations. On the 
first day of treatment she was premedicated with dexamethasone (5 mg), polaramine (5 mg) and 
paracetamol (1 g). After administration of 60 mL of MCLA-128 (out of 250 mL total) she presented 
with a grade 4 allergic reaction, and subsequent cardiorespiratory arrest, and died 9 hours after 
treatment initiation. The investigator reported that the allergic reaction was definitely related to the 
study drug. The patient had no history of hypersensitivity, allergic or anaphylactic reactions. As per 


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the investigator, the allergic reaction was the driver of the causality of the death however the patient’s 
comorbidities, notably severe aortic stenosis likely played a major contributing role.  
Key aspects of the MCLA-128 safety profile are: 
• 
IRRs, which were analyzed according to all preferred terms considered by the investigator as 
manifestations of IRRs occurring within 24 hours of the MCLA-128 infusion (including notably IRR, 
hypersensitivity, nausea, vomiting, pyrexia, etc.) were reported in 14 phase 1 patients (50%) and 
5 phase 2 patients (31%). All but 2 IRRs were grade 1-2 and resolved completely with symptomatic 
treatment. 
• 
No suspected cardiac clinical AEs or clinically significant LVEF declines occurred; overall 5/27 
(19%) evaluable patients had grade 2 LVEF decreases, none symptomatic or clinically significant 
(defined as LVEF decline > 10% from baseline and to a value of < 50%). 
• 
No severe (grade 3-4) diarrhea or diarrhea requiring treatment discontinuation was observed.  
1.2.3.3 
Pharmacokinetics, Cytokines and Immunogenicity  
In the 28 phase 1 patients Cmax and area under the concentration versus time curve (AUC) increased 
with increasing dose. Terminal half-life (t½) increased with increasing dose up to 360 mg, as is typically 
observed for antibodies that are cleared by target-mediated clearance, after which it did not increase 
significantly, giving an approximately dose-proportional increase of MCLA-128 exposure from 480 mg. 
Among the 16 patients treated at the RP2D of 750 mg q3w (6 phase 1, 10 phase 2), mean Cmax was 194 
µg/mL, and AUC0-∞ was 22500 µg·h/mL, Vss was 4.5 L (indicating that distribution is confined to the 
blood and interstitial fluids, typical of antibodies), CL was 37 mL/h, and t½ was 101 h. After 21 days, 
median trough levels were 2.6 µg/mL, well above the MCLA-128 concentration that results in 50% 
receptor occupancy in vitro (KD) (Alsina et al., 2017). 
An interim population PK analysis on PK samples of 26 phase 1 patients covering all dose levels, 
showed PK data were best described by a two-compartment model with parallel linear and 
concentration-dependent (nonlinear) clearance from the central compartment. The nonlinear 
clearance reflects elimination processes of MCLA-128 after its saturating binding to the targets. The 
linear clearance represents the elimination of unbound MCLA-128. Estimated parameters were in 
accordance with parameters calculated by the non-compartmental analysis and with PK 
characteristics of therapeutic antibodies in general. The Km value that determines the serum 
concentration at which a half maximal elimination rate is achieved was estimated at 0.290 µg/mL 
which is in the same range as the KD obtained for MCLA-128 on HER2-amplified BC cell lines. 
Only 1 patient (160 mg MCLA-128) of 34 evaluable (from both phase 1 and 2 patients) had a positive 
anti-drug-antibody (ADA) titer at Day 36, with no apparent effect on PK. All other patients were ADA-
negative throughout treatment. 
At the RP2D, modest and transient cytokine elevations from baseline were observed 2 hours after the 
end of the infusion, mainly in IFNγ (0.4-3.4 fold), IL-8 (0.7-8.4 fold) and TNFα (0.8-11.6 fold) (Alsina et 
al., 2017). 
1.2.3.4 
Clinical Activity Including MBC Patients 
Among the 28 evaluable phase 1 patients, 1 non-small cell lung cancer patient had a confirmed PR 
(360 mg, 18.0 months) and 3 patients had SD >3 months (breast, 3.6 months; colorectal, 7.3 months; 


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gastroesophageal junction, 13.4+ months). 
Sixteen phase 2 patients were evaluable, 9 MBC and 7 with other tumors. Antitumor activity was seen 
in 6 MBC patients (1 PR and 5 SD), and 2 other tumor types (2 SD including a gastric patient with 7+ 
cycles).  
Evaluation of efficacy in the overall MBC cohort at potentially active MCLA-128 doses (9 phase 2 
treated at 750 mg, 2 phase 2 treated at 480 mg [1 phase 1 patient treated at 40 mg was not included 
for efficacy evaluation]), 1 patient had PR and 7 had SD (4 lasting ≥ 5 months), giving a clinical benefit 
rate (CBR) in MBC patients of 64% (7/11 patients). All these patients were heavily pretreated, all with 
2-5 anti-HER therapy lines (Alsina et al., 2017). 
1.3 
Rationale for the Current Study 
Breast cancer management has a significant need in the MBC setting for new agents with novel 
mechanisms of action and non-overlapping toxicity, which can be combined with established breast 
cancer treatments to overcome resistance for different patient populations.  
1.3.1 
Preclinical Studies for MCLA-128 + Trastuzumab in HER2-Positive MBC 
There is a strong rationale to combine trastuzumab with MCLA-128 for the treatment of MBC. 
Trastuzumab is effective in blocking constitutive ligand-independent signaling through the HER2:HER3 
heterodimer in the context of HER2 overexpression. However, it has very poor growth inhibition 
activity in tumors and cell lines where HER2:HER3 signaling is driven by HER3 ligand dependency 
(Wehrman et al., 2006; Junttila et al., 2009). Preclinical and clinical evidence points to increased HER3 
expression and/or HER3 ligand upregulation as the main drivers leading to trastuzumab resistance 
(Sergina et al., 2007; Ocana et al., 2013). The bispecific antibody MCLA-128 docks HER2 present on the 
cancer cells to subsequently lock HER3 in an inactive confirmation. This results in potent inhibition of 
the HRG ligand-induced HER2:HER3 dimer formation and may overcome the resistance mechanism 
observed with trastuzumab. 
Preclinical studies showed that the combination of MCLA-128 and trastuzumab was more potent than 
single-agent MCLA-128 to block HRG-induced tumor proliferation, supporting the addition of MCLA-
128 to a trastuzumab-containing regimen in the clinic. In addition, the bispecific anti-HER2xHER3 
antibody MCLA-128 presents enhanced ADCC. The monovalent interaction of the antibody to HER2 
results in a greater density of antibody per tumor cell. In turn, this will result in greater recruitment of 
immune effector cells and, combined with ADCC, superior tumor cell killing activity. 
In light of the distinct mechanisms of action for MCLA-128 and trastuzumab, these preclinical data 
suggest that administration of MCLA-128 and trastuzumab in HER2-positive patients has the potential 
for additive or synergistic activity in this setting.  
1.3.2 
Preclinical Studies for MCLA-128 + Endocrine Therapy in Hormone Receptor-
Positive/HER2-Negative MBC 
Bidirectional crosstalk between ER and HER2/3 has been hypothesized to underlie ET resistance via 
their activation (Houston et al., 1999; Thrane et al., 2013). The HER2:HER3 heterodimer activates 
PI3K/AKT and MAPK downstream signaling cascades but can also induce ER phosphorylation 
independent of estrogen (Pietras et al., 1995; Curley et al., 2015) which may reduce the effectiveness 
of endocrine therapies (Arpino et al., 2008). On the other hand, HER2 may be preferentially 
upregulated by estrogen deprivation, while tamoxifen induces expression of EGFR and HER2 (García-


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Becerra et al., 2012). The nature of the HER2/ERα cross-talk seems to be conditioned by the context 
of endocrine resistance; in a series of paired biopsies from patients relapsing on tamoxifen evaluated 
in an in vivo model, conversion from HER2-negative to HER2-positive was rare, however <20% of 
tamoxifen-resistant patients relapsed with adaptive upregulation in HER2 and either suppressed or 
enhanced ERα expression and signaling (Gutierrez et al., 2005).  
Taken together, these data support a combined ER/HER2-targeted approach in patients with acquired 
ET resistance in ERα-positive/HER2-negative breast cancer. The EGF30008 trial comparing letrozole 
alone versus in combination with lapatinib in hormone receptor-positive MBC suggests this may be 
translated into the clinic, as although the addition of lapatinib did not confer benefit in the overall 
hormone receptor-positive/HER2-negative group, there was a trend toward a benefit in the 
endocrine-resistant hormone receptor-positive/HER2-negative subset (Johnston et al., 2009). 
A recent preclinical study took this concept a step further, demonstrating direct cross-talk between 
HER2/HER3 and ER with phosphorylation of ER only observed in cells expressing both HER2 and ER 
or HER3 and ER (Collins et al., 2017). The authors used an in vivo mouse model of ER+/HER2-low 
(HER2 IHC 1+ or 2+ without gene amplification) human breast cancer to evaluate a triple therapy 
targeting HER2 (pertuzumab), HER3 (lumretuzumab) and the ER (fulvestrant), resulting in long-lasting 
tumor regression. 
Preclinical studies support that adding MCLA-128 to hormonal treatment could delay or reverse 
resistance to therapy in ER+ HER2- (HER2 IHC 1+ or 2+ by HercepTest™) breast cancer. MCLA-128 with 
anti-ER drugs (tamoxifen and fulvestrant) combined with the AI letrozole was evaluated in two in vivo 
xenograft models of ER+ HER2-low breast cancer. All hormone therapies reduced tumor growth, while 
MCLA-128 single agent had no efficacy. However, when MCLA-128 was added to the hormone therapy 
regimen, it led to a further decreased in tumor growth. Mechanistically, HER2 expression was 
increased with fulvestrant and tamoxifen, which is supported by published studies (Osipo et al., 2007; 
García-Becerra et al., 2012). When MCLA-128 was added to anti-ER drugs, this increase in HER2 could 
be reversed. Most importantly, a proximity ligation assay showed that fulvestrant treatment 
upregulated the formation of HER2:HER3 dimers and enhanced activation of the Akt signaling 
pathway, which could be inhibited by adding MCLA-128. Together, these data show that the efficacy 
of hormonal therapies may be limited due to activation of the HER2/HER3 signaling axis, which could 
be reversed by MCLA-128. 
While the in vivo tumor models tested responded to hormonal therapy, there is also evidence that in 
the context of ET-resistant tumors, the inhibition of HER3 by MCLA-128 could be therapeutically 
beneficial, as suggested by Collins et al. (2017). The MCF-7 cell line engineered to respond to AIs was 
initially sensitive to letrozole, but tumors subsequently became resistant (Curley et al., 2015). The 
addition of an anti-HER3 antibody at the start of treatment was more effective than hormone therapy 
alone, as observed for MCLA-128. Importantly, the combination of the anti-HER3 with hormone 
therapy after resistance restored antitumor activity. This was not the case when the anti-HER3 was 
given as single agent, demonstrating that hormone receptor and HER3 inhibition work in synergy 
before and after the occurrence of HT resistance. 
In patients with ER-positive/low HER2 expression MBC, based on this strong preclinical evidence, a 
rescue approach will be used to evaluate the effect of the addition of MCLA-128 on the natural history 
of the disease when treated with ET. 


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1.3.3 
Rationale for MCLA-128 Combination Therapy Study Design 
The study will be carried out in two distinct patient populations, HER2-positive/amplified MBC who 
will be treated with MCLA-128 and trastuzumab ± chemotherapy (Cohort 1), evaluated as doublet and 
triplet combinations, and ER-positive/low HER2 expression MBC patients who will be treated with 
MCLA-128 combined with the same ET that each patient progressed on immediately prior to study 
entry (Cohort 2). 
The RP2D of 750 mg MCLA-128 IV, over 2 hours, q3w, was established in the phase 1/2 dose escalation 
study, a dose shown to be well tolerated. Mandatory premedication with all MCLA-128 infusions has 
been implemented to mitigate IRRs, and the infusion duration can be extended from 2 to 4 hours to 
further improve infusion tolerance. MCLA-128 is very well tolerated with few and mainly mild to 
moderate toxicities and potential toxicity associated with the proposed combination agents is 
expected to be manageable; the IRRs reported with MCLA-128 at the RP2D were almost all grade 1 or 
2 and were managed with medication, while the introduction of mandatory premedication improved 
management of this toxicity. Clinical cardiac toxicity has not been reported, and gastrointestinal 
toxicity is grade 1 or 2. 
The study design allows for cautious verification of the safety of combining two anti-HER2 monoclonal 
antibodies in Cohort 1, at multiple levels. The initial administration of the doublet agents, MCLA-128 
and trastuzumab will be on consecutive days. Consecutive administration but on the same day is 
anticipated for subsequent cycles if the combination is considered well tolerated. Subsequent 
evaluation of administration of the two antibodies from treatment initiation will be investigated in 
patients enrolled later, to support a practical administration regimen in the long-term. The same 
principle will be applied for assessment of the triplet combination, with the antibody doublet 
administration initially, followed by chemotherapy the next day. In addition, the doublet and triplet 
combinations themselves will be evaluated sequentially to ensure safety. The implementation of a 
safety run-in evaluation in a small group of patients for each combination will provide safety data 
before committing to continuing full recruitment. 
 
 
 


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2 
STUDY OBJECTIVES 
2.1 
Cohort 1: MCLA-128 + Trastuzumab ± Vinorelbine in HER2-Positive/Amplified MBC 
Primary objective: 
• 
Evaluate efficacy of MCLA-128 combined with trastuzumab ± vinorelbine in terms of clinical 
benefit rate (CBR) at 24 weeks based on RECIST 1.1 (per investigator review) in HER2-
positive/amplified MBC patients who have progressed on prior HER2-directed therapy that 
included trastuzumab, pertuzumab, and an HER2 antibody drug conjugate (ADC) in any sequence 
and in any setting. 
Secondary objectives: 
• 
Evaluate CBR at 24 weeks based on RECIST 1.1 per central review 
• 
Evaluate progression-free survival (PFS; per investigator and central review) 
• 
Evaluate overall response rate (ORR) based on RECIST 1.1 (per investigator and central review) 
• 
Evaluate duration of response (DoR) based on RECIST v1.1 (per investigator and central review) 
• 
Evaluate overall survival (OS) 
• 
Evaluate safety and tolerability of MCLA-128 in combination with trastuzumab ± vinorelbine  
• 
Characterize pharmacokinetics (PK) of MCLA-128 in combination with trastuzumab ± 
vinorelbine 
• 
Characterize immunogenicity of MCLA-128 in combination with trastuzumab 
Exploratory objective: 
• 
Evaluate potential correlations between biomarkers in tumor or blood samples and antitumor 
activity (including HER2, HER3, HER2:HER3 dimers, heregulin and other potential biomarkers) 
2.2 
Cohort 2: MCLA-128 + Endocrine Therapy in Estrogen Receptor [ER]-Positive/Low HER2 
Expression MBC 
Primary objective: 
• 
Evaluate efficacy of MCLA-128 combined with endocrine therapy in terms of CBR at 24 weeks 
based on RECIST 1.1 (per investigator review) in ER-positive and low HER2 expression MBC 
patients who have previously progressed on the same endocrine therapy 
Secondary objectives:  
• 
Evaluate CBR at 24 weeks based on RECIST 1.1 per central review 
• 
Evaluate PFS (per investigator and central review) 
• 
Evaluate ORR based on RECIST 1.1 (per investigator and central review) 
• 
Evaluate DoR based on RECIST 1.1 (per investigator and central review) 
• 
Evaluate OS 
• 
Evaluate safety and tolerability of MCLA-128 combined with endocrine therapy 
• 
Characterize PK of MCLA-128 combined with endocrine therapy 
• 
Characterize immunogenicity of MCLA-128 combined with endocrine therapy 
Exploratory objective: 
• 
Evaluate potential correlations between biomarkers in tumor or blood samples and antitumor 
activity (including HER2, HER3, HER2:HER3 dimers, heregulin and other potential biomarkers) 


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3 
STUDY DESIGN AND DURATION 
3.1 
Study Design 
This is a phase 2, open-label, multicenter international study to evaluate the efficacy of MCLA-128-
based combinations in two metastatic breast cancer (MBC) populations, HER2-positive/amplified 
(Cohort 1) and ER-positive/low HER2 expression (Cohort 2). 
Three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2. A total of up to 
120 evaluable patients will be included in approximately 20-30 centers in 7 countries in Europe and 
the USA. 
Cohort 1: Patients with HER2-positive/amplified MBC, having confirmed HER2 overexpression by 
immunohistochemistry (IHC) 3+ or IHC 2+ combined with positive fluorescence in situ hybridization 
(FISH), who have been treated with up to a maximum of 5 lines of HER2-directed therapy in the 
metastatic setting and have progressed on the most recent line as per RECIST v1.1, are eligible. 
Patients must have been treated previously with trastuzumab, pertuzumab and an HER2 ADC in any 
sequence and in any setting. For enrollment, HER2 status will be based on medical records, and 
eligibility will be confirmed subsequently as soon as possible, by central lab review. Patients found to 
be ineligible retrospectively will not be evaluable for the primary objective and may be replaced. 
Documented imaging proof of disease progression on the last prior line of therapy should be made 
available when possible.  
Initially MCLA-128 will be administered with trastuzumab (doublet combination). Safety will be 
reviewed by an Independent Data Monitoring Committee (IDMC). After the safety of the doublet has 
been assessed, MCLA-128 + trastuzumab + vinorelbine (triplet combination) will be evaluated in 
parallel with the doublet combination (see Figure 3-1 below). 
The doublet and triplet Cohort 1 combinations will both be evaluated in two steps with an initial 
safety run-in in 4 to 6 patients who will be reviewed by the IDMC, followed by a cohort efficacy 
expansion, as described below. The triplet combination go/no-go decision will be made by the IDMC 
after evaluation of the doublet safety run-in patients. If the triplet combination is considered safe, 
the expansion of the doublet and triplet combinations will be performed in parallel. Patients with be 
included with a 3:1 ratio for triplet or doublet respectively, favoring the triplet combination and 
taking into account previous exposure to vinorelbine. 
 
Figure 3-1: Study design for Cohort 1 combination therapies (doublet and triplet) 
 
Safety run-in: After 4-6 patients have received at least 2 complete cycles (6 weeks) of MCLA-128 + 
trastuzumab, a safety review will be performed by the IDMC. If the doublet combination is considered 
safe, the safety run-in for the triplet combination will be initiated in the next 4 to 6 successive eligible 
patients. Safety of the triplet will be evaluated by the IDMC after these 4-6 patients have received at 
least 2 complete cycles (6 weeks) of MCLA-128 + trastuzumab + vinorelbine. 


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Based on the observed safety in the first 4-6 patients (adverse events [AEs], serious adverse events 
[SAEs], relationship to study drug, and other clinically relevant parameters [e.g. laboratory 
parameters], available PK, immunogenicity, and cytokine data) the IDMC, investigators and Sponsor 
will decide on a potential additional run-in period for each combination (i.e. doublet and triplet).  
Expansion: After the safety run-in, each Cohort 1 combination therapy considered tolerable by the 
IDMC will be expanded to a total of up to 40 patients evaluable for efficacy.  
If the doublet combination regimen is not tolerated, Cohort 1 will be closed. If the triplet combination 
is not well tolerated but the doublet is acceptable, the doublet expansion will be continued.  
Cohort 2: Patients with ER-positive and low HER2 expression MBC (IHC 1+, or IHC 2+ combined with 
negative FISH) who have radiologic or photographic evidence of disease progression on the last line 
of prior endocrine therapy (administered for at least 12 weeks) that included an aromatase inhibitor 
or fulvestrant. Patients who have received up to 3 prior endocrine therapies in the metastatic setting 
and have progressed on a cyclin-dependent kinase inhibitor (in any line) are eligible. For enrollment, 
HER2 and HR status and radiologic/photographic documentation of prior progression will be based on 
medical records. Eligibility will be confirmed as soon as possible for HER2/HR status by central lab 
review and for prior disease progression by central imaging review. Patients found to be ineligible 
retrospectively will not be evaluable for the primary objective and may be replaced. 
MCLA-128 will be administered in combination with the same previous endocrine therapy on which 
progressive disease is radiologically/photographically documented. A total of up to 40 patients 
evaluable for efficacy will be included. 
Figure 3-2: Study design for Cohort 2 combination therapies  
 
The IDMC will meet to review safety and efficacy data at select time points during the study (e.g. 
completion of safety run in, completion of enrollment), according to an IDMC Charter (see section 
8.12). 
Imaging for all patients will be reviewed centrally to confirm on-study disease assessments for analysis 
of efficacy endpoints. 
All patients will receive MCLA-128 at 750 mg IV over 2 hours, Day 1, q3w, with 3-week cycles until 
disease progression or unacceptable toxicity (see also section 5.4). Trastuzumab and vinorelbine will 
be administered according to standard doses and regimens, and endocrine therapy will be 
administered as the same dose and regimen of the last line of endocrine therapy received prior to 
study entry on which the patient progressed.  
3.2 
Study Duration 
Recruitment in this study has been closed and there remain a few patients on treatment who have all 
been on treatment for at least 24 months at the time of Protocol Version 5.0 implementation.    


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The implementation of Protocol Version 5.0, allows as per Investigator discretion, patients who  have 
been treated for at least 2 years and continue to benefit from the study drug, to roll over in an 
alternative program e.g. Post-study or Expanded Access Use.  Patients who will continue in this 
protocol, will only be followed for local efficacy, related adverse events, all related Serious Adverse 
Events and LVEF. After treatment withdrawal patients should attend the combined EOT and Follow-
Up visit 35 ± 5 days after the last treatment administration. 
The study will be closed after the last patient on study has been followed-up for 35 ± 5 days after the 
last treatment administration or after the last patient is rolled over into an alternative program. 
Protocol Version 5.0 is applicable for the few patients who currently remain on treatment. Any 
patients who discontinued their treatment and are in Follow-Up at the time of amendment, will be 
assessed as per the previous Protocol Version 4.0. 
The Sponsor has the right to prematurely terminate or suspend the entire study or close a given study 
site at any time for any reason. Such a decision will be communicated to the investigator(s) in writing. 
 
4 
SELECTION OF PATIENTS 
4.1 
Number of Patients 
Across the two population cohorts, in total up to approximately 120 evaluable patients are planned 
to be accrued in this study. The final sample size will depend on the safety and efficacy encountered 
in each of the three treatment combinations. 
4.2 
Inclusion Criteria 
Patients must fulfill all of the following requirements to enter the study: 
1. Signed informed consent before initiation of any study procedures. 
2. Women with histologically or cytologically confirmed breast cancer with evidence of metastatic 
or locally advanced disease not amenable to any local therapy with curative intent: 
2.1 Cohort 1 (MCLA-128 + trastuzumab ± vinorelbine) 
a. Documented HER2 overexpression/amplification, defined as immunohistochemistry (IHC) 
3+ positive, or IHC 2+ combined with positive fluorescence in situ hybridization (FISH), 
based on local analysis on the most recent tumor biopsy (preferably metastatic, otherwise 
primary), either fresh or archival collected within 24 months before screening. 
b. Documented disease progression (by investigator assessment) on up to a maximum of 5 
lines of HER2-directed therapy administered in the metastatic setting and have progressed 
on the most recent line. Trastuzumab, pertuzumab and an HER2 antibody drug conjugate 
(e.g. T-DM1) must have been previously administered in any sequence and in any setting.  
 
2.2 Cohort 2 (MCLA-128 + endocrine therapy) 
a. Documented hormone receptor positive status (estrogen receptor positive [ER+] and/or 
progesterone receptor positive [PR+]), defined as ≥ 1% positive stained cells by local 
standards, based on local analysis on the most recent tumor biopsy. 


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b. Documented low-level HER2 expression, defined as IHC HER2 1+, or IHC HER2 2+ combined 
with negative FISH, based on local analysis on a fresh tumor biopsy or an archival biopsy 
collected within 24 months before screening (preferably metastatic, otherwise primary). 
c. No more than 3 lines of prior endocrine therapy (aromatase inhibitor or fulvestrant) for 
metastatic disease, with radiologic or photographic evidence of disease progression on the 
last line, after at least 12 weeks of therapy. 
d. Progression on a cyclin-dependent kinase inhibitor.  
e. No more than two previous chemotherapy regimens for advanced/metastatic disease.  
Note: Pre/peri-menopausal women can be enrolled if amenable to be treated with the LHRH 
agonist goserelin. Such patients must have commenced treatment with goserelin or an alternative 
LHRH agonist at least 4 weeks prior to study entry, and patients who received an alternative LHRH 
agonist prior to study entry must switch to goserelin for the duration of the trial. 
3. In Cohort 1, patients must have at least one lesion with measurable disease as defined by RECIST 
version 1.1. In Cohort 2, patients must have at least one lesion with measurable disease as 
defined by RECIST version 1.1. Patients with bone-only disease are eligible, even in the absence 
of measurable disease. Patients with bone-only disease must have lytic or mixed lesions (lytic + 
sclerotic). For Cohort 2, imaging documenting progression on the last line of hormone therapy 
must be available for central review. 
4. Age ≥ 18 years at signature of informed consent. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
6. Life expectancy of ≥ 12 weeks, as per investigator. 
7. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multiple gated 
acquisition scan (MUGA). 
8. Adequate organ function: 
a. Absolute neutrophil count (ANC) ≥ 1.5 X 109/L 
b. Hemoglobin ≥ 9 g/dL 
c. Platelets ≥ 100 x 109/L 
d. Serum calcium within normal ranges (or corrected with supplements) 
e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x upper limit of 
normal (ULN) and total bilirubin ≤ 1.5 x ULN (in cases of liver involvement, ALT/AST ≤ 5 x 
ULN and total bilirubin within normal ranges will be allowed) 
f. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min calculated according 
to the Cockroft and Gault formula or MDRD formula for patients aged > 65 years 
(Appendix 19.2) 
g. Serum albumin > 3.0 g/dL 
Note: For both cohorts, patients will be enrolled based on their HER2 status, HR status (Cohort 2 only), 
and disease progression on the prior line of therapy, as reported in their medical records. Evaluability 
for the primary endpoint will be confirmed by central review after enrolment. Any patient found to 
be ineligible retrospectively will not be evaluable for the primary objective and may be replaced. 
4.3 
Exclusion Criteria 
The presence of any of the following criteria excludes a patient from participating in the study: 
1. Central nervous system metastases that are untreated or symptomatic, or require radiation, 
surgery, or continued steroid therapy to control symptoms within 14 days of study entry. 
2. Known leptomeningeal involvement. 


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3. Advanced/metastatic, symptomatic, visceral spread, with a risk of life-threatening complications 
in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, 
peritoneal], pulmonary lymphangitis, and over 50% liver involvement). 
4. Participation in another interventional clinical trial or treatment with any investigational drug 
within 4 weeks prior to study entry. 
5. Any systemic anticancer therapy within 3 weeks of the first dose of study treatment. For 
cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, or 
anticancer immunotherapies, a washout period of 6 weeks is required. For patients in Cohort 2, 
this does not apply to the most recently received hormone therapy. 
6. Major surgery or radiotherapy within 3 weeks of the first dose of study treatment. Patients who 
received prior radiotherapy to ≥ 25% of bone marrow are not eligible, irrespective of when it 
was received. 
7. Persistent grade > 1 clinically significant toxicities related to prior antineoplastic therapies 
(except for alopecia); stable sensory neuropathy ≤ grade 1 NCI-CTCAE v. 4.03 is allowed. 
8. History of hypersensitivity reaction or any toxicity attributed to trastuzumab, murine proteins, or 
any of the excipients that warranted permanent cessation of these agents (applicable for Cohort 
1 only). 
9. Previous exposure to vinorelbine (applicable for Cohort 1 triplet combination only) 
10. Exposure to the following cumulative anthracycline doses: 
a. Doxorubicin or liposomal doxorubicin > 360 mg/m² 
b. Epirubicin > 720 mg/m² 
c. Mitoxantrone > 120 mg/m² and idarubicin > 90 mg/m² 
d. Other anthracycline at a dose equivalent to > 360 mg/m² doxorubicin 
e. For patients having received > 1 anthracycline, the cumulative dose must not exceed the 
equivalent of 360 mg/m² doxorubicin 
11. Chronic use of high-dose oral corticosteroid therapy (>10 mg of prednisone equivalent a day). 
12. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable 
angina. 
13. History of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or 
serious cardiac arrhythmia requiring treatment (except atrial fibrillation, paroxysmal 
supraventricular tachycardia). 
14. History of myocardial infarction within 6 months of study entry. 
15. History of prior or concomitant malignancies (other than excised non-melanoma skin cancer or 
cured in situ cervical carcinoma) within 3 years of study entry. 
16. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy. 
17. Current serious illness or medical conditions including, but not limited to uncontrolled active 
infection, clinically significant pulmonary, metabolic or psychiatric disorders. 
18. Known HIV, HBV, or HCV infection. 
19. Pregnant or lactating women; women of childbearing potential must use effective contraception 
methods (patient and/or partner, e.g., surgical sterilization, a reliable barrier method) prior to 
study entry, for the duration of study participation, and for 7 months after the last dose of MCLA-
128/trastuzumab. See Section 8.10. 
20. Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, 
ascites or other visceral locations). 
21. Patients with bone-only disease with blastic-only metastasis.    
 


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5 
STUDY TREATMENT 
MCLA-128 is an investigational medicinal product (IMP), and the companion drugs trastuzumab, 
vinorelbine and each endocrine therapy are considered non-IMP. 
5.1 
Formulations and Storage 
5.1.1 
MCLA-128 
MCLA-128 is formulated as a clear liquid solution for infusion at a target concentration of 20 mg/mL 
in 25 mM histidine, 220 mM trehalose and 0.16 mM polysorbate 20 at a pH of 6.0, in Type I clear glass 
vials with an extractable volume of 5 mL or 18.8 mL. MCLA-128 is manufactured by Boehringer 
Ingelheim Pharma GmbH & Co KG, Biberach, Germany on behalf of Merus NV. Table 5-1 provides 
details on composition of MCLA-128.  
 
Table 5-1: Composition of MCLA-128 for Intravenous Infusion, 20 mg/mL 
Active Component 
MCLA-128 bispecific humanized full length IgG1 antibody, 20 mg/mL 
Excipients 
25 mM histidine, 220 mM trehalose and 0.16 mM polysorbate 20, pH 6.0 
Vehicle 
Water for Injection 
Stability 
A shelf-life of 36 months has been established. After preparation of study 
drug, diluted MCLA-128 is stable for up to 12 hours at room temperature 
(time from preparation until end of infusion) or for up to 24 hours at 2-8°C 
and a subsequent 4 hours at room temperature. 
Storage & Handling 
2-8°C in the dark, no special storage or handling instructions are 
required. Infusion tubes do not need to be covered for light exposure. 
 
5.1.2 
Trastuzumab 
Trastuzumab will be supplied centrally as a lyophilized powder in single-dose vials (150 mg, to be 
reconstituted with 7.2 mL of Sterile Water for Injection) for IV administration. Details of the excipients, 
stability, storage and handling can be found in the most recent local SPC (see Appendix 19.5).  
5.1.3 
Vinorelbine 
Vinorelbine will be supplied centrally as single-use vials of 1 or 5 mL (10 mg/1 mL or 50 mg/5 mL) for 
IV administration. Details of the excipients, stability, storage and handling can be found in the most 
recent local SPC (see Appendix 19.5). 
5.1.4 
Endocrine Therapy 
Endocrine therapy will be provided locally or centrally depending on local requirements. Details of the 
excipients, stability, storage and handling can be found in the appropriate local SPC (see Appendix 
19.5). 
5.2 
Preparation for Administration 
5.2.1 
MCLA-128 
MCLA-128 is prepared for administration according to the instructions in the Pharmacy Manual for 
this study. In short, the required volume of formulated MCLA-128 to be injected (37.5 mL) is first 
removed from the saline bag (containing 250 mL) using a sterile syringe and a sterile 18-22G needle. 
The same volume of MCLA-128 (37.5 mL to give a 750 mg flat dose) is then added to the saline bag 
using a sterile syringe and an 18-22G needle. Upon mixing, the saline infusion bag can be kept at room 


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temperature for up to 12 hours (time from preparation until end of infusion). Alternatively, the saline 
infusion bag containing MCLA-128 can be kept at 2-8°C for up to 24 hours prior to the start of infusion 
and a subsequent 4 hours at room temperature. 
If the MCLA-128-containing saline infusion bag has been stored at 2-8°C, it should be allowed to reach 
room temperature (approximately 30 minutes prior to administration). A DEHP-free PVC infusion set 
containing an in-line 0.2 µm filter must be used to connect to the IV catheter. Flush the infusion line 
with NaCl 0.9%. The priming volume depends on the infusion line. The entire content of the infusion 
bag must be administered. The infusion rate should be adjusted accordingly to ensure the infusion is 
complete in approximately 120 minutes. After the end of the infusion, the infusion line must be 
flushed with NaCl 0.9% at the same rate to ensure the dosing is complete.  
5.2.2 
Companion Study Drugs 
For trastuzumab, vinorelbine and endocrine therapies, refer to the most recent local SPC for drug 
preparation (see Appendix 19.5). 
5.3 
Study Drugs Administration 
5.3.1 
Study Drugs 
5.3.1.1 
MCLA-128 and Premedication 
Premedication with paracetamol/acetaminophen, antihistamines, and corticosteroids is mandatory 
immediately before every MCLA-128 administration. A recommended regimen is provided below:  
• 
Paracetamol/ acetaminophen 1000 mg PO or IV 
• 
Dexchlorpheniramine 5 mg IV (or equivalent by PO or IV) 
• 
Dexamethasone 10 mg IV (or equivalent by PO or IV) 
The investigator can use equivalent drugs (e.g. prednisone instead of dexamethasone) and doses, in 
accordance with local standard practices.  
A flat dose of 750 mg MCLA-128 will be infused intravenously over 2 hours, on Day 1 every 3 weeks. 
The infusion duration may be extended up to ~4 hours where considered appropriate to avoid or 
reduce the incidence or severity of IRRs. 
5.3.1.2 
Trastuzumab 
Trastuzumab will be administered as an 8 mg/kg IV loading dose over 90 minutes for Cycle 1, then 6 
mg/kg for subsequent cycles. For Cycle 2, the trastuzumab administration should be maintained at 90 
min, and over 30-90 minutes thereafter. The trastuzumab dose should be recalculated if the patient’s 
body weight changes by more than ± 10% from baseline. When trastuzumab is administered on the 
same day as MCLA-128, the infusion is initiated 30 minutes after the end of the MCLA-128 infusion. 
Refer also to the most recent local SPC (see Appendix 19.5). 
5.3.1.3 
Vinorelbine 
Vinorelbine will be administered as an IV dose of 25 mg/m² over 10 minutes. A maximum body surface 
area of 2 m² should be used. When vinorelbine is administered on the same day as MCLA-128 and 
trastuzumab, the infusion is initiated 30 minutes after the end of the trastuzumab infusion. 


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Anti-emetic medication should be given according to local standard practices. Refer also to the most 
recent local SPC (see Appendix 19.5) 
5.3.1.4 
Endocrine therapies 
For endocrine therapy, patients will receive the same dose and regimen as that administered as the 
last line of endocrine therapy prior to study entry on which the patient progressed.  
Standard endocrine therapy doses and regimens are (refer also to the most recent local SPC; see 
Appendix 19.5): 
• 
Fulvestrant 500 mg, administered intramuscularly into the buttocks slowly (1-2 minutes per 
injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once every 28 days 
thereafter. Day 15 treatment will not be administered in patients with <40 days since the last 
fulvestrant administration prior to study entry. 
• 
Exemestane 25 mg per os, administered once daily (QD), after food. 
• 
Letrozole 2.5 mg per os, administered QD. 
• 
Anastrazole 1 mg per os, administered QD. 
5.3.2 
Combination Treatment Schedules  
Three combination treatment regimens are planned, two in Cohort 1 and one in Cohort 2: 
• 
Cohort 1 HER2-positive/amplified: an MCLA-128 + trastuzumab (doublet combination) will be 
evaluated initially, followed by an MCLA-128 + trastuzumab + vinorelbine (triplet combination) 
after safety of the doublet has been established and which will be evaluated in parallel with the 
doublet. 
• 
Cohort 2 hormone receptor-positive/low HER2 expression: MCLA-128 + endocrine therapy 
combination. 
For all combinations, a treatment cycle is 21 days (3 weeks), including Cohort 2 which may include 
q4w fulvestrant dosing. Day 1 of the subsequent cycle will be on Day 22 or after recovery from any 
AEs associated with the previous cycle. 
A 6-hour observation period will be implemented following infusion start for the initial MCLA-128 
and/or trastuzumab administration, and 2 hours for all subsequent administrations (i.e. when a single 
antibody - MCLA-128 or trastuzumab - is administered on a given day, or after trastuzumab when they 
are administered on the same day). 
 


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5.3.2.1 
Cohort 1: MCLA + Trastuzumab Doublet 
Safety run-in patients 
For Cycle 1, 750 mg MCLA-128 will be administered on Day 1 over 2 hours. An 8 mg/kg loading dose 
of trastuzumab will be administered on Day 2 of Cycle 1 over 90 minutes, 24 ± 2 hours after the MCLA-
128 infusion. If administration of both agents is well tolerated in Cycle 1, they can be given sequentially 
on Day 1 from Cycle 2, with 750 mg MCLA-128 administered first followed 30 minutes later by 6 mg/kg 
maintenance dose of trastuzumab. In Cycle 2, trastuzumab will be administered over 90 minutes. For 
subsequent cycles it will be administered at 6 mg/kg over 30-90 minutes. 
Figure 5-1: Doublet combination treatment administration in safety run-in patients  
 
 
* Followed by a 6-hour observation period; 
 
   For Cycle 2, trastuzumab must be infused over 90 min. 
Expansion patients  
Once the safety run-in period has been completed and if the doublet combination is considered safe 
by the IDMC, all patients treated thereafter with the doublet will receive both drugs on Day 1 for all 
cycles, with 750 mg MCLA-128 over 2 hours for all cycles, and an 8 mg/kg loading dose of trastuzumab 
over 90 minutes for Cycle 1, and 6 mg/kg over 30-90 minutes for subsequent cycles (90 minutes for 
Cycle 2), with a 30-minute interval between infusions.  
Figure 5-2: Doublet combination treatment administration in expansion patients 
 
* Followed by a 6-hour observation period from infusion start, for the 
initial administration and 2 hours for all subsequent administrations 
For Cycle 2, trastuzumab must be infused over 90 min. 
If any patient does not tolerate both drugs on the same day, the safety run-in Cycle 1 dosing schedule 
will be followed (MCLA-128 on Day 1 and trastuzumab on Day 2) for that patient only after discussion 
with the Sponsor. 
 


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5.3.2.2 
Cohort 1: MCLA + Trastuzumab + Vinorelbine Triplet 
Safety run-in patients 
For Cycle 1, patients will receive MCLA-128 and trastuzumab on the same day, with 750 mg MCLA-128 
over 2 hours followed 30 minutes later by an 8 mg/kg IV loading dose of trastuzumab over 90 minutes. 
Vinorelbine 25 mg/m² (up to maximum of 2 m2) IV over 10 minutes will be administered on Days 2 (24 
± 2 hours after the MCLA-128 infusion) and Day 9 of Cycle 1. 
If administration of all three agents is well tolerated in Cycle 1, they can all be given sequentially on 
Day 1 from Cycle 2, with 750 mg MCLA-128 administered first followed 30 minutes later by 6 mg/kg 
trastuzumab infused over 30-90 minutes (90 minutes for Cycle 2), followed 30 minutes later by 
vinorelbine. The second vinorelbine administration will be administered on Day 8. 
Figure 5-3: Triplet combination treatment administration in safety run-in patients 
 
* Followed by a 6-hour observation period from infusion start, for the initial 
administration and 2 hours for all subsequent administrations 
For Cycle 2, trastuzumab must be infused over 90 min. 
Expansion patients 
Once the safety run-in period has been completed and if the triplet combination is considered safe by 
the IDMC, all patients treated thereafter with the triplet will receive all three drugs on Day 1 for all 
cycles (750 mg MCLA-128 for all cycles, an 8 mg/kg IV loading dose of trastuzumab over 90 minutes 
for Cycle 1, and 6 mg/kg over 30-90 minutes for subsequent cycles (90 minutes for Cycle 2), and 25 
mg/m² vinorelbine, with a 30-minute interval between infusions). The second vinorelbine 
administration will be administered on Day 8 for all cycles. 
Figure 5-4: Triplet combination treatment administration in expansion patients 
 
* Followed by a 6-hour observation period from infusion start, for the initial 
administration and 2 hours for all subsequent administrations 
For Cycle 2, trastuzumab must be infused over 90 min. 


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If a given patient does not tolerate all three drugs on the same day, the safety run-in Cycle 1 dosing 
schedule will be followed (MCLA-128/trastuzumab on Day 1 and vinorelbine on Days 2 and 9) for that 
patient only. 
5.3.2.3 
Cohort 2: MCLA + Endocrine Therapy 
For all cycles, MCLA-128 will be given on Day 1 over 2 hours, along with the same dose and regimen 
of prior endocrine therapy on which the patient had progressed prior to study entry.  
Figure 5-5: Cohort 2 treatment administration in all patients 
A 6-hour observation period will be implemented following infusion start for the 
initial MCLA-128 administration, and 2 hours for all subsequent administrations 
* Same endocrine therapy on which the patient progressed prior to study entry. Can 
be administered before, during, or immediately after the MCLA-128 infusion. 
 
5.3.3 
Dose Adaptation 
5.3.3.1 
MCLA-128 and Trastuzumab 
Actions to take in the event of toxicity related to MCLA-128 and/or trastuzumab are summarized 
below. See Section 8.8 for additional details of AEs of special interest (IRRs, cardiotoxicity and 
diarrhea). 
Interruptions: MCLA-128 and trastuzumab infusions must be interrupted in the event of an IRR. IRRs 
include the preferred term (PT) “IRR” and any other PTs occurring within 24 hours of the MCLA-128 
or trastuzumab infusion that the investigator judges as a sign or symptom of an IRR (e.g., nausea, 
vomiting, abdominal pain, headache, hypotension, pyrexia, tremor, and hypersensitivity). 
The infusion should be stopped immediately, and the patient should receive symptomatic treatment 
according to the investigator’s or treating physician’s judgment.  
For non-severe IRRs, the MCLA-128 or trastuzumab infusion can be re-started upon clinical 
improvement of symptoms, at 50% of the infusion rate prior to the reaction and the infusion duration 
can be increased to 4 hours, to administer the totality of the dose.  
For severe IRRs (CTCAE grade 4, life-threatening), MCLA-128 or trastuzumab infusion should be 
stopped immediately and all study treatment discontinued definitively.  
For IRRs considered to be due to an IgE-mediated anaphylactic reaction, the MCLA-128 or trastuzumab 
infusion should be interrupted and not resumed, irrespective of the severity of the reaction, and is 
contraindicated for subsequent cycles. 
Delays: Planned MCLA-128 and trastuzumab administration can be delayed for up to 1 cycle (i.e., a 
maximum 6-week interval between infusions), in the event of the following: 
• 
Cardiotoxicity: In the event of LVEF < 50% with a decline of ≥ 10 ejection fraction points or LVEF 
≤ 44%, antibody administration will be delayed for 3 weeks and another LVEF evaluation 
performed. In the absence of improvement or if the patient has a confirmed documented LVEF 


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decrease to a value ≤ 44% or clinical signs and symptoms suggesting congestive heart failure, both 
antibodies will be withdrawn. See Appendix 19.3 for the algorithm for treatment management in 
the event of cardiotoxicity. 
• 
Diarrhea: In the event of persistent grade 2 (> 48 hours) or grade 3-4 diarrhea, administration of 
MCLA-128 and trastuzumab should be delayed (for a maximum of 6 weeks between infusions).  
Reductions: Dose reductions are not permitted for MCLA-128 or trastuzumab. 
Incomplete trastuzumab loading dose:  
• 
If the patient receives < 50% of the Cycle 1 loading dose, the remainder should be administered 
before Day 22, preferably within the first week. Thereafter, the usual maintenance dose should 
be administered 3 weeks after the first interrupted dose, as scheduled; e.g., if a patient received 
up to 50% of the scheduled loading dose, the remaining dose should be administered, preferably 
in the first week, then regular maintenance doses (6 mg/kg of trastuzumab) from Day 22, as 
scheduled. 
• 
If the patient receives between 50-75% of the Cycle 1 loading dose, the remainder should be 
administered before Day 22, preferably within the first 2 weeks of Cycle 1; e.g., if ~60% of the 
scheduled loading dose is administered, the remaining 40% should be administered preferably 
within 2 weeks, then regular maintenance doses (6 mg/kg of trastuzumab) from Day 22, as 
scheduled. 
• 
If the patient receives ≥ 75% of the Cycle 1 loading dose, additional loading is probably not 
necessary, however, the remainder of the loading dose may be given at the investigator's 
discretion. In this case, the remainder may be given at any time before the next scheduled dose 
or the patient may be given an additional loading dose on Day 22.  
If, after receiving an incomplete loading dose on Day 1, the patient cannot attend the site until Day 
22, a second loading dose should be given on Day 22. However, every effort should be made to give 
the remainder of the dose prior to Day 22. 
5.3.3.2 
Vinorelbine 
Dose reductions and delays are required in the event of toxicity as follows: 
Hematologic Toxicity:  
Hold or decrease the vinorelbine dose in patients with decreased neutrophil counts using the following 
schema. 
Neutrophils on Day of Treatment (cells/mm3)  
Percentage of Starting Dose 
≥ 1,500 (≥ grade 1) 
100%  
< 1,500 (grade 2) 
Do not administer. Repeat neutrophil count in 1 week. If 
treatment is delayed due to neutrophil count < 1,500 
cells/mm3 for ≥3 consecutive weeks, discontinue 
vinorelbine 
Note : For patients who experience fever and/or sepsis while neutrophil count is < 1,500 or had 2 
consecutive weekly doses held due to neutropenia, subsequent doses should be:  
> 1,500 (≥ grade 1) 
75%  
< 1,500 (grade 2) 
Do not administer.  
Repeat neutrophil count in 1 week.  


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Vinorelbine should be held if a patient experiences a reduction in platelets to <100,000 cells/mm3 and 
counts repeated 1 week later. If treatment is delayed due to platelets to <100,000 cells/mm3 for ≥3 
consecutive weeks, discontinue vinorelbine. 
Hepatic Impairment/Toxicity: Reduce vinorelbine dose in patients with elevated serum total bilirubin 
concentration according to the following schema. 
Serum total bilirubin concentration (mg/dL) 
Percentage of Starting Dose  
≤ 2.0  
100%  
2.1 to 3.0  
50%  
> 3.0  
25%  
Concurrent Hematologic Toxicity and Hepatic Impairment: Administer the lower doses based on the 
corresponding starting dose of vinorelbine determined from the above schemas. 
Neurologic Toxicity: Discontinue vinorelbine for NCI-CTCAE v. 4.03 ≥ grade 2 peripheral neuropathy or 
autonomic neuropathy causing constipation. 
5.3.3.3 
Endocrine Therapies 
Treatment adaptations for endocrine therapies will be as per the SPC. Note that for fulvestrant: 
Delays: In cases of fulvestrant-related toxicity as per investigator’s judgement, the injection can be 
delayed for up to 7 days, after which the planned monthly injection should be skipped. Fulvestrant 
should not be administered if the platelet count is < 50,000/mm3. 
Reductions: Dose reductions are not permitted. 
5.3.3.4 
Supportive Care Guidelines for Study Treatment Toxicity 
Toxicity will be managed by the investigator according to the local standard of care. Supportive 
treatment must be reported in the concomitant medication section of the eCRF. 
5.4 
Treatment Withdrawal 
Study treatment will be administered until any of the following occurs, at which point it will be 
definitively discontinued, except in cases of perceived benefit and in agreement with the Sponsor: 
• 
Confirmed progressive disease (as per RECIST) 
• 
Unacceptable toxicity (including a confirmed documented LVEF decrease to a value <40% or 
clinical signs and symptoms suggesting congestive heart failure) 
• 
Withdrawal of consent 
• 
Patient non-compliance 
• 
Investigator decision (e.g. clinical deterioration; in the rare event that a patient discontinues due 
to global deterioration of health status considered related to the underlying disease but without 
objective evidence of disease progression at that time, it should be reported as “symptomatic 
deterioration” – all efforts should be made to document objective progression) 
• 
Treatment interruption > 6 consecutive weeks 
• 
Withdrawal of any of the study drugs (MCLA-128, trastuzumab, vinorelbine or endocrine 
 
 


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• 
 therapy) 
In all cases, the reason for and date of study treatment discontinuation must be recorded in the eCRF 
and documented in the patient's medical records. As far as possible, there should be only one reason 
for treatment discontinuation. If several reasons apply (e.g. concomitant progressive disease and 
toxicity) the primary reason must be reported.  
As far as possible, all examinations scheduled for the final study day must be performed for all patients 
who receive any study medication but who do not complete the study according to protocol. 
The investigator must make every effort to contact patients lost to follow-up, especially when a 
patient is treated in another non-study center. 
 
5.5 
Packaging and Labeling 
5.5.1 
MCLA-128 
MCLA-128 is provided as single-use glass vials of MCLA-128 for intravenous administration. All vials 
and secondary packaging are labelled for the purpose of the clinical trial in accordance with applicable 
regulatory requirements. Labels are prepared in the local language(s) of the countries involved. 
 
5.5.2 
Companion Study Drugs 
Commercial preparations of trastuzumab, vinorelbine and fulvestrant, exemestane, letrozole, and 
anastrazole will be used. Trastuzumab and vinorelbine which are centrally supplied by Merus will 
include a label (in the local language) specifying they are for the purpose of the clinical trial, in 
accordance with applicable local regulatory requirements.  
5.6 
Supplies and Accountability 
The study drugs supplied by Merus must be used only as directed in the protocol and as detailed in 
the Pharmacy Manual. They must only be dispensed to patients enrolled in this study and must be 
kept in a locked area with restricted access and stored and handled in accordance with the 
manufacturer’s instructions and temperature traceability. 
Sufficient vials of MCLA-128, trastuzumab and vinorelbine will be supplied to the Pharmacy at each 
Investigational site. If a vial is broken or unusable, it should be replaced. Although the Sponsor need 
not be notified immediately in these cases, documentation of the use and/or loss of any vial must be 
recorded by the pharmacist on the medication accountability form. 
It is the Investigator/Institution’s responsibility to establish a system for handling study medication to 
ensure that: 
• 
Deliveries of study medication are correctly received by a responsible person and recorded; 
• 
Study medication is handled and stored safely and properly as stated on the label, in this protocol 
document and in the Pharmacy Manual; 
• 
Study medication is only dispensed to study patients in accordance with this protocol, the local 
prescribing information (as appropriate) and the Pharmacy Manual; 
• 
Used vials of study medication are destroyed by the investigational site according to local 
procedures and regulations; 


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• 
Any unused study medication should be destroyed or returned to Merus or their designee in 
liaison with the study monitor. 
The pharmacist of the investigational center must inventory and acknowledge receipt of all shipments 
of study medication and accurately document the delivery, use, destruction or return of used, partially 
used or unused vials of MCLA-128, trastuzumab and vinorelbine, including dates, quantities, patient 
numbers, batch numbers or other identification numbers. Records must be accurate and kept up to 
date. Throughout the study, delivery records for all study medications must be reconciled with records 
of usage and any returned stock. Records of usage should include the identification of the patient to 
whom the study medication was dispensed and the quantity and date of dispensing. Any discrepancies 
must be accounted for and documented. Certificates of delivery and return must be signed by the 
responsible pharmacist, with copies retained in the Pharmacy File. Unused study medication will be 
returned after written approval or request by the Sponsor.  
The Sponsor’s study monitor will periodically check the supplies of study medication held by the 
pharmacist to verify accountability of all study medication used. The Sponsor’s study monitor will 
verify that a final report of drug accountability to the unit dose level is prepared and maintained in 
the Pharmacy Study File. 
Complete instructions and contact information for ordering clinical supplies will be supplied in the 
Investigator File. 
5.7 
Compliance 
Administration of MCLA-128, trastuzumab and vinorelbine will be supervised by the investigator or 
designee. Any delegation of this responsibility must follow Section 15.2. The hormone therapy given 
to patients in Cohort 2 should be administered as per local standard of care.    
The dose, date and start and stop time of administration of all study drugs (MCLA-128, trastuzumab, 
vinorelbine, and endocrine therapy), any interruptions, and any immediate reactions at the time of 
infusion must be reported in the eCRF. 
In Cohort 2, to be considered compliant for hormone therapy, patients must receive at least 75% of 
the planned hormone dose according to the planned regimen. 
 
6 
PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS 
6.1 
Medical Conditions 
Additional illnesses, independent of the treated condition, present at the time informed consent is 
obtained or within 4 weeks prior to first study treatment administration must be documented in the 
eCRF. Relevant past illnesses (including other cancers) must be documented in the eCRF. 
Medical conditions first occurring or detected during the study or worsening of a concomitant illness 
during the study, are to be considered TEAEs and must be documented in the adverse events section 
of the eCRF.  
6.2 
Medications 
All treatments taken by patients at study entry or within 4 weeks prior to initiating treatment or at 
any time during the study, along with all prescription, non-prescription or over-the-counter 


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medications, including herbal remedies, dietary and nutritional supplements and complementary and 
alternative therapies, are considered concomitant medications and must be documented in the eCRF.  
Permitted 
• 
Systemic corticosteroids will be used as a part of a mandatory premedication regimen before 
each MCLA-128 administration (see Section 5.3.1.1).  
• 
In cases of hypersensitivity or IRRs, paracetamol/acetaminophen, diphenhydramine, 
chlorpheniramine, or other antihistamines can be used according to local clinical practice, as 
clinically indicated.  
• 
Any medication considered necessary for the patient’s safety and wellbeing may be given at the 
discretion of the Investigator. 
• 
Supportive treatment of symptoms and AEs or standard treatment of concomitant conditions, 
including aspirin, transfusion support, G-CSF, antibiotics, inhaled steroids (for asthma), 
antiemetics, antidiarrheals (e.g. loperamide), and bisphosphonates (according to their product 
license and routine clinical practice). 
• 
Pre/peri-menopausal women who started treatment with goserelin or an alternative LHRH 
agonist at least 4 weeks prior to study entry may continue to receive goserelin, and patients who 
received an alternative LHRH agonist prior to study entry must switch to goserelin for the 
duration of the trial. 
• 
Concurrent radiation treatment will be permitted during this study for symptom control without 
evidence of progression. 
Prohibited concomitant medications (risk of immunosuppression) 
• 
Chronic oral corticosteroid therapy > 10 mg/day prednisone equivalent excluding inhaled and 
topical steroids. 
• 
Tumor necrosis factor (TNF)-alpha inhibitors. 
• 
Anti-T cell antibodies. 
Prohibited medications (other) 
• 
Any investigational drug during the study or within 4 weeks prior to the first dose of study 
treatment. 
• 
Any other anticancer therapy (other than the last endocrine therapy in Cohort 2) during the study 
or within 3 weeks of the first dose of study treatment. For cytotoxic agents that have major 
delayed toxicity, e.g. mitomycin C and nitrosoureas, or anticancer immunotherapies, a washout 
period of 6 weeks is required. 
• 
Initiation of herbal remedies for cancer treatment. Herbal remedies initiated prior to study entry 
and continuing during the study are permitted and must be reported in the eCRF. 
• 
Major surgery or radiotherapy within 3 weeks prior to the first dose of study treatment.  
• 
Prior radiotherapy to ≥25% of bone marrow. 
• 
Yellow fever vaccine while on therapy (Cohort 1) or within 3 weeks prior to the first dose of study 
treatment. 
 


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7 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS 
Screening, enrollment and on-study assessments to perform by visit are detailed below. Tables of 
assessments by visit and by cohort are provided for all patients, and for Cohort 1 and Cohort 2 specific 
assessments.  
Further details of assessments and analyses for safety, efficacy, PK, biomarkers, cytokines, and 
immunogenicity are provided in Sections 8, 9, 10, 11, 12, and 13, respectively. 


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Table 7-1: Study procedures for all patients 
 
Protocol 
Section 
Screening 
STUDY TREATMENT 
PERIOD 
1 Cycle = 21 days 
STUDY 
TREATMENT 
PERIOD 
AS PER 
PROTOCOL 
VERSION 5.0 
END OF 
TREATMENT 
VISIT (EOT) 
FOLLOW-UP 
PERIOD 
END OF 
TREATMENT 
VISIT (EOT) &  
FOLLOW-UP 
VISIT 
AS PER 
PROTOCOL 
VERSION 5.0 
STUDY PROCEDURES (all 
patients) 
 
≤28 days 
before 
treatment 
Day 1 of
each 
cycle 
As indicated  
on-study 
1 Cycle = 21 days 
35±5 days 
from last dosing 
Every 
3 months 
35±5 days 
from last dosing 
General Assessments 
 
 
 
 
 
 
 
 
Informed consent 
15.3 
X 
 
 
 
 
 
 
Patient enrollment form 
 
X 
 
 
 
 
 
 
Eligibility criteria 
4 
X 
 
 
 
 
 
 
Demographics, medical history 
- 
X 
 
 
 
 
 
 
Diagnosis and prior treatment 
- 
X 
 
 
 
 
 
 
Baseline symptoms and 
complaints 
8 
X 
 
 
 
 
 
 
Concomitant medication 
6.2 
 
Continuous 
X 
 
 
 
Laboratory Tests 
 
 
 
 
 
 
 
 
Serum pregnancy test (other 
than for patients with proven 
menopause or surgically sterile) 
8.10 
X 
≤7 days 
before 
treatment 
 
 
 
X 
 
X 
Urine pregnancy test (a serum 
test must be carried out to 
confirm a positive result) 
8.10 
 
X 
 
X 
 
Up to 7 months 
after last MCLA-
128/trastuzumab 
treatment 
 
Urinalysis (dipstick) 
8.2 
X 
As clinically indicated 
 
X 
 
 
Tumor Assessments 
 
 
 
 
 
 
 
 
CT/MRI scans of chest, abdomen, 
pelvis, and brain 
9.1 
X 
 
X 
every 6 weeks 
after start of 
X 
every 4 cycles 
(12 weeks). In 
If previous 
imaging 
For patients who 
discontinue for 
reasons other 
For patients 
who 
discontinue for 


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Protocol 
Section 
Screening 
STUDY TREATMENT 
PERIOD 
1 Cycle = 21 days 
STUDY 
TREATMENT 
PERIOD 
AS PER 
PROTOCOL 
VERSION 5.0 
END OF 
TREATMENT 
VISIT (EOT) 
FOLLOW-UP 
PERIOD 
END OF 
TREATMENT 
VISIT (EOT) &  
FOLLOW-UP 
VISIT 
AS PER 
PROTOCOL 
VERSION 5.0 
STUDY PROCEDURES (all 
patients) 
 
≤28 days 
before 
treatment 
Day 1 of
each 
cycle 
As indicated  
on-study 
1 Cycle = 21 days 
35±5 days 
from last dosing 
Every 
3 months 
35±5 days 
from last dosing 
any clinically indicated sites of 
disease and bone lesions as 
appropriate throughout 
treatment; clinical evaluation of 
superficial disease 
* Follow-up brain scans should 
only be conducted if lesions are 
present at baseline 
study 
treatment until 
progression 
case of 
symptomatic 
deterioration 
signs or signs of 
PD in between 
the 
assessments an 
unscheduled 
assessment 
must be 
performed. 
assessment is >6 
weeks prior 
than progression, 
as clinically 
indicated 
reasons other 
than 
progression, as 
clinically 
indicated 
Radionuclide bone scan, whole 
body 
9.1 
X 
 as close as 
possible 
and ≤9 
weeks 
before 
starting 
study 
treatment 
 
As clinically 
indicated to 
assess baseline 
or suspected 
new bone 
metastases 
As clinically 
indicated to 
assess baseline or
suspected new 
bone metastases
 
As clinically 
indicated to 
assess suspected 
new bone 
metastases for 
patients who 
discontinue for 
reasons other 
than progression 
 
As clinically 
indicated to 
assess 
suspected new 
bone 
metastases for 
patients who 
discontinue for 
reasons other 
than 
progression 
 
 
 


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Tumor markers (CA15-3, CEA, 
CA27-29) 
(as far as possible, measures 
should be made in the same 
laboratory)  
9.2 
X 
within 7 
days before
treatment  
X 
 
 
X 
For patients with 
elevated levels at 
screening who 
discontinue for 
reasons other 
than progression 
For patients 
with elevated 
levels at 
screening who 
discontinue for 
reasons other 
than 
progression. 
Other Clinical Assessments 
 
 
 
 
 
 
 
 
Adverse events 
8 
 
Continuous 
X 
 
Related cardiac 
events up to 1 
year 
X 
Serious adverse events 
8 
 
Continuous 
X 
 
Suspected only, up 
to 1 year 
X 
LVEF (by ECHO or MUGA) and 12-
lead electrocardiogram (ECG) 
8.8.2 
X 
As close as
possible 
to and 
within 4 
weeks 
prior to 
Day 1 
Cycle 1. 
 
X 
Pre-dose Day 1, 
every 4 cycles  
(C5, C9, etc) 
unless 
performed <7 
days, and as 
clinically 
indicated 
LVEF/ECG every 6
months and at any
time during the 
study if clinically 
indicated. 
X  
if >6 weeks since 
last assessment 
All patients will 
undergo LVEF/ECG 
every 6 months for 
1 year after the last 
MCLA-128 dose. 
Patients who 
discontinue due to 
decrease in LVEF 
and/or possible 
CHF should 
continue LVEF 
assessments as 
clinically indicated 
(≤18 weeks 
between 
assessments), until 
initiation of a new 
anticancer therapy, 
LVEF values return 
to ≥50% or for 1 
year, whichever is 
first. 
X 
Pharmacokinetics 
10 
 
 
Protocol 
Versions 1.0, 
 
 
 
 


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2.0 and 3.0 
only:  
Cycles 1, 2, 3, 5, 
then every 4 
cycles  
Immunogenicity assessment 
13 
 
 
Protocol 
Versions 1.0, 
2.0 and 3.0 
only:  
Pre-dose Day 1 
Cycles 1, 3, 5 
then every 4 
cycles (C9, C13, 
etc)  
 
Protocol Versions 
1.0, 2.0 and 3.0 
only:  
X 
 
 
Fresh tumor OR archival sample 
within 24 months prior to 
screening (for HER2 status, 
exploratory biomarkers, and HR 
status as appropriate)* 
11.1.1 
X 
 
Optional sample 
12 weeks after 
start of study 
treatment 
 
Optional 
(preferably from 
site of 
progression) 
 
Optional 
(preferably from 
site of 
progression) 
Liquid biopsy (for exploratory 
biomarkers) 
11.1.2 
 
 
Pre-dose Day 1 
Cycle 1, then 
every 4 cycles 
(C5, C9, etc) 
 
X 
 
 
Other investigations as clinically 
indicated  
- 
X 
X 
X 
x 
X 
X 
X 
*For Cohort 2 patients with bone-only disease, primary tumor tissue will be used (unless it is determined that testing for HER2 expression in a bone bio 
 
 


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Table 7-2: Study procedures and timings specific to Cohort 1 patients (doublet and triplet combinations) 
 
Protocol 
Section 
Screening 
STUDY TREATMENT PERIOD  
1 Cycle = 21 days 
STUDY TREATMENT
PERIOD  
AS PER PROTOCOL 
VERSION 5.0 
 
END OF 
TREATMENT 
VISIT 
END OF 
TREATMENT 
VISIT (EOT) &  
FOLLOW-UP VISIT 
AS PER PROTOCOL
VERSION 5.0 
STUDY PROCEDURES (Cohort 1) 
 
≤7 days before 
treatment  
Days 1, 2, 8 and 9 of each cycle as specified 
1 Cycle = 21 days  
35±5 days  
from last dosing 
35±5 days 
from last dosing 
Clinical Assessments 
 
 
 
 
 
 
Physical examination, ECOG PS, height 
(screening only) and weight, vital signs  
Appendix 
19.1 
X 
Doublet: Days 1 and 8 of Cycle 1 and Day 1 of 
each subsequent cycle 
Triplet safety run-in: Days 1,2 and 9 of Cycle 
1 and Days 1 and 8 of each subsequent cycle 
Triplet expansion: Days 1 and 8 of each cycle 
 
X 
X 
Cytokine panel 
12 
 
Doublet safety run-in: Days 1 and 2 of Cycle 
1 and Day 1 of Cycle 2 
Triplet safety run-in: Day 1 of Cycles 1 and 2 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
Complete blood count (CBC)  
8.2 
X 
Doublet: Days 1 and 8 of Cycle 1 and Day 1 of 
each subsequent cycle 
Triplet safety run-in: Days 1 and 9 of Cycle 1 
and Days 1 and 8 of each subsequent cycle  
Triplet expansion: Days 1 and 8 of each cycle 
Days 1 and 8 of 
each cycle 
X 
X 
Serum chemistries 
8.2 
X 
Doublet: Days 1 and 8 of Cycle 1 and Day 1 of 
each subsequent cycle 
Triplet safety run-in: Days 1 and 9 of Cycle 1 
and Days 1 and 8 of each subsequent cycle 
Triplet expansion: Days 1 and 8 of each cycle 
Days 1 and 8 of 
each cycle 
X 
X 
Study Treatment 
 
 
 
 
 
 
MCLA-128 premedication (immediately 
prior to MCLA-128) 
5.3.1.1 
 
Day 1 of each cycle 
X 
 
 
MCLA-128 (intravenous) 
5.3.1.1 
 
Day 1 of each cycle 
X 
 
 
Trastuzumab (intravenous; 30 min after 
MCLA-128 when given on the same day) 
5.3.1.2 
 
Doublet safety run-in: Day 2 of Cycle 1 and 
Day 1 of each subsequent cycle 
X 
 
 


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Protocol 
Section 
Screening 
STUDY TREATMENT PERIOD  
1 Cycle = 21 days 
STUDY TREATMENT
PERIOD  
AS PER PROTOCOL 
VERSION 5.0 
 
END OF 
TREATMENT 
VISIT 
END OF 
TREATMENT 
VISIT (EOT) &  
FOLLOW-UP VISIT 
AS PER PROTOCOL
VERSION 5.0 
STUDY PROCEDURES (Cohort 1) 
 
≤7 days before 
treatment  
Days 1, 2, 8 and 9 of each cycle as specified 
1 Cycle = 21 days  
35±5 days  
from last dosing 
35±5 days 
from last dosing 
Doublet expansion and all triplet: Day 1 of 
each cycle 
Vinorelbine (intravenous; 30 min after 
trastuzumab when given on the same day) 
 
5.3.1.3 
 
Triplet safety run-in: Days 2 and 9 of Cycle 1, 
then Days 1 and 8 of each subsequent cycle 
Triplet expansion: Days 1 and 8 of each cycle 
X 
 
 
 
7-3: Study procedures and timings specific to Cohort 2 patients (MCLA-128 + endocrine therapy combination) 
 
Protocol 
Section 
Screening 
STUDY TREATMENT PERIOD  
1 Cycle = 21 days 
STUDY TREATMENT 
PERIOD  
AS PER PROTOCOL 
VERSION 5.0 
END OF TREATMENT
VISIT 
END OF TREATMENT 
VISIT (EOT) &  
FOLLOW-UP VISIT 
AS PER PROTOCOL 
VERSION 5.0 
STUDY PROCEDURES (Cohort 2) 
 
≤7 days before    
treatment  
Day 1 of each 
cycle  
Day 8 of Cycle 1 
only 
1 Cycle = 21 days  
35±5 days  
from last dosing 
35±5 days 
from last dosing 
Clinical Assessments 
 
 
 
 
 
 
 
Physical examination, ECOG PS, height 
(screening only) and weight, vital signs  
Appendix 
19.1 
X 
X 
X 
 
X 
X 
DEXA scan (bone mineral density) 
- 
X 
Up to 6 months 
prior to Day 1 
Cycle1 
X 
Every 12 months since last evaluation 
X 
Every 12 months 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
Complete blood count (CBC) 
8.2 
X 
X 
X 
Day 1 of each cycle 
X 
X 
Serum chemistries 
8.2 
X 
X 
X 
Day 1 of each cycle 
X 
X 
Study Treatment 
 
 
 
 
 
 
 


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Protocol 
Section 
Screening 
STUDY TREATMENT PERIOD  
1 Cycle = 21 days 
STUDY TREATMENT 
PERIOD  
AS PER PROTOCOL 
VERSION 5.0 
END OF TREATMENT
VISIT 
END OF TREATMENT 
VISIT (EOT) &  
FOLLOW-UP VISIT 
AS PER PROTOCOL 
VERSION 5.0 
STUDY PROCEDURES (Cohort 2) 
 
≤7 days before    
treatment  
Day 1 of each 
cycle  
Day 8 of Cycle 1 
only 
1 Cycle = 21 days  
35±5 days  
from last dosing 
35±5 days 
from last dosing 
MCLA-128 premedication (immediately 
prior to MCLA-128) 
5.3.1.1 
 
X 
 
X 
 
 
MCLA-128 (intravenous) 
5.3.1.1 
 
X 
 
X 
 
 
Endocrine therapy (as per last prior line 
immediately before study entry) 
5.3.1.4 
 
Same dose and regimen on which the 
patient most recently progressed 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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7.1 
Screening, Eligibility and Enrolment Procedures 
Each candidate patient will be examined before starting the study to determine eligibility for 
participation (as per Table 7-1, Table 7-2 and Error! Reference source not found.). This must be done 
within 28 days prior to the first study treatment administration.  
All patients must provide written informed consent prior to any specific study procedures being 
performed. 
A centralized patient enrolment process will be used to track patient screening and planned timing of 
Cycle 1, Day 1. The investigator (or designee) must verify that the patient meets eligibility criteria and 
has signed the Informed Consent Form, then request patient inclusion by faxing/e-mailing the Patient 
Enrolment Request Form (provided separately) to the Sponsor’s Medical expert (or designee) as 
specified on the form.  
Patients must be approved for enrolment by the Sponsor prior to treatment start. For Cohort 1, eligible 
patients will be allocated centrally by the Sponsor to the doublet or triplet regimen (when both 
expansion phases are running in parallel) as follows. After completion of the evaluation of the doublet 
safety run-in patients, if the doublet combination is considered toxic, all inclusions in Cohort 1 will be 
stopped. If the doublet is considered safe, the next 4 to 6 eligible successive patients will be treated 
with the triplet combination. If the triplet combination is considered toxic in these patients, further 
exploration of the triplet combination will be stopped, and only the doublet combination will be 
evaluated for efficacy. If both the doublet and triplet combinations are considered safe, they will be 
expanded for efficacy evaluation in parallel. Eligible patients will be allocated centrally by the Sponsor 
to one of the two cohorts using a 3:1 ratio for the triplet or doublet respectively and taking into 
account previous exposure to vinorelbine. For Cohort 2, no treatment assignment is required. 
After validation of eligibility (as per Request Form, the enrolment form signed by the Sponsor’s 
Medical Monitor or designee will be returned to the investigator within 24 hours (on working days), 
with or without inclusion agreement. For patients not included, the reason for inclusion refusal will be 
specified. 
Patients who signed an Informed Consent Form but who failed to start treatment will be considered 
a screen failure and reported on the screening log in the Investigator Site File. Screen failures will not 
be reported in the eCRF. If the patient is screened and not enrolled, only SAEs suspected to be caused 
by study procedures should be reported.    
Patients who are enrolled but are not treated will be reported in the eCRF. eCRF pages for 
demographic information, informed consent, inclusion/exclusion and the “leading question” on the 
AE (to confirm if any AEs occurred during screening) must also be completed for screen failure 
patients. No other data will be entered into the clinical database for these patients unless they 
experienced an SAE during the screening phase. 
For included patients, the patient cohort and combination therapy arm allocated will be specified on 
the form, along with a unique patient number. Included patients will only receive a unique patient 
number when treatment is about to be started, which must be within 7 days after enrolment.  
The unique patient number will consist of 6 digits (2 for the center, 1 for the cohort, and 3 for the 
patient by consecutive increasing order of inclusion; XX-X-XXX). Once a number has been assigned, it 
must not be used again. 
 


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7.2 
Evaluations On-Study  
On-study evaluations will be performed as per the tables of assessments (Table 7-1, Table 7-2, and 
Error! Reference source not found.). A ± 3 day window is permitted for visit timing with the 
exception of the first follow-up tumor assessment at Day 43 which must only have a +3 day window. 
All safety assessments should occur prior to dosing on each scheduled dosing day and the results 
should be available prior to deciding to dose on that day. With the implementation of Protocol 
Version 5.0 imaging assessments should occur every 6 12 weeks and their timing should not be 
influenced by dose delays or interruptions. Tumor biopsies for biomarker collection should coincide 
with the imaging assessment schedule. 
7.3 
End of Treatment Visit and Follow-Up  
A visit will be performed 35 days (± 5 days) after the last study drug intake as per Table 7-1, Table 
7-2, and Error! Reference source not found..  
After the last treatment administration, patients will be followed up for safety for 30 days and then 
until resolution of any TEAEs for which a relationship to study drug cannot definitely be excluded (or 
categorized as sequelae). 
In addition, patients will be followed 35 ± 5 days after the last treatment intake, as per Table 7-1, 
Table 7-2, and Error! Reference source not found., as follows: 
• 
Patients who discontinue treatment for reasons other than disease progression will be followed-
up for tumor assessments (imaging and tumor markers), disease progression, start of a new 
anticancer therapy, or 35 ± 5 days after the last treatment intake, whichever is earlier. 
• 
Patients who discontinue treatment due to a drop in LVEF will have MUGA/ultrasound as clinically 
indicated (≤18 weeks between assessments) until initiation of a new anticancer therapy, 
resolution of LVEF to ≥50%, or 35 ± 5 days after the last treatment intake, whichever is earlier.  
• 
All patients will undergo LVEF 35 ± 5 days after the last MCLA-128 dose.  
• 
All patients will be followed up for survival status, related cardiac events and suspected related 
SAEs for up to 35 ± 5 days after the last treatment intake. 
 
8 
SAFETY ASSESSMENTS 
In emergency situations, the investigator should immediately contact a Sponsor representative at 
the telephone number or email address given on the title page of this protocol. 
Patients will be monitored for signs and symptoms of AEs throughout the study by a qualified 
oncologist, with experience in clinical research. All AEs will be reported in the eCRF, including 
seriousness, NCI-CTCAE v. 4.03 grade severity, causal relationship to the study medication, and 
action taken. The first concern will be the safety of the study participant.  
Incidence, severity and relationship of AEs and laboratory abnormalities, SAEs, discontinuations and 
dose adaptations due to AEs will be recorded. 
8.1 
Clinical Safety 
Clinical and physical examinations, as well as vital signs evaluation, will be performed. Patient data 
will be analyzed for evidence of cumulative toxicity with repeated cycles of therapy. AEs and signs 
and symptoms of disease observed by the investigator (preferably by the same physician for a same 


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patient) or reported by patients will be recorded and graded according to NCI-CTCAE v. 4.03. All 
events, including those considered not related to the study drug, must be reported in the eCRF.  
[ https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf ] 
If symptomatic clinical deterioration occurs while progressive disease is evident from the patient’s 
clinical symptoms but is not supported by tumor measurements or the investigator elects not to 
perform further disease assessments, the determination of clinical progression is based on 
symptomatic deterioration. These determinations should be a rare exception as every effort should 
be made to document the objective progression of underlying malignancy with imaging. If there is any 
uncertainty about an AE being due only to the disease under study, it should be reported as an AE or 
SAE. 
8.2 
Laboratory Measurements 
Clinical laboratory tests will be performed at local laboratories. Laboratory test results will be recorded 
on the laboratory results section of the eCRF. In addition, any laboratory result abnormality fulfilling 
the criteria for an AE or SAE should be reported as such. Any clinically significant treatment-emergent 
laboratory abnormality (accompanied with clinical symptoms, requiring a change in study medication 
[reduction, interruption, discontinuation] or requiring a change in concomitant therapy) should be 
recorded as a single AE in the eCRF. 
Table 8-1: Hematology and chemistry sampling 
Sample 
Time Point 
Analytes 
Complete blood count 
(hematology)  
Chemistry blood 
sample 
Screening; Cycle 1 Day 1 and Day 8, 
and Day 1 of every subsequent cycle 
unless there is an ongoing ≥ grade 2 
AE, then perform as clinically indicated 
until resolution or return to baseline, 
and End of Treatment. 
NOTE: For patients in the Cohort 1 
triplet treatment arm, hematology 
and chemistry samples will be 
collected every cycle at Day 8 
CBC: Hemoglobin, RBC, WBC and 
differential, and platelet counts 
 
Chemistry: Na, K, Ca, Mg, P, Cl, HCO3, 
creatinine, total protein, albumin, alkaline 
phosphatase, total bilirubin, AST, ALT, 
LDH 
 
NOTE: Collect additional analytes as 
clinically indicated  
Dipstick urinalysis will be performed at screening and then as clinically indicated.  
8.3 
Definitions (21 CFR§312.32) 
• 
Adverse event (AE) means any untoward medical occurrence associated with use of a drug in 
humans, whether or not considered drug related. The term treatment emergent adverse event 
[TEAE] covers any unfavorable and unintended sign, symptom, syndrome, or illness that develops 
or worsens during the period of observation after the first treatment administration in the clinical 
study. Surgical or other procedures themselves are not TEAEs. The condition for which the 
surgery/other procedure is required, is a TEAE, if it occurs or is detected during the study period. 
Planned surgical or other procedures planned/permitted by the study protocol and the 
condition(s) leading to these measures are not TEAEs, if the condition(s) was (were) known before 
the start of study treatment. In the latter case the condition should be reported as medical history. 
• 
Adverse drug reaction (ADR) is an AE caused by the drug. 


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• 
Suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that the 
drug caused the AE. A “reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE. SAR implies a lesser degree of certainty about causality 
than an ADR, and include: 
-  A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure; 
- One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
- An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those 
events occur more frequently in the drug treatment group than in a concurrent or historical 
control group. 
 
• 
Serious adverse event (SAE) or serious suspected adverse reaction (SSAR) is an event that, in the 
view of either the investigator or Sponsor, results in any of the following outcomes: 
- 
Death occurring on study or within 30 days after the last administration of study drug 
(regardless of relationship to study treatment) or within any interval if related to the study 
drug. Although death may occur as a result of the disease, all deaths occurring within 30 days 
of the last administration of study drug must be managed as SAEs and reported as such; 
- 
A life-threatening AE; 
- 
Inpatient hospitalization or prolongation of existing hospitalization; 
- 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions;  
- 
A congenital anomaly/birth defect. 
In addition, medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred. Important 
medical events that may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the patient’s safety or may require intervention to prevent one of the outcomes listed 
in the definition above should also usually be considered serious. Examples of such events include: 
- 
Overdose, even without complications (see Section 8.11) 
- 
An AE requiring intensive treatment without hospitalization 
- 
A diagnosis of a new cancer type during the course of a treatment  
- 
A pregnancy diagnosed in a female patient treated with the study medication must be 
reported to the Sponsor immediately.  
See Section 8.10 for SAE reporting for pregnancies. Only pregnancies with an outcome meeting any of 
the serious criteria defined above (i.e., congenital anomaly, stillbirth, neonatal death) should be 
reported as an SAE. For any pregnancy without an adverse outcome, the Investigator should complete 
the appropriate section of the SAE report form and state clearly that no AE was observed. 
Hospitalizations for the following reasons should not be reported as SAEs: 
- 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
- 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 


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- 
Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
- 
Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of an SAE given above.  
Reporting disease progression as an SAE: Progression of the underlying malignancy is not reported as 
an AE if it is clearly consistent with suspected progression of the underlying cancer as defined by 
RECIST, or other criteria as determined by the protocol. Clinical symptoms of progression should be 
reported as AEs/SAEs if there is any uncertainty that they are due only to the progression of the 
underlying malignancy or they do not fit the expected pattern of progression for the disease under 
study. The PT “disease progression” should not be used.  
In rare cases, progression may be evident in the patient’s clinical symptoms but is not supported by 
the tumor measurements, or disease progression is so evident that the investigator elects not to 
perform further disease assessments. Every effort should be made to document the radiologic 
objective progression of the underlying malignancy.  
• 
Life-threatening AE or life-threatening SAR is an AE that, in the view of either the investigator or 
Sponsor, places the patient at immediate risk of death. It does not include an AE or SAR that, had 
it occurred in a more severe form, might have caused death. 
• 
Unexpected AE or unexpected SAR is an AE or SAR that is not listed in the investigator brochure 
or is not listed at the specificity or severity that has been observed. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator 
brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if 
the investigator brochure listed only cerebral vascular accidents. “Unexpected”, as used in this 
definition, also refers to AEs or SARs that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacologic properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation. 
8.4 
Documentation  
All TEAEs occurring during the course of the study, whether or not considered related to the study 
drug or to underlying disease, must be individually recorded in the eCRF, including the nature of the 
event, date and time of onset (where appropriate), duration of effect, action taken, seriousness, 
severity, and relationship to study medication. Any consequent change to the dosage schedule or 
corrective therapy should be recorded.  
Every attempt should be made to describe the TEAE in terms of a diagnosis. If a clear diagnosis has 
been made, individual signs and symptoms will not be recorded. If a clear diagnosis cannot be 
established, each sign and symptom must be recorded individually. 
All patients who experience a TEAE, regardless of the relationship to study treatment, must be 
monitored to determine the outcome. The clinical course of the AE will be followed up even after the 
end of the period of observation for related TEAEs, until a satisfactory explanation is found or the 
investigator considers it medically justifiable to terminate follow-up. Should the AE result in death, a 
post-mortem examination should be considered as far as possible. 


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After last study treatment administration, patients will be observed for at least 30 days to document 
any late side effects and until resolution in cases of TEAEs for which a relationship to the study drugs 
cannot definitely be excluded. Patients will be followed up until resolution or attribution of sequelae 
for any treatment-related AEs. 
AEs already recorded and designated as “continuing” should be reviewed at each subsequent 
assessment. If resolved, details are to be recorded in the eCRF. If an AE worsens in frequency of 
attacks/symptoms or in severity, a new record of the event must be started (i.e., distinct AE reports 
are required for differing frequencies and/or severity of the same event to enable comprehensive 
safety reports and later analysis).  
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, must be reported 
under “concomitant procedures” in the eCRF and not as an AE. The medical condition for which the 
procedure was performed must be reported. 
8.5 
Grade and Severity 
All AEs, whether or not they are considered related to the study drug, must be graded using the NCI 
Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03, which can be found at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. The worst 
grade is to be documented. 
AE grades usually reflect their severity, with grade 1 meaning “mild”, grade 2 meaning “moderate”, 
grade 3 meaning “severe”, grade 4 meaning “life-threatening” and grade 5 meaning “fatal”. 
The term “severity” is used to describe the intensity of an AE; the event itself, however, may be of 
relatively minor clinical significance (e.g., ‘severe’ headache). This is not the same as “serious”. 
Seriousness of AEs is based on the outcome/action of an AE and associated with events that pose a 
threat to a patient’s life or functioning (see definition in Section 8.3 above). 
Intensity of the AE will be evaluated using the following criteria: 
● Mild: The patient is aware of the sign or symptom, but finds it easily tolerated. The event is of 
little concern to the patient and of little clinical significance. The event is not expected to have any 
effects on the patient’s overall health or wellbeing. 
● Moderate: The patient has discomfort enough to cause interference with or change in usual 
activities. The event is of some concern to the patient’s health or wellbeing and may require 
medical intervention and/or close follow-up. 
● Severe: The AE interferes considerably with the patient’s usual activities. The event is of definite 
concern to the patient and/or poses substantial risk to the patient’s health or wellbeing. The event 
is likely to require medical intervention and/or close follow-up and may be incapacitating or life-
threatening. Hospitalization and treatment may be required. 
8.6 
Relationship to Study Treatment 
All TEAEs occurring during treatment with an investigational agent may be related to the 
investigational agent. All TEAEs, regardless of the supposed relationship to study treatment, must 
therefore be collected. However, the investigator often has arguments to think that a TEAE is or is not 
related to the study treatment. Albeit subjective, and susceptible to be challenged, the assessment of 
relationship to study treatment is an important role of the investigator. Thus, the investigators should 


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decide, based on their knowledge and medical expertise, whether, in their opinion, an AE is 
“reasonably related” or “unlikely related” to the study treatment (or to study specific procedures).  
8.7 
SAE Reporting Requirements 
SAEs and other AEs that fulfill a reason for expedited reporting to Pharmacovigilance (overdose and 
pregnancy) must be documented on the SAE Report Form at the time the SAE is detected. This form 
must be completed by the investigator and sent within 24 hours to the Sponsor’s Pharmacovigilance 
representative as per the contact details provided on the form. 
The SAE report form and guidelines for completing it are provided in the Investigator Study File. The 
Sponsor is responsible for ensuring that all legal reporting requirements are met. 
The initial report must be as complete as possible, including details of the current illness and AE(s), 
and an assessment of the causal relationship between the event(s) and the study medication. 
Information not available at the time of the initial report (e.g., an AE end date or laboratory values 
received after the report) must be documented on a follow-up SAE report form. 
The IDMC will be provided with monthly listings of suspected SAEs. Investigators will be informed of 
serious unexpected suspected AEs as per the standard reporting requirements.  
The Sponsor must immediately declare all SUSARs resulting in death or endangering the life of a 
patient, and a follow-up report must be provided within the following 8 days. All other SUSARs must 
be declared within 15 days and follow-up report must be provided within the following 8 days. 
8.8 
AEs of Special Interest 
8.8.1 
Infusion-related reactions 
Patients will be monitored closely during the MCLA-128 infusion period for signs of IRRs. IRRs include 
the preferred term (PT) “IRR” and any other PTs occurring within 24 hours of the MCLA-128 or 
trastuzumab infusion that the investigator judges as a sign or symptom of an IRR (e.g., nausea, 
vomiting, abdominal pain, headache, hypotension, pyrexia, tremor, and hypersensitivity). 
All patients must be pre-medicated with antihistamines, paracetamol/acetaminophen and 
corticosteroids before each MCLA-128 infusion. If an IRR develops during administration of MCLA-128, 
the infusion should be stopped immediately, receive symptomatic treatment according to the 
investigator’s or treating physician’s judgment (e.g. antipyretics, bronchodilators, oxygen, 
corticosteroids, and vasopressors, anti-IL-6 compounds), and the patient should be monitored until 
resolution of the symptoms and signs.  
Upon complete resolution of non-severe IRRs, the infusion may be resumed at 50% of the infusion 
rate prior to the reaction and the infusion duration can be increased to 4 hours, to administer the 
totality of the dose. For severe IRRs (CTCAE grade 4, life-threatening), study treatment should be 
discontinued definitively. 
For IRRs considered to be due to an IgE-mediated anaphylactic reaction, the MCLA-128 infusion should 
not be resumed, irrespective of the severity of the reaction, and is contraindicated for subsequent 
cycles.  
Local irritation at the injection site should be treated according to routine treatment guidelines.  


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8.8.2 
Cardiotoxicity  
Cardiac function will be assessed by evaluating LVEF and 12-lead ECG. The LVEF assessment will be 
made preferably by echocardiogram (ECHO), although a multiple gated acquisition (MUGA) scan may 
be used if this method is standard practice at the investigational site. One method of evaluation is 
adequate and the same method should be used for each assessment for an individual patient.  
With the implementation of Protocol Version 5.0, LVEF and ECG assessments will be performed every 
6 months and at any time during the study if clinically indicated and at the End Of Treatment visit 
(EOT) & Follow-up visit  
MCLA-128 will be discontinued in any patient with a confirmed documented LVEF decrease to a value 
<40%, and/or if clinical signs and symptoms suggesting congestive heart failure develop. These 
patients should continue LVEF assessments as clinically indicated (≤18 weeks between assessments), 
until LVEF values return to ≥50%, or for 1 year, whichever is first. 
Appendix 19.3 provides the algorithm for performing any additional required assessments of LVEF, as 
well as the continuation or discontinuation of treatment with MCLA-128 and/or trastuzumab in study 
patients with asymptomatic decline in LVEF during study treatment. 
All related cardiac events will be followed up for 35+5 days after treatment discontinuation. 
8.8.3 
Diarrhea 
Diarrhea is common with anti-HER2 therapies including monoclonal antibodies. Patients must be 
advised to inform the medical team if they develop grade 1 or 2 diarrhea that does not resolve within 
48 h, or diarrhea with fever. Patients experiencing diarrhea should be managed rapidly, and 
investigators should make all efforts to determine if it is drug-related or due to a gastrointestinal 
infection. If grade 1 or 2 (< 48 h) diarrhea occurs, symptomatic measures should be initiated (e.g. 
loperamide and hydration). If persistent grade 2 diarrhea (> 48 hours) or grade 3 occurs, patients must 
be evaluated in the clinic. Stool cultures should be performed and patients should be hospitalized and 
rehydrated with oral and IV fluids if necessary. Treatment delay is indicated until event resolution. 
Patients must be withdrawn if > 6 weeks between infusions. 
8.9 
Period of Observation 
For the purposes of this study, the period of observation for collection of AEs extends from the start 
of treatment with the study drugs until 35 ± 5 days after the last study drug administration. Related 
AEs and SAEs that were ongoing at the time of the EOT visit must continue to be monitored during 
follow-up until resolution, stability (i.e. sequelae), change of causality from related to non-related, or 
initiation of further antitumor therapy. 
If the investigator detects an SAE after the end of the period of observation, and considers the event 
possibly related to prior study treatment, he/she should contact the Sponsor to determine how the 
AE should be documented and reported. 
All new related cardiac events and new suspected related SAEs will be followed up until resolution or 
stability or for 35 ± 5 days after the last treatment administration or until initiation of a new anticancer 
treatment, whichever occurs first. 
In addition, all patients will be followed up for up to 35 ± 5 days after the last treatment administration 
or until initiation of a new anticancer treatment, whichever occurs first, for disease status (patients 
who have not progressed at end of treatment) and survival status. 


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8.10 Patients of Reproductive Potential 
Pregnant or breast-feeding women are excluded from this study. Absence of pregnancy must be 
demonstrated by a serum test within 1 week prior to initiating treatment or any study procedure with 
a potential risk to the fetus and at the End of Treatment visit, and by urine testing on Day 1 of each 
cycle from Cycle 2, and every 3 months up to 7 months after MCLA-128/trastuzumab discontinuation 
unless there is proven menopause (>12 months of amenorrhea) or surgical/chemical castration. 
Female patients must not become pregnant or start breast-feeding during the study, and women of 
childbearing potential (i.e. without proven menopause) must use medically effective contraception 
during the study and for 7 months after the last MCLA-128/trastuzumab intake. 
In the event of a pregnancy during the course of this study, the Sponsor must be notified immediately 
and the patient should be immediately withdrawn from study. The investigator should counsel the 
patient, and discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
The pregnant patient should be followed during the entire course of the pregnancy and postpartum 
period. 
Parental and neonatal outcomes must be recorded even if they are completely normal and without 
AEs. Offspring should be followed up for at least 8 weeks after delivery. Longer observation periods 
may be determined by the Sponsor if an adverse outcome of the pregnancy was observed. 
Pregnancies occurring during the study up to 7 months after the final dose of MCLA-128/trastuzumab 
must also be reported to the Sponsor’s Pharmacovigilance representative on the appropriate section 
of the SAE report form, according to SAE reporting requirements (see Section 8.7). Note that a 
pregnancy is only considered an SAE if the outcome meets any of the serious criteria defined in Section 
8.3 (i.e., congenital anomaly, stillbirth, neonatal death). For any pregnancy without an adverse 
outcome, the Investigator should complete the appropriate section of the SAE report form and state 
clearly that no AE was observed. 
The following non-hormonal methods of contraception are acceptable: 
• 
True abstinence when this is in line with the preferred and usual lifestyle of the patient. [Periodic 
abstinence (e.g., calendar, ovulation, symptothermal post-ovulation methods) and withdrawal are 
not acceptable methods of contraception]. 
• 
Patients with a sole partner who is vasectomized (with appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate) 
Or two of the following effective forms of contraception:  
• 
Placement of intrauterine device (IUD) or intrauterine system (IUS). Consideration should be given 
to the type of device being used, as there are higher failure rates quoted for certain types, e.g. 
steel or copper wire. The risks (in terms of potential stimulation of hormone-responsive breast 
cancer by systemically absorbed hormones) and benefits (effective contraception) of hormone-
releasing IUDs/IUSs should also be carefully considered for individual patients. 
• 
Condom with spermicidal foam/gel/film/cream/suppository 
• 
Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, cream or 
suppository.  
The use of barrier contraceptives should always be supplemented with the use of a spermicide. The 
following should be noted: 


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• 
Failure rates indicate that, when used alone, the diaphragm and condom are not highly effective 
forms of contraception. Therefore the use of additional spermicides does confer additional 
theoretical contraceptive protection.  
• 
However, spermicides alone are ineffective at preventing pregnancy when the whole ejaculate is 
spilled. Therefore, spermicides are not a barrier method of contraception and should not be used 
alone. 
It should be noted that two forms of effective contraception are required. A double barrier method is 
acceptable which is defined as condom and occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/suppository. 
8.11 Misuse and Overdose 
Drug misuse and drug overdose for any of the study drugs should be reported to the Sponsor’s 
Pharmacovigilance representative on the appropriate section of the SAE report form, according to SAE 
reporting requirements (see Section 8.7), even if it does not result in an adverse outcome (in which 
case it should be clearly stated that no AEs were observed). 
Overdose with MCLA-128 is defined as any dose administration where >10% over the correct dose 
amount is administered, whether or not associated with an AE. Symptoms of overdose with MCLA-
128 are not yet known. In the case of accidental overdose, patients should be treated symptomatically. 
An antidote is not available. See the SPCs for companion drugs as to definition of overdose and action 
to take. 
If the pharmacy discovers that an overdose has or may have been administered they must contact the 
Investigator and study coordinator. 
8.12 Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC), composed of at least 2 physicians expert in the 
domain of early clinical development in MBC, will meet to review safety and efficacy data at select 
time points during the study (e.g. completion of safety run in, completion of enrollment), and decide 
on the addition of extra patients in the expansion parts in Cohort 1, opening of the triple combination 
cohort, and any ad hoc safety decisions. The principal investigators, the Sponsor’s medical expert(s) 
and other representatives may be called upon to assist as observers.  
The composition, functioning (meeting frequency, data received, etc.), and responsibilities of the 
IDMC will be detailed in the IDMC Charter (provided separately). All decisions by the IDMC and their 
rationale will be recorded in meeting minutes. 
 
9 
EFFICACY ASSESSMENTS 
9.1 
RECIST Tumor Measurement and Analysis 
Efficacy will be measured in terms of tumor response according to RECIST criteria (version 1.1) 
(Eisenhauer et al., 2009)(Appendix 19.4).  
With the implementation of Protocol version 5.0, tumor measurements will be done every 4 cycles 
(12 weeks) (chest, abdomen and pelvis CT scan) until progression; In case of symptomatic signs of PD 
in between the assessments an unscheduled assessment must be performed to confirm progression; 
and at the End of Treatment/Follow-up visit for patients who discontinue for reasons other than 
progression, as clinically indicated. 


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Full body bone scan will be performed at screening as clinically indicated to assess suspected bone 
metastases, and localized CT will be performed at screening for any bone lesions detected by the full 
body bone scan that are not otherwise seen on the chest, abdomen and pelvis CTs, and then repeated 
at the same frequency as the chest, abdomen and pelvis exams. A brain MRI or CT will be performed 
at screening, and if brain metastases are detected then at the same frequency as the chest, abdomen 
and pelvis exams using the same method performed at screening. 
Note: Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers (for example, skin nodules). Skin lesions must be documented by 
color photography, including a ruler to estimate the size of the lesion. If the skin lesion has a 
subcutaneous soft tissue component a localized CT should be performed if it is not visible on the chest 
abdomen and pelvis CT/MRI.  
 
Table 9-1: Tumor imaging assessments 
Body Location 
Modality 
Timing 
Chest, abdomen & pelvis 
CT 
Screening, every 6 weeks after start of study treatment until 
disease progression per RECIST 1.1, death or withdrawal of 
consent, EOT (if most recent evaluation is > 6 weeks from EOT). 
For patients who discontinue for reasons other than 
progression, assessments should continue as clinically indicated 
per the investigator’s discretion until eventual progression per 
RECIST 1.1 or for 1 year whichever occurs first. 
Bone 
Full body 
bone scan 
As close as possible to and within 9 weeks before starting study 
treatment. If disease progression was documented after the last 
bone scan and the patient manifests increased bone pain 
and/or evidence of a change in the bone lesion with other 
imaging modalities, a more recent bone scan collected within 4 
weeks will be required. Bone scans should be performed as 
clinically indicated to assess suspected new bone metastases 
on-study and during follow-up. 
Localized CT 
Screening if bone metastases are detected and then at the same 
frequency as the chest, abdomen and pelvis exams 
Brain 
CT/MRI 
Screening, and if brain metastases are detected then at the 
same frequency as the chest, abdomen and pelvis exams 
Skin 
Color 
photography 
If skin lesions are present, at the same time points and 
frequency at the chest abdomen and pelvis CT 
Localized CT 
Screening if subcutaneous soft tissue component is detected 
and then at the same frequency as the chest, abdomen and 
pelvis exams 
Any other location 
CT/MRI 
As clinically indicated, any other areas of disease (i.e. neck) 
should be completed as appropriate 
9.1.1 
Central review  
For Cohort 2, eligibility will be confirmed in terms of prior disease progression on or after the most 
recent line of therapy by central imaging review as soon as possible after enrolment, and it is 
mandatory that prior imaging be available. For Cohort 1, as far as possible, documented imaging proof 
of disease progression on the last prior line of therapy should be made available. 


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9.1.2 
Imaging Technique  
To ensure comparability, the baseline and subsequent tumor measurements to assess response 
should be performed using identical imaging techniques (i.e., preferably the same machine, contrast 
agent and standard volume of contrast agent, etc.). 
 
9.1.3 
Evaluation of Lesions 
Table 9-2: Evaluation of response in target lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
Partial Response 
(PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progression (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study).  
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  
The appearance of one or more new lesions is also considered progression) 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
 
Table 9-3: Evaluation of non-target lesions 
Complete Response 
(CR) 
Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (<10 mm short axis)  
Non-CR / Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progression (PD) 
Unequivocal progression of existing non-target lesions; see Section 4.3.4 of 
Eisenhauer et al., 2009 (Appendix 19.4) for further details.  
Note: the appearance of one or more new lesions is also considered 
progression. Unequivocal progression of existing non-target lesions, other 
than pleural effusions without cytological proof of neoplastic origin, in the 
opinion of the treating investigator (in this circumstance an explanation 
must be provided)1.  
1Although clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of 
the treating physician should prevail and the progression status should be confirmed later by the Medical 
Monitor. 


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9.1.4 
Definition of Best Overall Tumor Response  
Overall response is calculated for each assessment time point as per Table 9-4. 
Table 9-4: Overall response in patients with target (+/- non-target) disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable 
The best overall response is determined once all data for a given patient are available and is defined 
as the best response recorded between the start and end of treatment, as described in Table 9-5. 
Table 9-5: Best overall response 
Overall response 
First time point 
Overall response 
Subsequent time points 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable 
1. If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response 
would depend on whether minimum duration for SD was met. However, sometimes CR may be claimed when subsequent 
scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time point. Under 
these circumstances, the original CR should be changed to PR and the best response is PR. 
 


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In the rare event that a patient experiences global deterioration of health status considered related 
to the underlying malignant disease which requires discontinuation of treatment but without 
objective evidence of disease progression at that time, they should be reported as “symptomatic 
deterioration” as the cause of treatment discontinuation. Every effort should be made to document 
the objective progression even after discontinuation of treatment.  
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the 
next scheduled assessment, progression is confirmed, the date of progression should be the earlier 
date when progression was suspected. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete response 
status. 
Carcinomatous meningitis diagnosed by cytologic evaluation of cerebral spinal fluid will also be 
defined as progressive disease. Medical photography can be used to monitor chest wall recurrences 
of subcutaneous lesions. 
In Cohort 2, in the absence of measurable disease at baseline, patients with bone-only lesions, lytic 
or mixed (lytic + sclerotic), will be allowed to enter the study. 
 
The following will be considered disease progression among these patients: 
• 
The appearance of one or more new lytic lesions in bone 
• 
The appearance of one or more new lesions outside of bone 
• 
Unequivocal progression of existing bone lesions 
 
Note: Pathologic fracture, new compression fracture, or complications of bone metastases will not 
be considered as evidence of disease progression, unless one of the above-mentioned criteria is 
fulfilled. 
9.2 
Tumor Markers 
The tumor markers CA15-3, CEA, and CA27-29 will be assessed on Day 1 of every cycle as part of 
routine laboratory analyses. As far as possible, measures should be made in the same laboratory. 
Evolution of each tumor marker will be followed throughout treatment. 
 
 
 


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10 PHARMACOKINETICS ASSESSMENTS 
PK sampling is no longer applicable as of Protocol Version 4.0. 
For Protocol Versions 1.0, 2.0 and 3.0, PK blood sampling (4 mL per sample) will be performed in all 
patients to measure serum MCLA-128. Trastuzumab will be measured in all Cohort 1 patients. No PK 
sampling will be performed for vinorelbine or endocrine therapy. PK blood sampling will be performed 
at the following time points: 
Table 10-1: MCLA-128 PK blood sampling (Cohort 1, doublet and triplet) 
Cycle 
Day 
Run in 
Expansion 
Scheduled time relative to MCLA-128 
dose 
1 
1 
X 
X 
Predose (0-2 h before) 
1 
1 
X 
X 
EOI (0-10 min before EOI) 
1 
1 
X 
X 
2 h (±15 min) after EOI 
1 
1 
X 
X 
4 h (±30 min) after EOI 
1 
2 
X 
X 
22 h (±2 h) after EOI 
1 
8 
X* 
X 
Any time 
2 
1 
X 
X 
Predose (0-2 h before) 
2 
1 
X 
X 
EOI (0-10 min before EOI) 
2 
1 
X 
 
2 h (±15 min) after EOI 
2 
1 
X 
 
4 h (±30 min) after EOI 
2 
2 
X 
 
22 h (±2 h) after EOI 
2 
8 
X 
 
Any time 
3 
1 
X 
X 
Predose (0-2 h before) 
3 
1 
X 
X 
End of Infusion (0-10 min before EOI) 
5 
1 
X 
X 
Predose (0-2 h before) 
5 
1 
X 
X 
EOI (0-10 min before EOI) 
Every 4 cycles (C9, C13, 
etc.) 
1 
X 
X 
Predose 
* Cycle 1 Day 9 for patients treated in the triplet safety run-in combination;  
EOI, end of infusion 
 
Table 10-2: Trastuzumab PK blood sampling (Cohort 1) 
Cycle 
Day 
Doublet 
Triplet 
Scheduled time relative to 
trastuzumab dose 
 
 
Run-in 
Expansion 
Run-in 
Expansion 
 
1 
1 
 
X 
X 
X 
Predose (0-2 h before) 
1 
1 
 
X 
X 
X 
EOI (0-10 min before EOI) 
1 
2 
X 
 
 
 
Predose (0-2 h before) 
1 
2 
X 
 
 
 
EOI (0-10 min before EOI) 
2 
1 
X 
X 
X 
X 
Predose (0-2 h before) 
2 
1 
X 
X 
X 
X 
EOI (0-10 min before EOI) 
EOI, end of infusion 


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Table 10-3: MCLA-128 PK blood sampling (Cohort 2) 
Cycle 
Day 
Scheduled time relative to MCLA-128 dose 
1 
1 
Predose (0-2 h before) 
1 
1 
EOI (0-10 min before EOI) 
1 
1 
2 h (±15 min) after EOI 
1 
1 
4 h (±30 min) after EOI 
1 
2 
22 h (±2 h) after EOI 
1 
8 
Any time 
2 
1 
Predose (0-2 h before) 
2 
1 
EOI (0-10 min before EOI) 
3 
1 
Predose (0-2 h before) 
3 
1 
EOI (0-10 min before EOI) 
5 
1 
Predose (0-2 h before) 
5 
1 
EOI (0-10 min before EOI) 
Every 4 cycles (C9, C13, etc.) 
1 
Predose (0-2 h before) 
EOI, end of infusion  
Planned PK blood sampling times should be adhered to as closely as possible. It is essential that the 
actual time (i.e., infusion start and stop) be recorded accurately in the patient’s records and the eCRF, 
along with the date of collection of each blood sample. Full instructions for sample preparation, 
storage and shipping are provided in the Central Laboratory Manual. 
Serum samples must be sent as soon as possible to the central laboratory for analysis, particularly for 
the first 4-6 safety run-in patients treated in each combination arm, to allow for availability of results 
when reviewing safety data. If 2 patients in the same center are treated at the same time or a few 
days apart, samples of these 2 patients should be sent together.  
Based on 5 treatment cycles, in total the following amounts of blood will be drawn per patient from a 
peripheral venous access for PK analysis (for each additional cycle, 1 additional 2-mL blood sample will 
be drawn):  
• 
Cohort 1 doublet and triplet safety run-in patients: 20 blood samples of 4 mL each, i.e. 
approximately 80 mL of blood. 
• 
Cohort 1 doublet and triplet expansion patients: 16 blood samples of 4 mL each, i.e. 
approximately 64 mL of blood. 
• 
Cohort 2 patients: 13 blood samples of 4 mL each, i.e. approximately 52 mL of blood. 
 
11 PHARMACODYNAMICS ASSESSMENTS 
 
Sample collection for Biomarker analyses is no longer applicable as of Protocol Version 5.0. 
11.1 Sample collection 
Collection of tumor and blood samples for HER2 and HR status and biomarker analyses is detailed 
below. The time and date of collection of all samples (tumor and blood) will be recorded in the eCRF. 
Analyses will be performed centrally. Full instructions for tumor and liquid biopsy sample preparation, 
storage and shipping are provided in the Central Laboratory Manual, as well as guidelines for 
procedures to follow for any unused samples obtained from a patient who withdraws consent at any 
time during or after the study. 


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11.1.1 Tumor sample  
A mandatory formalin-fixed paraffin-embedded (FFPE) tumor sample is required from all patients 
(both cohorts) at screening for HER2 status and exploratory biomarkers for all patients, and for HR 
status for Cohort 2. The tumor sample can be either a fresh sample or an archival sample collected 
within 24 months before screening. All efforts should be made to obtain a fresh tumor sample. The 
tumor sample should preferably be from a metastatic site, otherwise primary tissue is acceptable.  
Due to the difficulty to assess HER2 expression using IHC and FISH in bone tissue, a primary FFPE tumor 
specimen will be used for biomarker analyses in the event that Cohort 2 patients have bone-only 
disease, unless it is determined that testing for HER2 expression in a bone biopsy is possible. 
 
Table 11-1: Tumor biomarker sampling  
Sample 
Time Point 
FFPE tumor sample  
(one sample per time 
point) 
Screening: A fresh tumor sample OR an archival sample collected within 24 
months before screening (preferably metastatic otherwise primary)*.  
12 weeks from the start of first study treatment (optional): Fresh tumor 
sample. 
EOT, within 35 days of last treatment (optional): Fresh tumor sample. 
*For Cohort 2 patients with bone-only disease, primary tumor tissue will be used (unless it is determined that testing 
for HER2 expression in a bone biopsy is possible) 
 
FFPE tissue blocks must have a tumor content > 40%. A block of adequate size (at least 5 mm deep 
core with a surface area of 2.5 mm²) or a minimum of 30 unbacked glass slides, each containing a 
freshly cut unstained 4-5 µm section, is required (separate instructions will be provided for slide 
shipping). 
Samples will be sent to the sponsor-designated central laboratories for assessment of HER2 and HR 
status and biomarkers. 
For enrollment, HER2 (all patients) and HR status (Cohort 2) will be based on medical records and 
eligibility will be confirmed by central lab review after enrollment. Any patient found retrospectively 
to be ineligible for either of these parameters will not be evaluable for the primary objective and may 
be replaced. 
11.1.2 Liquid Biopsy 
For all patients (Cohorts 1 and 2), the following blood samples will be collected as follows.  
Table 11-2: Liquid biopsy biomarker sampling  
Peripheral blood sample 
Time Point (all pre-dose) 
 1 x 6 mL and 2 x 10 mL  
Day 1 and Day 85 (Day 1 Cycle 5) of study treatment 
2 x 10 mL 
Every 12 weeks (Day 1 Cycles 9, 13, 17, etc.) thereafter 
2 x 10 mL 
End of Treatment (within 35 ± 5days of ending treatment) 
 
 
 
 
 


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11.2 Analyses 
11.2.1 Tumor HER2 and Hormone Receptor Status 
HER2 and HR status for eligibility for study enrolment will be based on medical records. For all patients, 
eligibility will be confirmed centrally from the screening tumor biopsy after enrolment.  
Cohort 1: HER2 amplification will be confirmed by IHC 3+ or IHC 2+ combined with positive FISH. 
Cohort 2: ER-positive status and low HER2 expression will be confirmed by IHC 1+, or IHC 2+ combined 
with negative FISH. 
11.2.2 Exploratory Biomarker Analyses 
Exploratory biomarker and pharmacodynamic analyses will be performed on tumor tissue and blood 
(liquid biopsy) from the screening tumor biopsy and any optional on-study biopsies to assess potential 
correlations between evidence of activity and expression of HER2, and exploratory biomarkers such 
as HER3 and HER2:HER3, and other candidate biomarkers.  
Identification of new markers correlating with disease activity and activity of treatment is evolving, 
the definitive list of analyses will be determined during the course of the study. The tumor tissue and 
blood samples collected under informed consent may be used to develop and validate assays and 
allow the generation of statistically meaningful biomarker data. Tumor tissue and blood samples 
remaining after the pre-defined biomarker assessments (e.g., aliquots of tumor cell RNA or DNA) may 
be used for re-testing, developing, and validating assays related to HER2-positive breast cancer or the 
prediction of response to MCLA-128, or further assessment of the defined marker panels. Specific 
patient research consent will be required for long-term storage of their samples and additional 
exploratory analysis. 
11.2.2.1 Tumor Tissue Biomarkers  
In addition to HER2 status by IHC and FISH, the following exploratory analyses will be performed if 
sufficient tumor sample is available: 
• 
HER3 protein, HER2:HER3 dimerization, and downstream signaling proteins (eg PIK3CA) 
including HER3:pPIK3A binding will be assessed by an appropriate method such as proximity 
ligation assay (PLA). 
• 
Heregulin mRNA expression (NRG1) will be evaluated using in situ hybridization or RT-PCR, and 
protein analysis will be performed if an appropriate method (such as IHC) is available. 
If sufficient material is available the following exploratory analyses will be performed: 
• 
pHER2, pHER3, pAKT and pERK1/2 (members of the MAPK and AKT signaling pathway) will be 
assessed using a method such as Reverse Phase Protein Array (RPPA) analysis or IHC and will be 
scored relative to total HER2, HER3, AKT and ERK respectively. Expression of inhibitors of 
proteins in MAPK and AKT signaling pathway such as PTEN will be assessed by IHC. 
• 
Mutations in cancer-related genes including those associated with HER2 and HER3 signaling. 
• 
Heregulin-gene fusions, if required and if a validated assay is available. 
11.2.2.2 Liquid Biopsy Biomarkers 
Exploratory analyses will include: 
• 
Fc receptor polymorphism to determine ADCC activity by genotyping on PBMCs (Day 1 only). 
• 
Plasma ctDNA mutation analysis in cancer-related genes including those associated with HER2 
and HER3 signaling. 


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• 
Exploratory serum biomarkers such as soluble serum HER2 (ADVIA centaur) and heregulin 
(using research-based quantitative methods such as ELISA). 
12 CYTOKINE ASSESSMENTS 
Blood samples (5 mL) will be collected in Cohort 1 safety run-in patients only, to assess a serum 
cytokine panel (TNFα, IFNγ, IL-1β, IL-6, IL-8, IL-10) as follows: 
 
Table 12-1: Cytokine blood sampling (Cohort 1 doublet safety run-in) 
Cycle 
Day 
Scheduled time relative to            
MCLA-128 dose 
Scheduled time relative to       
trastuzumab dose 
1 
1 
Predose (0-2 h before) 
 
1 
1 
2 h after EOI 
 
1 
1 
4 h after EOI 
 
1 
2 
22 h after EOI* 
Predose (0-2 h before) 
1 
2 
 
2 h after trastuzumab EOI 
2 
1 
Predose (0-2 h before) 
 
2 
1 
2 h after EOI 
Immediately after EOI 
2 
1 
4 h after EOI 
2 h after EOI 
2 
2 
22 h after EOI 
20 h after EOI 
* Corresponds to pre-dose trastuzumab ~24 h after MCLA-128 initiation and can be 0-2 h before the infusion. 
EOI, end of infusion  
Table 12-2: Cytokine blood sampling (Cohort 1 triplet safety run-in) 
Cycle 
Day 
Scheduled time relative to           
MCLA-128 dose 
Scheduled time relative to       
trastuzumab dose 
1 & 2 
1 
Predose (0-2 h before) 
 
1 & 2 
1 
2 h after EOI 
Immediately after EOI 
1 & 2 
1 
4 h after EOI 
2 h after EOI 
1 & 2 
2 
22 h after EOI 
20 h after EOI 
EOI, end of infusion  
Additional cytokine samples may be collected in the expansion part of the study as needed. 
Full instructions for sample preparation, handling procedures, aliquoting of samples, storage and 
shipping of these serum samples will be provided in the Central Laboratory Manual for this study. 
Serum samples must be sent as soon as possible to the central laboratory for analysis, particularly for 
the first 4-6 safety run-in patients treated in each combination arm, to allow for availability of results 
when reviewing safety data. If 2 patients in the same center are treated at the same time or a few 
days apart, samples of these 2 patients should be sent together. 
Cytokine results will be reported separately including per-patient listings with descriptive statistics. 
 
13 IMMUNOGENICITY ASSESSMENTS 
Anti-MCLA-128 antibody sampling is no longer applicable as of Protocol Version 4.0. 
For Protocol Versions 1.0, 2.0, and 3.0 blood samples (5 mL) will be collected in all patients to assess 
serum titers of anti-MCLA-128 antibodies on Day 1 at pre-dose for each of Cycles 1, 3 and 5, and every 
4 cycles thereafter (Cycle 9, Cycle 13 etc.), and at the End of Treatment Visit. 
Full instructions for sample preparation, handling procedures, aliquoting of samples, storage and 
shipping of these serum samples will be provided in the Central Laboratory Manual for this study.  


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Immunogenicity results will be reported separately including per-patient listings with descriptive 
statistics. 
14 STATISTICAL CONSIDERATIONS 
14.1 Sample Size 
Cohort 1 safety run-in: 4 to 6 evaluable patients in the safety run-in will have power to detect an AE 
with a true incidence of 33% is 80 to 90%. 
Cohort 1 efficacy expansion: 40 evaluable patients with observed CBR of > 45% will provide adequate 
precision to exclude 30% (lower limit of 90% CI > 30%). The threshold for the CBR rate at 24 weeks is 
defined based on the assumption that PFS follows an exponential distribution with a median of 5 
months (clinically relevant) and 3.5 months (not clinically relevant). 
Cohort 2: 40 evaluable patients with observed CBR of at least 45% will provide enough precision to 
exclude 30% (lower limit of 90% CI > 30%). The threshold for CBR at 24 weeks is defined based on the 
assumption that PFS follows an exponential distribution with a median of 5 months (clinically relevant) 
and 3.5 months (not clinically relevant).  
The final number of patients will depend on the safety and efficacy outcomes during the study. Up to 
~130 patients are anticipated, allowing for a total of 40 patients in each of the three planned 
combination regimens and a ~10% rate of non-evaluable patients. 
14.2 Study Endpoints 
14.2.1 Definitions 
All efficacy endpoints will be defined and analyzed based on tumor assessment by RECIST 1.1 
(Eisenhauer et al., 2009) (Appendix 19.4). Carcinomatous meningitis diagnosed by cytologic evaluation 
of cerebral spinal fluid will also be defined as progressive disease. See also Section 9.1. 
• 
Clinical benefit rate (CBR): the proportion of patients with a best overall response of CR, PR 
(confirmed a minimum of 4 weeks later) or SD ≥24 weeks, based on tumor assessments up to 
PD, death or the next anti-cancer therapy, whichever occurs earlier. 
• 
Overall response rate (ORR): the proportion of patients with best overall response of CR or PR. 
Objective response is defined as a CR or PR (RECIST 1.1) on two consecutive occasions ≥4 weeks 
apart.  
• 
Progression-free survival (PFS): the time from treatment start until first documented 
radiographic progression as determined by the investigator using current RECIST or death due 
to any cause, whichever occurs first. 
• 
PFS ratio (Cohort 2 only): the ratio of PFS observed on the previous regimen to PFS recorded on 
study treatment. 
• 
Duration of Response (DoR): the time from the date of initial confirmed response (CR or PR) 
until the date of progression or death due to any cause.  
• 
Overall Survival (OS): the time from treatment start until death due to any cause. 


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14.2.2 Endpoints 
Primary (Cohort 1 and 2)  
• 
CBR per investigator radiologic review at 24 weeks  
Key secondary  
• 
Cohort 1: CBR at 24 weeks per central review, and ORR, PFS, and DoR per investigator and 
central review 
• 
Cohort 2: CBR at 24 weeks per central review, and PFS per investigator and central review 
 
 
Other secondary (Cohort 1 and 2) 
• 
Safety: incidence, severity and relationship of AEs, laboratory abnormalities, SAEs, ECG and 
LVEF measurements, and vital signs 
• 
Tolerability: discontinuations due to AEs, dose modifications due to AEs, immunogenicity, and 
cytokine assessments 
• 
Other efficacy: DoR (Cohort 2), PFS ratio (Cohort 2), ORR (Cohort 2), and OS (Cohorts 1 and 2) 
• 
Pharmacokinetics: serum Cmax, C0h, AUC, CL, Vss, tmax and t1/2 for MCLA-128 and serum CEOI and 
C0h for trastuzumab 
14.3 Analysis Populations 
Treated population: patients who receive at least one dose of MCLA-128. 
Evaluable for efficacy: patients who receive at least 2 complete cycles (6 weeks) of treatment and 
have undergone baseline assessment and one on-study tumor assessment, or who discontinue early 
due to disease progression. 
Note: For both cohorts, patients will be enrolled based on their HER2 status, HR status (Cohort 2 only), 
and disease progression on the prior line of therapy, as reported in their medical records. Evaluability 
for the primary endpoint will be confirmed by central review after enrolment. Any patient found to 
be ineligible retrospectively will not be evaluable for the primary objective and may be replaced. Non-
eligible patients are: 
• 
Cohort 1: patient is not HER2-positive/amplified (by central lab), and/or disease progression 
under the last line of therapy by imaging is not confirmed (by central imaging review). 
• 
Cohort 2: is not low HER2 expression (by central lab), and/or disease progression under the last 
line of therapy by imaging is not confirmed (by central imaging review). 
14.4 Statistical Analyses 
Patient disposition and demographics will be analyzed in the treated population, efficacy will be 
analyzed in the evaluable for efficacy population, and safety will be analyzed in the treated population. 
Quantitative variables will be summarized using descriptive statistics. Continuous variables will be 
presented as N, mean and/or median, standard deviation, range. Categorical variables will be 
presented using frequencies and percentage. 
Results will be summarized by cohort and treatment (i.e., Cohort 1 doublet, Cohort 1 triplet and Cohort 
2), according to the treatment patients actually receive. 
Full details of analyses including handling of missing data, will be provided in the Statistical Analysis 
Plan. 


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14.4.1 Analysis of the Primary Efficacy Endpoint 
Criteria for success: 
Cohort 1 (doublet and triplet): To be eligible, patients must have progressed on a maximum of 5 lines 
of HER2-directed therapy in the metastatic setting; trastuzumab with pertuzumab and an HER2 
antibody drug conjugate (e.g. T-DM1) in any sequence and in any setting must have been previously 
administered. Although the level of antitumor activity is not well defined for patients in the metastatic 
setting progressing on T-DM1, the current assumptions are based on the TH3RESA trial (Krop et al., 
2014) in which patients had a median of 4 previous regimens for advanced disease including both 
trastuzumab-containing and lapatinib-containing therapies. In this trial the T-DM1 arm showed a 
median PFS of 6.2 months (95% CI, 5.59 - 6.87) while in the control arm (investigator choice, primarily 
trastuzumab-based regimen) PFS was 3.3 months (95% CI, 2.89 - 4.14). It is assumed here that a 
clinically relevant median PFS is 5 months, therefore the activity threshold for CBR at 24 weeks is set 
to 45%. 
Cohort 2: Eligible patients must have progressed on a maximum of 3 lines of endocrine therapy in the 
metastatic setting and on a CDK4/6 inhibitor. There are no well-established data that can serve as a 
reference for this population. Our assumptions are based on the phase 3 BELLE-3 study in patients 
who had progressed on an aromatase inhibitor and everolimus which demonstrated median PFS of 
3.9-4.3 months in the overall and PIK3CA-mutated populations treated with buparlisib (a PI3K 
inhibitor) and fulvestrant, and 1.8 months in the fulvestrant-only arm (Angelo et al., 2016). It is 
assumed here that a clinically relevant median PFS is 5 months, therefore the activity threshold for 
CBR at 24 weeks is set to 45%. 
Observed CBR in both cohorts will be presented with accompanying 90% exact binomial confidence 
interval. 
Patients with only non-measurable disease at baseline will be analyzed for best overall response and 
CBR, and will be considered as a SD if their response is a ‘Non-CR/Non-PD’. 
 
14.4.2 Analysis of Other Efficacy Endpoints 
Observed ORR in both cohorts will be presented with accompanying 90% exact binomial confidence 
interval. Only patients with measurable disease will be included in analyses.  
For PFS, OS and DoR the survival function will be estimated using the Kaplan-Meier product limit 
method; probability estimates and 90% CI will be provided at specified time points; median duration 
and 90% CI will also be provided. DoR will be estimated for responders only. 
For patients in Cohort 2, the number and proportion of any patients with a PFS ratio ≥ 1.3 (Von Hoff 
et al., 2010) will be tabulated together with 90% exact CI, along with descriptive data of the PFS ratio 
for each of these patients. 
For patients with elevated tumor markers (CA15-3, CEA, and CA27-29) at baseline, evolution over time 
will be evaluated. 
14.4.3 Analysis of the Safety Endpoints 
The safety of MCLA-128 in combination with trastuzumab ± vinorelbine (Cohort 1) or with ET (Cohort 
2) will be assessed by AEs, ECG and LVEF measurements, laboratory test results, and vital signs. 
Adverse events: AEs will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA®) 
preferred term (PT) and by system organ class (SOC) according to incidence and severity (based on 


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NCI-CTCAE v. 4.03). For each patient, the maximum severity of a given AE recorded will be used. AEs 
of special interest (including IRRs) will be tabulated. In addition, AEs leading to discontinuation of study 
treatment and SAEs will be summarized. 
Cardiac safety: The number and percentage of patients with congestive heart failure (NCI-CTCAE 
v.4.03 grades 3, 4, and 5) and asymptomatic LVEF events (NCI-CTCAE grades 1 and 2, as per MUGA or 
ECHO) at any time during the study will be summarized.  
The baseline LVEF value and the maximum absolute decrease (or minimum absolute increase if 
patients’ post-baseline LVEF measures are all above the baseline value) in LVEF measures from 
baseline will be summarized. LVEF measurements and change in LVEF from baseline will be 
summarized by scheduled visits in graphical and tabular format. 
For each ECHO/MUGA evaluation following the initiation of study drug, the number and percentage 
of patients with dose delay and/or infusion interruption and ECHO/MUGA repeated will be 
summarized. The change in LVEF at that time point will be summarized using descriptive statistics. 
Laboratory data: Laboratory toxicities will be defined based on local laboratory normal ranges and 
CTCAE version 4.03. For parameters without CTCAE grade the tables will be based on normal ranges. 
Toxicities for select laboratory abnormalities will be tabulated according to incidence and severity, 
and shift tables for the worst post-baseline value will be presented. For each patient, the maximum 
severity of a given laboratory toxicity will be used. 
Vital signs: Maximal changes in vital signs will be summarized in tabular form.  
14.4.4 Analyses of PK, Immunogenicity, Cytokines and Biomarkers 
PK, immunogenicity, cytokines and biomarkers will be analyzed centrally and results for each will be 
presented separately. 
For pharmacokinetics, serum concentrations of MCLA-128 and trastuzumab will be measured using 
validated bioanalytical methods at all time points. Descriptive statistics will be used to summarize PK 
parameters. Mean values for Cmax, C0h, AUC, CL, Vss, tmax and t1/2 will be calculated from the individual 
serum concentration versus time profiles of MCLA-128. Mean values for CEOI and C0h will be calculated 
for trastuzumab. Additional PK parameters may be calculated as appropriate. A population PK analysis 
of MCLA-128 may be performed with the available PK data.  
14.5 Interim Analysis 
No formal interim analysis is planned.  
 
15 ETHICAL AND LEGAL ASPECTS 
15.1 Ethical Conduct 
This clinical study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), as 
defined in ICH Guidance E6: Good Clinical Practice: Consolidated Guidance, the Declaration of Helsinki, 
the European Union (EU) Clinical Trials Directive 2001/20/EC, the GCP Directive 2005/28/EC, and 
applicable national and local regulatory requirements. 
15.2 Delegation of Investigator Duties 


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The investigator must ensure that all persons assisting with the trial are adequately qualified, informed 
about the protocol, any amendments to the protocol, the study treatments, and their trial-related 
duties and functions. 
The investigator must maintain a list of sub-investigators and other appropriately qualified persons to 
whom he/she has delegated significant trial-related duties. 
15.3 Patient Information and Informed Consent 
All patients will be informed that participation is voluntary and that they can cease participation at 
any time without necessarily giving a reason and without losing the right to receive appropriate 
medical care for their condition. Before being enrolled in the clinical study, patients must give written 
informed consent to participate in the study.  
A Patient Information Leaflet (PIL), including an Informed Consent Form (ICF) (provided separately) 
will be given to each patient screened in the study. This document contains all the information 
required by the ICH E6 Guideline for Good Clinical Practice and any additional elements required by 
local regulations. The master document (in English) is also translated into the national language(s) and 
in terms that are understandable to any patient. In addition to the document, the investigator should 
provide oral information and answer all of the patient’s questions. Patients must have adequate time 
for reflection and to ask questions and should not sign the ICF when it is first given to them.  
The patient's consent must be confirmed by their dated signature and the name and dated signature 
of the principal investigator or sub-investigator conducting the informed consent discussions. 
A copy of the signed consent document must be given to the patient. The original signed consent 
document will be retained in the Investigator Study File. 
The investigator will not undertake any measure specifically required for the clinical study until valid 
consent has been obtained. 
15.4 Confidentiality 
Patient names will not be supplied to the Sponsor. Only the patient number and initials will be 
recorded in the eCRF and provided to any vendors working on behalf of the Sponsor. If the patient 
name appears on any document (e.g., laboratory report), it must be eliminated on the copy of the 
document supplied to the Sponsor. Study data stored on a computer will be kept in accordance with 
local data protection laws. Patients will be informed that representatives of the Sponsor, independent 
ethics committee (IEC)/ institutional review board (IRB), or regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information made available 
for inspection will be handled in strictest confidence and in accordance with local data protection laws. 
The investigator will maintain a patient identification list (patient number with the corresponding 
patient codes, names, and date of birth) to enable records to be identified, which must be maintained 
in strict confidence.  
15.5 Approval of the Clinical Study Protocol and Amendments 
Before the start of the study, the clinical study protocol, PIL/ICF, and any other appropriate documents 
will be submitted to the IEC/IRB and to the national Health Authorities, in accordance with local legal 
requirements. 
Before the first patient is enrolled in the study, all ethical and legal requirements must be met. 


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The IEC/IRB and the authorities must be informed of all administrative changes and any important 
finding that could modify the risk of exposed patients. They also must be informed or their 
authorization obtained for all subsequent amended protocols, in accordance with local legal 
requirements.  
The investigator must keep a record of all communication with the IEC/IRB and the Health 
Authorities. 
15.6 Ongoing Information for IEC/ IRB and Health Authorities 
The Sponsor must submit the following to all investigators, the IEC/IRB and Health Authorities: 
• 
Information on serious or unexpected AEs from any investigational site, as soon as possible. 
• 
Expedited safety reports according to regulations. 
• 
Periodic reports on the study progress. 
15.7 Study Closure  
The study must be closed at the site on completion. Furthermore, the Sponsor or the investigator has 
the right to close a study site at any time. Study materials must be returned, disposed of or retained 
as directed by the Sponsor. 
15.8 Record Retention 
The Investigator is required to maintain copies of all essential study documentation, including the 
Investigator Study File, a disc containing all CRF data (including the full audit trail and all data queries), 
signed informed consent forms, and records for the receipt and disposition of study medication, for a 
period of at least 15 years after study completion, as specified by ICH GCP and longer if required by 
local or regulatory authorities. Beyond this period, the investigator must obtain approval in writing 
from the Sponsor before destruction of any records. 
The documents to be retained include: 
• 
Original signed ICFs for all patients 
• 
Patient identification code list, screening log and enrollment log 
• 
Composition of the IEC/IRB  
• 
List of sub-investigators and other appropriately qualified persons to whom the investigator has 
delegated significant trial-related duties, together with their roles in the study and signatures 
• 
Records of all communications between the investigator and the IEC/IRB, and between the 
investigator and Sponsor (or CRO) 
• 
A disc containing all CRF data and of documentation of corrections on data correction forms 
(DCF) for all patients (i.e., audit trail) 
• 
Investigational product accountability records 
• 
Record of any body fluids or tissue samples retained 
• 
All other source documents (patient medical records, hospital records, laboratory records, etc.) 
• 
All other documents as listed in Section 8 of the ICH E6 Guideline for Good Clinical Practice 
15.9 Liability and Insurance 
Liability and insurance provisions for this study are provided separately. The Sponsor has taken out an 
insurance covering their civil responsibility. A copy of the country-specific insurance certificates will 


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be maintained in the Investigator Study File and Trial Master File. Details of the insurance will be made 
available to patients in the ICF.  
15.10 Financial Disclosure 
Before the start of the study, the investigator will disclose to the Sponsor any proprietary or financial 
interests he or she might hold in the investigational products or the Sponsor company as outlined in 
the financial disclosure form provided by the Sponsor. The investigator agrees to update this 
information in case of significant changes during the study or within one year of its completion. The 
investigator also agrees that, where required by law or regulation, the Sponsor may submit this 
financial information to domestic or foreign regulatory authorities in applications for marketing 
authorizations. 
Similar information will be provided by each sub-investigator to whom the investigator delegates 
significant study related responsibilities. 
16  STUDY MONITORING AND AUDITING 
Monitoring and auditing procedures developed or endorsed by the Sponsor will be followed, in order 
to comply with GCP guidelines. The investigator/institution must provide direct access to the on-site 
study documentation and medical records.  
16.1 Monitoring and Source Data Verification 
Monitoring will be done by in-person visits by Sponsor representatives (study clinical research 
associate [CRA] and medical monitors) who will check the eCRFs for completeness and clarity, and 
crosscheck them with source documents. In addition to the monitoring visits, frequent 
communications (letter, telephone, e-mail and fax), by the study monitors will ensure that the 
investigation is conducted according to protocol design and regulatory requirements. 
A file for each patient must be maintained by the investigator that includes the signed informed 
consent form and all source documentation related to that patient. The Investigator must ensure the 
completeness and the availability of source documents from which the information in the CRF was 
derived. 
At each study monitoring visit, the Investigator or designee will make available all records pertaining 
to the study. To allow sufficient time to assemble the documentation, monitoring visits will be 
confirmed by the site monitor in advance of planned visits. 
Study close-out will be performed by the study monitor upon study closure. 
16.2 On-Site Audits/Inspections 
An external auditor, appointed by the Sponsor or the EC/IRBs, as well as inspectors, appointed by 
domestic and foreign regulatory authorities, may request access to all source documents, CRFs, and 
other study documentation for on-site audits or inspections. Direct access to these documents must 
be guaranteed by the investigator, who must provide support at all times for these activities. Medical 
records and other study documents may be copied during audit or inspection provided that patient 
names are obliterated on the copies to ensure confidentiality. Prior notice will be given to any sites 
selected for auditing. 
 


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17  DOCUMENTATION AND USE OF STUDY FINDINGS 
17.1 Documentation of Study Findings 
All CRF data will be collected using an electronic Case Report Form (eCRF) within a fully validated and 
CFR 21 Part 11 compliant Electronic Data Capture (EDC) system. All data will be entered into the CRF 
by the designated and appropriately trained site personnel whose name, initials, position, and 
signature must be supplied to the Sponsor.  
The investigator, or designated representative, should complete the eCRF pages as soon as possible 
after data are collected, preferably on the same day that a study patient is seen for an examination, 
treatment, or any other study procedure and at the latest before the next monitoring visit. An 
explanation should be given for all missing data. 
Data will be source data verified and reviewed by the study site monitor(s) before data cleaning by 
Data Management is performed. A source data location list will be prepared prior to study start and 
will be filed in both the Trial Master File and the Investigator Study File and updated as necessary. All 
queries will be raised and resolved within the EDC system. During entry, data will be checked by 
programing and once saved into the database further programing checks will be performed. During 
the conduct of the study, all system users will have real-time access to the data; the level of access to 
the data and study privileges will depend on their role. 
The completed eCRFs must be reviewed and signed by the investigator named in the clinical study 
protocol or by a designated co-investigator. 
All errors detected after the monitoring visit will be queried using Data Correction Forms (DCFs). The 
Sponsor will answer the question and/or correct errors in the DCF duly signed and dated. Original DCFs 
will be collected by the Sponsor’s study monitor, while a copy will be kept by the investigator and 
recorded in the Investigator Study File with the corresponding eCRFs. 
A copy of the eCRF will be printed and filed in the Trial Master File. The Sponsor will retain the originals 
of all eCRFs. The investigator will retain a copy of all completed eCRF pages and DCFs. 
17.2 Confidentiality, Use of Study Findings and Publication Policy 
All information concerning the product as well as any matter concerning the operation of the Sponsor, 
such as clinical indications for the drug, its formula, methods of manufacture and other scientific data 
relating to it, that have been provided by the Sponsor and are unpublished, are confidential and must 
remain the sole property of the Sponsor. The investigator will agree to use the information only for 
the purposes of carrying out this study and for no other purpose unless prior written permission from 
the Sponsor is obtained. 
Samples and/or data will be processed centrally and the results will be sent electronically to the 
Sponsor or designated CRO. Data that will be processed centrally includes central imaging review data 
(CT/MRI) and centrally analyzed laboratory data including PK and blood/tumor biomarker samples. 
The Sponsor has full ownership of the original eCRFs completed as part of the study. 
By signing the clinical study protocol, the investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for medical 
and pharmaceutical professionals. The authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement. 


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The Sponsor will ensure that a clinical study report on the study is prepared. 
All materials, documents and information supplied by the Sponsor to the investigator, and all 
materials, documents and information prepared or developed in the course of the study to be 
performed under this protocol, shall be the sole and exclusive property of the Sponsor. Subject to 
obligations of confidentiality, the investigator reserves the right to publish only the results of the work 
performed pursuant to this protocol, provided, however, that the investigator provides an authorized 
representative of the Sponsor with a copy of any proposed publication for review and comment at 
least 45 days in advance of its submission for publication. In addition, if requested, the investigator 
will withhold publication an additional 90 days to allow for filing a patent application or taking such 
other measures as Sponsor deems appropriate to establish and preserve its proprietary rights. 
It is agreed that, consistent with scientific standards, publication of the results of the study shall be 
made only as part of a publication of the results obtained by all sites performing the protocol. 
 
 


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Zhu Y, Singh B, Hewitt S, Liu A, Gomez B, Wang A, Clarke R. 2006. Expression patterns among 
interferon regulatory factor-1, human X-box binding protein-1, nuclear factor kappa B, 


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nucleophosmin, estrogen receptor-alpha and progesterone receptor proteins in breast cancer tissue 
microarrays. Int J Oncol 28:67–76. 
 


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19 APPENDICES 
19.1 Appendix 1: ECOG Performance Status 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
 
 
 


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19.2 Appendix 2: Calculation of renal clearance 
 
Cockroft &Gault formula: Patients aged < 65 years 
 
Male = 1.25 x weight (kg) x (140-age) / serum creatinine (µmol/L)  
Female = 1.04 x weight (kg) x (140-age) / serum creatinine (µmol/L) 
 
MDRD (Modification of Diet in Renal Disease) formula: Patients aged > 65 years 
 
Male = 186 x (serum creatinine (µmol/L) x 0,0113)-1,154 x age- 0,203 
        x 1,21 in subjects with black skin  
        x 0.742 in female 
 
Clearance can be calculated using tools available via the internet, e.g.  
http://filfola.fr/medecine/cockroft_MDRD.html 
or http://mdrd.com/ 
 
 


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19.3 Appendix 3: Algorithm for MCLA-128 (MCLA) and trastuzumab (T) treatment with 
symptomatic LVEF decline  
  
 


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19.4 Appendix 4: New Response Evaluation Criteria in Solid Tumors - Revised RECIST Guidelines 
(Version 1.1) 
 
 


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19.5 Appendix 5: Summary of Product Characteristics (SPC)/Package Insert 
 
For the most recent version of the locally applicable SPC see the following links: 
EMA: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search
.jsp&mid=WC0b01ac058001d124 
USA:  
https://www.accessdata.fda.gov/scripts/cder/daf/ 
 
Belgium:  
http://bijsluiters.fagg-afmps.be 
France:  
http://base-donnees-publique.medicaments.gouv.fr  
Portugal:  
http://app7.infarmed.pt/infomed/pesquisa.php  
Spain:  
https://www.aemps.gob.es/cima/inicial.do 
 
 


Signature Page for MCLA-128-CL02_Protocol_v5.0 _11Apr22 VV-CLIN-000090 v1.0
Signature Page for MCLA-128-CL02_Protocol_v5.0 _11Apr22 VV-CLIN-000090 v1.0
Approval
Sharon Bowen
Regulatory
12-Apr-2022 13:02:14 GMT+0000
Approval
Ernesto Wasserman
Clinical
12-Apr-2022 13:38:40 GMT+0000
Approval
Jim Ford
Clinical
12-Apr-2022 15:14:39 GMT+0000
Approval
Viktoriya Stalbovskaya
Biometrics
12-Apr-2022 17:39:08 GMT+0000
Approval
Anastasia Vliet
Clinical
14-Apr-2022 10:53:08 GMT+0000

SAP_001.pdf: 
 
 
 
 
MCLA-128-CL02  
Phase II study of MCLA-128-based combinations in 
metastatic breast cancer (MBC): MCLA-
128/trastuzumab/chemotherapy in HER2-positive MBC and 
MCLA-128/endocrine therapy in estrogen receptor positive 
and low-HER2 expression MBC 
Statistical analysis plan  
(SAP) 
 
PROJECT: 
MCLA-128-CL02 
VERSION: 
Amendment 1  
DATE: 
07 December 2022  
 
 
 
 
 
 
The information contained in this document, especially unpublished data, is a confidential 
communication from Merus N.V. (Merus) 


Statistical analysis plan MCLA-128-CL02 
Version Amendment 1, 07 December 2022  
 
 
 
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Page 2 of 43 
1 
APPROVAL PAGE 
 
Prepared by  
Tioka Rabeony 
Biostatistician, 4Clinics 
Signature  
 
Date 
 
 
Reviewed and approved by 
Shola Adeyemi, PhD 
Project Statistician, Merus N.V. 
Signature  
 
Date 
 
 
 
Ernesto Wasserman, MD 
Sr VP Clinical Development, Merus N.V. 
Signature  
 
Date 
 
 
 
Jim Ford, MD 
Executive Director of Clinical Trials, Merus N.V. 
Signature  
 
Date 
 


Statistical analysis plan MCLA-128-CL02 
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2 
HISTORY OF CHANGES 
 
Date, author 
Changes 
17-Sep-2020, Anne-Sophie 
Le Bescond (4Clinics) 
Original version 
20-Aug-2021, Manon 
Andre (4Clinics) 
Amendment 1  
 
-To replace “Treated population” by “Safety Set” and “Evaluable for efficacy 
population” by “Per-protocol Efficacy Set” to be CDISC compliant  
-To update the definition of on-treatment period  
-To update the list of tables and figures 
-To suppress randomization wording as no randomization done 
-To add the grading for Corrected Calcium 
 
16-Dec-2021, Manon 
André (4Clinics) 
Addition of derivation of emergence, relationship and severity for AEs with 
missing information   
Update safety set definition 
25-Nov-2022, Tioka 
Rabeony (4Clinics) 
Clarification on efficacy set, endpoints definition,  
Other changes from original version: 
 
sensitivity analyses are rewritten for clarity;  
 
On-treatment period (Section 2.1) is redefined at from the date of 
first administration of study treatment to 30 days after last dose of 
study treatment including start and stop date, instead of 35 days 
after 
 
 
 


Statistical analysis plan MCLA-128-CL02 
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3 
TABLE OF CONTENTS 
APPROVAL PAGE 
2 
HISTORY OF CHANGES 
3 
TABLE OF CONTENTS 
4 
ABBREVIATIONS 
7 
1 
INTRODUCTION 
9 
1.1 
Study design 
9 
1.2 
Study objectives and endpoints 
11 
1.3 
Sample size 
12 
2 
Data analysis and statistical methods 
13 
2.1 
Data analysis general information 
13 
2.2 
Analysis sets 
14 
2.3 
Subgroups of interest 
15 
2.4 
Patient disposition, demographics and other baseline characteristics 
17 
2.5 
Treatments (study treatment, rescue medication, concomitant therapies, compliance) 
19 
2.6 
Analysis of the primary objective 
23 
2.7 
Analysis of secondary efficacy objectives 
24 
2.8 
Other efficacy endpoints 
28 
2.9 
Safety analyses 
28 
2.9.1 
Adverse events 
28 
2.9.2 
Laboratory data 
30 
2.9.3 
ECG 
31 
2.9.4 
Left ventricular ejection fraction (LVEF) 
31 
2.9.5 
Vital signs 
31 
2.10 
Pharmacokinetic analysis 
32 
2.10.1 
Immunogenicity 
32 
2.10.2 
Cytokines (Safety run-in only) 
33 
2.11 
Biomarkers 
33 
2.12 
Exploratory analyses 
34 
2.13 
Interim analysis 
34 
2.14 
Changes from protocol 
Error! Bookmark not defined. 
3 
Appendix 
35 


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3.1 
Imputation rules 
35 
3.1.1 
Study drug 
35 
3.1.2 
AE, Concomitant medication and safety assessment date imputation 
35 
3.1.3 
Other imputation rules 
36 
3.1.4 
Assessment of disease response using RECIST 1.1 
37 
3.1.5 
CTCAE grading of laboratory parameters 
38 
4 
References 
40 
5 
Appendix 1 - Planned CSR outputs 
41 
 
 
 


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List of Figures 
Figure 1: Study design for Cohort 1 combination therapies (doublet and triplet) 
9 
Figure 2: Study design for Cohort 2 combination therapies 
9 
Figure 3: Cohort 1 Doublet treatment administration 
10 
Figure 4: Cohort 1 Triplet treatment administration 
10 
Figure 5: Treatment administration for Cohort 2 (all cycles) 
10 
 
List of Tables 
Table 1: 
Clinically notable changes in vital signs 
32 
Table 2: 
Imputation of start dates (AE, concomitant medications) and assessments (laboratory 
data, ECG, vital signs) 
36 
Table 3: 
Imputation of end dates (AE, concomitant medications) 
36 
Table 4: Overall response in patients with target (+/- non-target) disease 
37 
Table 5: Best overall response 
38 
  
 
 
 
 


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4 
ABBREVIATIONS 
 
 
ADCC 
Antibody-Dependent Cell-Mediated Cytotoxicity 
ADR 
Adverse Drug Reaction 
AE 
AESI 
Adverse Event 
Adverse Event of Special Interest 
ALT 
ALP 
Alanine Transaminase 
Alkaline Phosphatase 
AST 
ATC 
Aspartate Transaminase 
Anatomical Therapeutic Chemical 
AUC 
Area Under The Curve 
BMI 
BOR 
BSA 
CBR 
Body Mass Index 
Best Overall Response 
Body Surface Area 
Clinical Benefit Rate 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Drug Concentration  
CR  
Complete Response/Complete Remission 
CSR 
CT 
Clinical Study Report 
Computed Tomography 
CTCAE 
Common Terminology Criteria For Adverse Events 
ctDNA 
CTP 
Circulating Tumor DNA 
Clinical Trial Protocol 
DI 
DOR 
DSUR 
ECG 
ECHO 
ECOG 
eCRF 
EOI 
EOT 
ER 
FDA 
FISH 
HER 
HGLT 
HLT 
HR 
HRG 
IB 
IDMC 
IG 
IHC 
IRR 
IV 
LLOQ 
LVEF 
MBC 
MedDRA 
MUGA 
MRI 
ORR 
OS 
PD 
Dose Intensity 
Duration of Response 
Development Safety Update Report 
Electrocardiogram 
Echocardiogram 
Eastern Cooperative Oncology Group 
Electronic Case Report Form 
End of Infusion 
End of Treatment 
Estrogen Receptor 
Food and Drug Administration 
Fluorescence In Situ Hybridization 
Human Epidermal Growth Factor Receptor 
High Level Group Term 
High Level Term 
Heart Rate 
Heregulin 
Investigator’s Brochure 
Independent Data Monitoring Committee 
Immunogenicity 
Immunohistochemistry 
Infusion-Related Reaction 
Intravenous 
Lower Limit Of Quantitation 
Left Ventricular Ejection Fraction 
Metastatic Breast Cancer 
Medical Dictionary for Regulatory Activities 
Multiple Gated Acquisition 
Magnetic Resonance Imaging 
Overall Response Rate 
Overall Survival 
Progressive Disease 


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PDI 
PFS 
PK 
PO 
PR 
PT 
QD 
q3w 
QTcF 
RDE 
RDI 
RECIST 
RQ-PCR 
RT-PCR 
SAE 
SAP 
SAS 
SD 
SOC 
SMQ 
t1/2 
Tmax 
TBL 
TFL 
TTR 
ULN 
UNK 
V 
Vss 
WBC 
WHO-DD 
Planned Dose Intensity 
Progression-Free Survival 
Pharmacokinetic(s) 
Per Os  
Partial Response/Partial Remission 
Preferred Term 
Once Daily 
Once Every 3 Weeks 
Corrected QT Interval by Fredericia 
Recommended Dose for Expansion 
Relative Dose Intensity 
Response Evaluation Criteria In Solid Tumors 
Real-Time Quantitative Polymerase Chain Reaction 
Reverse Transcription Polymerase Chain Reaction 
Serious Adverse Event 
Statistical Analysis Plan 
Statistical Analysis System 
Stable Disease 
System Organ Class 
Standardized MedDRA Queries 
Terminal half-Life 
Time to Maximum Plasma Concentration 
Total Bilirubin 
Tables, Figures, Listings 
Time To Response 
Upper Limit of Normal 
Unknown 
Apparent Volume Of Distribution 
Volume Of Distribution At Steady State 
White Blood Cell 
World Health Organization – Drug Dictionary 
 
 
 


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5 
INTRODUCTION 
This document provides the statistical analysis plan (SAP) of the preplanned analysis for the Clinical 
Study Report (CSR) of study MCLA-128-CL02. 
This SAP provides detailed statistical methodology for the analysis of data that will be presented in 
the CSR. This version of the SAP is based on the Protocol version 5.0 (11 April 2022). 
The details for the methodology and conventions that will be used for the analysis of pharmacokinetics 
(PK) data of the study MCLA-128-CL02 are described in a separate PK analysis plan. 
 
All changes to the planned analysis described in this document required before or after database lock 
will be made through an amendment or addendum, respectively. Note that obvious corrections will 
be made at the time of analysis to address minor formatting or spelling mistakes present in the TFL 
shells document without the need to amend. 
The SAP may also serve as a reference for the creation of any outputs required outside of the CSR, 
e.g., IB updates, development safety update report (DSUR), maximum tolerated dose/ recommended 
dose for expansion (MTD/RDE) declaration, abstracts, posters, presentations, manuscripts.  
This SAP presents information relevant to the analyses that will be performed. Clinical background 
information is available in the clinical trial protocol (CTP).  
 
5.1 
Study design 
This is a phase 2, open-label, multicenter international study to evaluate the efficacy of MCLA-128-
based combinations in two metastatic breast cancer (MBC) populations, HER2-positive/amplified 
(Cohort 1) and estrogen receptor (ER)-positive/low HER2 expression (Cohort 2). Three combination 
treatments are being evaluated, two in Cohort 1 and one in Cohort 2, in 20-30 sites in 7 countries in 
Europe and the USA. 
 
Figure 1: Study design for Cohort 1 combination therapies (doublet and triplet) 
 
 
Figure 2: Study design for Cohort 2 combination therapies  
 


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An Independent Data Monitoring Committee (IDMC), composed of at least 2 physicians expert in the 
domain of early clinical development in MBC, reviews safety and efficacy throughout the study and 
decides on the addition of extra patients in the expansion parts, opening of the triple combination 
cohorts, and any ad hoc safety decisions. 
For all combinations a cycle is considered 3 weeks (including Cohort 2 which may include q4w 
fulvestrant dosing). 
Figure 3: Cohort 1 Doublet treatment administration 
Safety Run-In 
 
* Followed by a 6-hour observation period from infusion start, for the initial 
administration and 2 hours for all subsequent administrations. 
For Cycle 2, trastuzumab must be infused over 90 min 
Expansion 
 
* Followed by a 6-hour observation period from infusion start, for the 
initial administration and 2 hours for all subsequent administrations. 
For Cycle 2, trastuzumab must be infused over 90 min 
 
Figure 4: Cohort 1 Triplet treatment administration 
Safety Run-In 
 
* Followed by a 6-hour observation period from infusion start, for the 
initial administration and 2 hours for all subsequent administrations. 
For Cycle 2, trastuzumab must be infused over 90 min 
Expansion 
 
* Followed by a 6-hour observation period from infusion start, for the initial 
administration and 2 hours for all subsequent administrations. 
For Cycle 2, trastuzumab must be infused over 90 min 
 
For both the doublet and the triplet combinations, if an individual patient does not tolerate all drugs 
on the same day, the safety run-in Cycle 1 dosing schedule is maintained for that patient. 
 
Figure 5: Treatment administration for Cohort 2 (all cycles) 
 
A 6-hour observation period will be implemented following infusion start for the 
initial MCLA-128 administration, and 2 hours for all subsequent administrations. 
* Same endocrine therapy under which the patient progressed prior to study entry. 
Can be administered before, during, or immediately after the MCLA-128 infusion. 


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Study treatment is administered until confirmed progressive disease (as per RECIST 1.1), unacceptable 
toxicity, withdrawal of consent, patient non-compliance, investigator decision (e.g. clinical 
deterioration), treatment interruption > 6 consecutive weeks, withdrawal of any study drug. Patients 
will be followed up for safety for at least 35 ± 5 days following the last study drug administration and 
until recovery/stabilization of related toxicities, and for disease progression and survival status for 1 
year and for LVEF assessments for 2 years. 
No formal interim analysis is planned.  
 
5.2 
Study objectives and endpoints 
Cohort 1: MCLA-128 + Trastuzumab ± Vinorelbine in HER2-Positive/Amplified MBC 
Primary objective: 
 
Evaluate efficacy of MCLA-128 combined with trastuzumab ± vinorelbine in terms of clinical 
benefit rate (CBR) at 24 weeks based on RECIST 1.1 (per investigator review) in HER2-
positive/amplified MBC patients who have progressed on prior HER2-directed therapy that 
included trastuzumab, pertuzumab, and an HER2 antibody drug conjugate (ADC) in any sequence 
and in any setting. 
Secondary objectives: 
 
Evaluate CBR at 24 weeks based on RECIST 1.1 per central review 
 
Evaluate progression-free survival (PFS; per investigator and central review) 
 
Evaluate overall response rate (ORR) based on RECIST 1.1 (per investigator and central review) 
 
Evaluate duration of response (DOR) based on RECIST v1.1 (per investigator and central review) 
 
Evaluate overall survival (OS) 
 
Evaluate safety and tolerability of MCLA-128 in combination with trastuzumab ± vinorelbine  
 
Characterize pharmacokinetics (PK) of MCLA-128 in combination with trastuzumab ± 
vinorelbine 
 
Characterize immunogenicity of MCLA-128 in combination with trastuzumab 
Exploratory objective: 
 
Evaluate potential correlations between biomarkers in tumor or blood samples and antitumor 
activity (including HER2, HER3, HER2:HER3 dimers, heregulin and other potential biomarkers) 
Cohort 2: MCLA-128 + Endocrine Therapy in Estrogen Receptor [ER]-Positive/Low HER2 Expression 
MBC 
Primary objective: 
 
Evaluate efficacy of MCLA-128 combined with endocrine therapy in terms of CBR at 24 weeks 
based on RECIST 1.1 (per investigator review) in ER-positive and low HER2 expression MBC 
patients who have previously progressed on the same endocrine therapy. 
Secondary objectives:  
 
Evaluate CBR at 24 weeks based on RECIST 1.1 per central review 


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 
Evaluate PFS (per investigator and central review) 
 
Evaluate ORR based on RECIST 1.1 (per investigator and central review) 
 
Evaluate DOR based on RECIST 1.1 (per investigator and central review) 
 
Evaluate OS 
 
Evaluate safety and tolerability of MCLA-128 combined with endocrine therapy 
 
Characterize PK of MCLA-128 combined with endocrine therapy 
 
Characterize immunogenicity of MCLA-128 combined with endocrine therapy 
Exploratory objective: 
 
Evaluate potential correlations between biomarkers in tumor or blood samples and antitumor 
activity (including HER2, HER3, HER2:HER3 dimers, heregulin and other potential biomarkers) 
 
Endpoints 
Primary  
Cohorts 1 and 2: CBR per investigator radiologic review at 24 weeks  
Key secondary  
Cohort 1: CBR at 24 weeks per central review, and ORR, PFS, and DOR per investigator and central 
review 
Cohort 2: CBR at 24 weeks per central review, and PFS per investigator and central review 
Other secondary (both cohorts): 
Safety: Incidence, severity and relationship of AEs, laboratory abnormalities, SAEs, ECG and LVEF 
measurements and vital signs 
Tolerability: discontinuations due to AEs, dose modifications due to AEs, immunogenicity, and 
cytokine assessments 
Other efficacy: DOR (Cohort 2), PFS ratio (Cohort 2), ORR (Cohort 2), and OS (Cohorts 1 and 2) 
Pharmacokinetics: Cmax, C0h, AUC, CL, Vss, tmax and t1/2 for MCLA-128, and CEOI and C0h for trastuzumab. 
 
5.3 
Sample size 
Cohort 1 safety run-in: 4 to 6 evaluable patients in the safety run-in will have power of 80 to 90% to 
detect an AE with a true incidence of 33%. 
Cohort 1 efficacy expansion: 40 evaluable patients with observed CBR of > 45% will provide adequate 
precision to exclude 30% (lower limit of 90% CI > 30%). The threshold for the CBR rate at 24 weeks is 
defined based on the assumption that PFS follows an exponential distribution with a median of 5 
months (clinically relevant) and 3.5 months (not clinically relevant). 
Cohort 2: 40 evaluable patients with observed CBR of at least 45% will provide enough precision to 
exclude 30% (lower limit of 90% CI > 30%). The threshold for CBR at 24 weeks is defined based on the 
assumption that PFS follows an exponential distribution with a median of 5 months (clinically relevant) 
and 3.5 months (not clinically relevant).  
The final number of patients will depend on the safety and efficacy outcomes during the study. Up to 
~130 patients are anticipated, allowing for a total of 40 patients in each of the three planned 
combination regimens and a ~10% rate of non-evaluable patients 


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6 
Data analysis and statistical methods 
6.1 
Data analysis general information 
Study data will be analyzed by Merus and/or a designated CRO(s) using the most updated SAS® 
version.  
The timing of the primary analysis is not specified in the protocol. The analysis of the primary endpoint 
will be conducted once all enrolled patients complete at least 24 weeks RECIST assessment or 
discontinue.  
The final analysis will be conducted once all patients discontinue from the study and include additional 
data for patients continuing to receive study treatment past the data cutoff date of the primary CSR. 
Data from participating centers in this study protocol will be combined (a center effect will not be 
assessed). The data will be summarized for demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements using descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum) for quantitative data and 
contingency tables (frequencies and percentages) for qualitative data. 
Data will be summarized by cohort and treatment, i.e. Cohort 1 Triplet, Cohort 1 Doublet, Cohort 2, 
unless specified otherwise. 
Date of first/last administration of study treatment  
The date of first (last) administration of study treatment is derived as the first (last) date when a dose 
of either MCLA-128 or any combination drug (trastuzumab, vinorelbine, endocrine therapy) was 
administered and recorded on the dosage administration record eCRF. 
Study day 
The study day, describes the day of the event or assessment date, relative to the reference start date.  
The study day is defined as: 
 
The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date + 1, if the event is on / after the reference start date; 
 
The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date, if the event precedes the reference start date. 
The reference start date for all assessments (safety, efficacy etc) is the start of study treatment.  
The study day will be displayed in the data listings. If an event starts before the reference start date, 
the study day displayed on the listing will be negative. 
Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration is 
reported in months, duration in days will be divided by 30.4375. If duration is reported in years, 
duration in days will be divided by 365.25. 
Baseline 
For all evaluations including safety and efficacy, the last available assessment on or before the date of 
start of study treatment is taken as the “baseline” assessment. If both time of assessment and time of 


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treatment start are captured (e.g. pre-dose ECG), the last available assessment before the treatment 
start date/time is used for baseline. 
For safety parameters where the study requires multiple replicates per time point (e.g. ECGs or vital 
signs), the average of these measurements would be calculated for baseline if not already available in 
the database. 
In rare cases where multiple measurements meet the baseline definition, with no further flag or label 
that can identify the chronological order, then the following rule should be applied: if values are from 
central and local laboratories, the value from central assessment should be considered as baseline. If 
multiple values are from the same laboratory (local or central) or are collected for ECGs or vital signs, 
then the value closest to day 1 in the dataset should be considered as baseline. 
If patients have no value as defined above, the baseline result will be missing. 
Study periods 
For each patient, the overall observation period will be divided into three mutually exclusive 
segments:  
1. Pre-treatment period: from the day of patient’s informed consent to the day before the first 
administration of study treatment 
2. On-treatment period: from the date of first administration of study treatment to 30 days after 
last dose of study treatment including start and stop date 
3. Post-treatment period: starting at day 31 after last administration of study treatment. 
If incomplete dates prevent assignment to pre-, on-, or post-treatment periods, then the respective 
data will be assigned to the on-treatment period. 
Safety summaries will include only data from the on-treatment period with the exception of baseline 
data which will be summarized where appropriate, e.g. change from baseline summaries. In addition, 
a separate summary for death, including on-treatment and post-treatment deaths will be provided. In 
particular, summary tables for AEs will summarize only on-treatment events with a start date during 
the on-treatment period, i.e. treatment-emergent AEs. 
However, all safety data, including those from the pre- and post-treatment period, will be listed, and 
those collected during the pre- and post-treatment period will be flagged. 
 
6.2 
Analysis sets 
Safety Set 
Patients who receive at least one dose of MCLA-128. 
Efficacy Set 
Patients who receive at least 2 complete cycles (6 weeks) of treatment and have undergone baseline 
assessment and one on-study tumor assessment, or who discontinue early due to disease progression 
(including deaths due to study indication). 


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The table below provides the rules for exclusion of patients from the efficacy population. If a patient 
has both central and local non-missing result, central assessment supersedes local assessment; in case 
the central assessment result is not available, local result will be used instead. 
Note: Patients will be enrolled based on their HER2 status, hormone receptor (HR) status (Cohort 2 
only), and disease progression on the prior line of therapy, as reported in their medical records. 
Evaluability of patients for the primary endpoint will be confirmed by central review of their HER2 
status, HR status (Cohort 2 only) after enrolment.  
Analysis set 
Protocol deviations leading to 
exclusion 
Non protocol deviation 
leading to exclusion 
Safety Set  
No written informed consent 
No dose of study medication 
Efficacy Set 
No written informed consent 
 
 
Patient received less than 2 
complete cycles, or was not 
evaluated at baseline and at least 
once during study, unless 
progressive disease was 
documented 
Cohort 1: patient is not HER2-
positive/amplified (by central or 
local lab). 
Cohort 2:  
- patient is not low HER2 by IHC 
(by central or local lab),  
- patient is not ER positive (by 
central or local lab) 
- disease progression under the 
last line of therapy by imaging is 
not confirmed (by central or local 
imaging review). 
 
When a key central result is missing then all HER2 status, hormone receptor (HR) status (Cohort 2 
only) eligibility should be assessed on local results. 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a patient withdraws informed consent from all further 
participation in the trial, will not be included in the analysis. The date on which a patient withdraws 
full consent will be recorded in the site file and is not captured in the eCRF.   
Additional data which are collected in the clinical database and for which there is a separate informed 
consent (e.g. biomarker) will not be included in the analysis if that additional consent was not given 
by the patient.  
6.3 
Subgroups of interest 
The following subgroups are defined: 
Cohort 1: 


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 
prior lines of therapy in metastatic setting: 0-2, >2 
 
history of brain metastases (current or antecedent): present, absent 


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Cohort 2: 
 
HER2 IHC: 1+, 2+ 
 
visceral involvement: present, absent 
 
CDK4/6 inhibitor as last treatment: yes, no 
 
prior treatment: up to 4 months, over 4 months  
 
type of hormonal therapy: fulvestrant, aromatase inhibitors 
 
6.4 
Patient disposition, demographics and other baseline characteristics 
The Safety Set will be used for all baseline and demographic summaries and listings unless otherwise 
specified. 
Analysis sets 
The number (%) of patients in each analysis set will be summarized by cohort and treatment (i.e., 
Cohort 1 doublet, Cohort 1 triplet and Cohort 2). 
Disposition 
The number (%) of treated patients included in the Safety Set will be presented overall and by cohort 
and treatment. The number (%) of screened and not-treated patients and the reasons for screening 
failure will also be displayed. The number (%) of patients in the Safety Set who are still on treatment 
at the cut-off, as well as those who discontinued the study phases and the reasons for discontinuation 
will be presented overall and by treatment group. 
A table with the following summaries will be provided (with % based on the total number of patients 
in the Safety Set): 
 
Number (%) of patients who are still on-treatment (based on the ‘End of Treatment’ page not 
completed);  
 
Primary reason for study treatment discontinuation (based on the ‘End of Treatment’ page) 
 
Number (%) of patients who have entered the survival follow-up (based on the ‘End of Treatment’ 
or ‘Follow-up’ page). 
Protocol deviations 
The number (%) of patients in the Safety Set with any protocol deviations will be tabulated by 
deviation category (as specified in the study Protocol Deviations Document) overall and by cohort 
and treatment for the Safety Set.  
Major protocol deviations leading to exclusion from analysis sets will be tabulated separately overall 
and by cohort and treatment. All protocol deviations will be listed. 
Basic demographic data 
All demographic and baseline disease characteristics data will be summarized and listed by cohort and 
treatment (i.e., Cohort 1 doublet, Cohort 1 triplet and Cohort 2). Categorical data (e.g. gender, age 
groups: <65 and ≥ 65 years, race, ethnicity, performance status) will be summarized by frequency 
counts and percentages; the number and percentage of patients with missing data will be provided. 
Continuous data (e.g. age, weight, height, body surface area, body mass index) will be summarized by 
descriptive statistics (N, mean, median, standard deviation, minimum and maximum).  


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BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using height at Baseline.  
Body 
Surface 
Area 
(BSA) 
will 
be 
calculated 
using 
Gehan 
and 
George 
formula: 
BSA[m2]=234.94*(height[cm]**0.422)*(weight[kg]**0.515)/10000  
Diagnosis and extent of cancer  
Summary statistics will be tabulated for diagnosis, treatment and extent of cancer. This analysis will 
include the following, as appropriate:  
 
Primary site of cancer 
 
Histological type 
 
Hormonal status at diagnosis: Progesterone-receptor staining level (IHC), estrogen-receptor 
staining level (IHC) 
 
HER2/neu status at diagnosis (IHC, FISH) 
 
Stage at initial diagnosis 
 
Time from initial diagnosis to study entry 
 
Time from first metastatic disease to study entry 
 
Most recent hormonal status, local and central assessment 
 
Most recent HER2 status (IHC, FISH), local and central assessment 
 
HER2 IHC score (0, 1, 2, 3) 
 
HER2 H-score (quantitative) 
 
HER2 status (positive, negative, unknown) 
 
HER2 amplification. Amplification is not assessed in all patients and for statistical 
summaries needs to be considered by IHC score 
 
HER2:HER3 dimer score  
 
NRG1 score 
 
Stage at time of study entry 
 
TNM stage at study entry 
 
Time from most recent relapse/progression to inclusion (in months) 
 
Non-measurable disease only 
 
Number and type of metastatic sites involved including visceral and no visceral involvement 
 
Tumor burden at study entry (mm).   
Note: Presence/absence of target and non-target lesions will be based on the data collected on RECIST 
target/non-target lesion assessment eCRF pages. Metastatic sites will be based on diagnosis page. 
Number of metastatic sites corresponds to the number of organs involved. Non-visceral sites include 
bones and soft tissue (e.g., lymph nodes, skin lesions).  
Prior antineoplastic therapy 
All prior anti-neoplastic medication, radiotherapy and surgery will be listed. 
The number (%) of patients who received any prior anti-neoplastic medication, radiotherapy or 
surgery will be summarized. 
The summary of prior anti-neoplastic medications will include  
 
Number of prior therapies including chemotherapy, anti-HER2 and hormonal therapy 


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 
Number of prior therapies including chemotherapy and anti-HER2 in metastatic setting 
 
Number of prior chemotherapy regimens 
 
Number of prior anti-HER2 directed therapies 
 
Number of prior anti-HER2 directed therapies in metastatic setting 
 
Number of prior hormonal therapies 
 
Number of patients with prior anthracycline therapy 
 
Best response to last treatment (defined to be the best response during the last treatment 
regimens recorded),  
 
Reason for discontinuation of last treatment,  
 
Time (in months) from start of last treatment to progression.  
Prior antineoplastic medications will also be summarized by Anatomical Therapeutic Chemical (ATC) 
class, and preferred term.  
The summary of prior anti-neoplastic radiotherapy will include radiotherapy locations, (including all 
locations recorded for each patient), setting at last radiotherapy, and best response at last 
radiotherapy, as appropriate. 
The summary of prior anti-neoplastic surgery will include procedure at last surgery. 
Medical history 
A listing and a summary by SOC and PT of medical history and current medical conditions will be 
provided, using the latest Medical Dictionary for Regulatory Activities (MedDRA) terminology available 
at the time of reporting. 
 
6.5 
Treatments (study treatment, rescue medication, concomitant therapies, compliance) 
Incomplete or missing start and end dates will be handled as described in 7.1.1, 7.1.2 and 7.1.3. 
Study treatment 
Duration of exposure, time to last infusion, total number of infusions received, total number of cycles 
received, cycle duration, actual cumulative dose, dose intensity (DI) and relative dose intensity (RDI) 
will be summarized by cohort and treatment, separately for each component of study treatment. The 
duration of exposure will also be presented for the study treatment combination (MCLA-128 and any 
combination drug (trastuzumab, vinorelbine, endocrine therapy)). Duration of exposure will be 
categorized into time intervals; frequency counts and percentages will be presented for the number 
(%) of patients in each interval.  
The number (%) of patients who have dose reductions, interruptions, delays or permanent 
discontinuation, and the corresponding reasons, will be tabulated.   
Patient listings of all doses administered on treatment along with dose change reasons will be 
produced.   
The Safety Set will be used for all summaries and listings of study treatment. 


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Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of exposure 
to MCLA-128 and/or any combination drug (trastuzumab, vinorelbine, endocrine therapy), if 
applicable: 
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) – (date 
of first administration of study treatment) + 1.  
The last date of exposure to study treatment is the latest of the last dates of exposure to MCLA-128 
and/or any combination drug (trastuzumab, vinorelbine or endocrine therapy) (see table below). 
Summary of duration of exposure of study treatment in appropriate time units will include categorical 
summaries (based on clinically meaningful time intervals) and continuous summaries.  
Scenario 
Definition of last date of exposure of 
study drug  
Example 
Scenario 1: Study drug 
with a cyclic 
administration (half-
life in days)  
The last administration of study drug 
planned end date of the last cycle in which 
the last dose of the investigational drug 
was last administered. 
Note:  If the patient died or was lost to 
follow-up before the derived last date, the 
last date of exposure to investigational 
drug is the date of death or the date of 
last contact, respectively.  
If the derived last date of exposure goes 
beyond the data cutoff date, it should be 
truncated to the date of data cutoff. 
Example 1: In a once a week 
administration of an investigational 
drug, the last date of exposure is the 
date of administration in the last 
cycle + 6 days. 
Example 2: In a 21-day cycle with 
one or several infusions in the 
beginning of the cycle, the last date 
of exposure is the date of first 
infusion in the last cycle + 20 days. 
Scenario 2: Daily 
administration of the 
study drug (half-life 
<24 hours) 
Date of last administration of a dose of 
the study drug. 
Example 3: A patient had a 
permanent discontinuation of the 
study drug 06Jan2013 after being 
put on a temporary interruption 
since 01Jan2013. In this case the last 
date of exposure is 31Dec2012.  
 
Time to last infusion 
For biologics with a prolonged half-life, the duration of exposure even after 1 dose can be weeks. 
Therefore, the time to last infusion can be used to describe when patients received their last dose of 
study treatment: 
Time to last infusion (days) = (date of last infusion) – (date of first administration of study drug) + 1 
Summary of time to last infusion should be expressed in the same units as duration of exposure and 
will include categorical summaries (based on clinically meaningful time intervals) and continuous 
summaries. 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study treatment 
exposure and will be summarized for each study treatment component.  


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The planned cumulative dose for a study treatment component refers to the total planned dose as 
per the protocol up to the last date of study treatment administration. 
The actual cumulative dose refers to the total actual dose administered, over the duration for which 
the patient is on the study treatment as documented in the Dose Administration eCRF.  
When the actual dose administered is not collected in eCRF (for Vinorelbine at C1 D8/9),  
the intended dose will be used instead .  
For patients who did not take any drug, the cumulative dose is by definition equal to zero. 
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded over the 
dosing period and the planned cumulative dose is the planned starting dose summed over the same 
dosing period. 
For intermittent dosing, the actual cumulative dose should be defined based on the days when the 
patient is assumed to have taken a non-zero dose during dosing periods. 
Dose intensity and relative dose intensity 
DI will be described for patients with dose and dates of administration available:  
DI (dosing unit / unit of time) = Actual cumulative dose (dosing unit) / Duration of exposure to study 
treatment (unit of time). 
If the dosing unit is mg and the unit of time is a day: 
e.g., DI (mg/day) = Actual cumulative dose (mg) / Duration of exposure (day) 
 
 
= 1200 (mg) / 18 (Day) = 66.7 (mg/day) 
For patients who did not take any drug, the DI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (dosing unit / unit of time) = Planned cumulative dose (dosing unit) / Duration of exposure (unit 
of time). 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (dosing unit / unit of time) / PDI (dosing unit / unit of time).   
DI and RDI will be summarized for combination studies separately for each study treatment 
component, using the duration of exposure of each component. DI will not be summarized for 
endocrine therapy in Cohort 2. 
Infusion and drug interruptions, dose reductions, delays or permanent discontinuations 
The table below provides definitions and sources of data for the key categories related to dose 
administration. 
Option 
Description 
128-CL02 
Dose administration CRF 
name 
CRF page name and dataset name 
MCLA-128 treatment administration (EX1 
and EX1C1) 
Trastuzumab treatment administration 
(EX2 and EX2C1) 


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Option 
Description 
128-CL02 
Vinorelbine treatment administration (EX3 
and EX3C1) 
Hormonal intake treatment (EX4) 
Dose planned 
Dose planned per protocol or 
prescribed for the visit 
Y 
Dose administered 
Dose actually administered to a 
patient 
Y 
Infusion interrupted 
Interruption of an infusion that may 
or may not resume 
Y 
Infusion re-start time 
Start and stop time for re-started 
infusion after interruption 
Y 
Drug interrupted 
The actual dose is 0 and the patient 
did not receive any drug at the 
intended visit 
-- 
Dose reduced 
Planned dose is lower than previous 
planned dose or administered dose 
is lower than planned dose - can be 
derived programmatically 
-- 
Drug withdrawn 
Permanent discontinuation of study 
drug 
-- 
Dose delay 
The infusion is administered prior to 
the next scheduled administration 
but outside the protocol-defined 
window - to be derived 
programmatically 
-- 
Premedication 
Information on premedication used 
Entered on the same page as treatment 
administration  
 
Dose reduction: A dose change where the prescribed dose level is lower than the previous prescribed 
dose level or where the actual dose administered/total daily dose is lower than the calculated dose 
amount based on the prescribed dose. Therefore any dose change to correct a dosing error will not 
be considered a dose reduction.  Only dose change is reported in the eCRF. The number of reductions 
will be derived programmatically. 
Compliance 
Compliance to the study treatment will be summarized in terms of the RDI according to predefined 
categories of < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and proportion of patients in 
each category will be presented, for each treatment type in cohort 1. 
Post treatment anti-cancer therapy 


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Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized by 
ATC class, preferred term, overall and by treatment group/cohort. 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures), other 
than the study treatment, administered to a patient during the study treatment period.  
Concomitant medications will be coded using the WHO-DD(most recent version), ATC classification 
system and summarized by lowest ATC class and preferred term using frequency counts and 
percentages.  
Incomplete or missing start and end dates will be handled as described in Table 2. 
Surgical and medical procedures will be coded using MedDRA and summarized by SOC and preferred 
term.  
Concomitant medication summaries will include: 
 
Baseline concomitant medication: medications starting prior to start of study treatment and 
continuing after the start of study treatment. 
 
On-study concomitant medication: medications starting on or after the start of study 
treatment and up to 30 days after the start of the last dose of study treatment  
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior to the 
start of study treatment or starting more than 30 days after the last date of study treatment will be 
flagged in the listing. The Safety Set will be used for all concomitant medication tables and listings. 
Study drug premedication is a concomitant medication administered to patients to prevent 
development of IRRs. The number (%) of patients who received study drug premedication will be 
summarized overall and by infusion, as well as type of premedication by ATC class and preferred term. 
 
6.6 
Analysis of the primary objective 
Evaluation of antitumor activity will be based on investigator assessment according to RECIST v1.1. 
The primary endpoint for Cohort 1 (doublet and triplet) and Cohort 2 is CBR at 24 weeks +/- 3 days i.e. 
from 165 to 171 days, per investigator assessment. 
Clinical benefit rate (CBR) 
CBR is the proportion of patients with confirmed CR or PR, or SD lasting 24 weeks – 3 days or longer 
i.e. 39 days or more, according to RECIST 1.1 criteria. SD is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest sum on study (if the 
baseline sum is the smallest, this is the reference for calculation of PD) . For the primary objective 
analysis, CBR will be calculated in the Efficacy Set based on the investigator assessments up to PD, 
death or the next anti-cancer therapy, whichever occurs earlier. 
Patients with only non-measurable disease at baseline will be analyzed for best overall response 
(secondary objective) and CBR, and will be considered as a SD if their response is a ‘Non-CR/Non-PD’. 


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Observed CBR in both cohorts will be presented with accompanying 90% exact binomial confidence 
interval. 
Two sensitivity analyses of CBR will be performed: 
- 
Sensitivity 1 on efficacy set but excluding patients from both cohorts with unavailable central 
assessment of HER2 status, hormone receptor (HR) status (Cohort 2 only) (keeping cohort 2 
patients without central imaging) 
- 
Sensitivity 2 on patients who received at least 2 complete cycles (6 weeks) of treatment and 
had undergone baseline assessment and one on-study tumor assessment, or who 
discontinued early due to disease progression (i.e. without confirmation of their eligibility on 
central assessment of HER2 status, hormone receptor (HR) status (Cohort 2 only)) 
 
6.7 
Analysis of secondary efficacy objectives  
The following variables will be used to evaluate antitumor activity in the Efficacy Set: CBR at 24 weeks 
+/- 3 days i.e. 165 to 171 days, per central assessment, BOR, ORR, DOR, PFS, and OS. 
Two sensitivity analyses of BOR and ORR will be performed: 
- 
Sensitivity 1 on efficacy set but excluding patients from both cohorts with unavailable central 
assessment of HER2 status, hormone receptor (HR) status (Cohort 2 only) (keeping cohort 2 
patients without central imaging) 
- 
Sensitivity 2 on patients who received at least 2 complete cycles (6 weeks) of treatment and 
had undergone baseline assessment and one on-study tumor assessment, or who 
discontinued early due to disease progression (i.e. without confirmation of their eligibility on 
central assessment of HER2 status, hormone receptor (HR) status (Cohort 2 only))) 
 
Key secondary: 
Cohort 1: CBR at 24 weeks per central review, and ORR, PFS, and DOR per investigator and central 
review 
Cohort 2: CBR at 24 weeks per central review, and PFS per investigator and central review 
Other secondary (both cohorts): 
DOR (Cohort 2), PFS ratio (Cohort 2), ORR (Cohort 2), and OS (Cohorts 1 and 2) 
 
Best overall response (BOR) 
The BOR is the best response recorded from the start of the treatment until disease 
progression/recurrence.   
The following categories are defined: 
 
Complete response (CR) - at least two determinations of CR at least 4 weeks apart before 
progression where confirmation is required or one determination of CR prior to progression 
where confirmation is not required. 
 
Partial response (PR) - at least two determinations of PR or better at least 4 weeks apart before 
progression (and not qualifying for a CR) where confirmation is required or one determination 
of PR prior to progression where confirmation is not required 
 
Stable disease (SD) - at least one SD assessment (or better) > 6 weeks +/- 3 days i.e. 39 days or 
more after start of treatment (and not qualifying for CR or PR). 


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 
Progressive disease (PD) - progression after start of treatment (and not qualifying for CR, PR or 
SD). 
 
Not evaluable (NE) - all other cases (i.e. not qualifying for confirmed CR or PR, without SD after 
more than 6 weeks, or PD). 
An assessment of the concordance between independent radiological review and local assessment 
of the BOR for each patient will be provided by cohort and treatment, overall across all treatments. 
The calculation will be based on the percent agreement (the proportion of response outcomes that 
match in the Independent Reviewer and Investigator Assessments):  Percent Agreement = (Number 
of matched responders + Number of matched non-responders) / total number of patients assessed. 
Overall response rate (ORR)  
ORR is the proportion of patients with a BOR of CR or PR (RECIST v1.1).  
Confirmed Objective response is defined as a CR or PR (RECIST 1.1) on two consecutive occasions ≥4 
weeks apart. 
Disease control rate (DCR)  
DCR is the proportion of patients with a BOR of CR, PR, or SD (RECIST v1.1). Both confirmed and 
unconfirmed BOR will be analyses. 
BOR, ORR, DCR and CBR will be summarized by cohort and treatment. For ORR accompanying 2-sided 
90% exact binomial CIs will be provided (Clopper and Pearson, 1934).  Waterfall plots will be provided 
by cohort and treatment showing best change in sum of diameters for RECIST v1.1. Individual lesion 
measurements and overall response assessments will be listed by patient and assessment. 
Percent change from baseline over time in sum of diameters of target lesions will be presented 
graphically for patients with measurable disease. Swimmer plots with duration of exposure, DOR and 
indicator of clinical benefit at 24 weeks may be produced. 
Progression-free survival 
For assessment per RECIST v1.1, PFS is the time from the date of treatment start to the date of event 
defined as the first documented progression or death due to any cause.  If a patient has not had an 
event, PFS is censored at the date of last adequate tumor assessment. More details are provided in 
the table below based on the draft FDA guidance for industry on clinical trial endpoints for the 
approval of NSCLC drugs and biologics. 
Description of censoring and progression date rules 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments 
start of treatment 
Censored 
Progression documented between 
scheduled visits 
Date of progression 
Progressed 
No progression 
Date of last adequate assessment (not NE and not 
missing) 
Censored 
Treatment discontinuation for 
undocumented progression 
Date of last adequate assessment (not NE and not 
missing) 
Censored 
Treatment discontinuation for 
toxicity or other reason 
Date of last adequate assessment (not NE and not 
missing) 
Censored 


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Situation 
Date of Progression or Censoring 
Outcome 
New anticancer treatment started 
Date of last adequate assessment (not NE and not 
missing) 
Censored 
Death before first progressive 
disease assessment 
Date of death 
Progressed 
Death between adequate 
assessment visits 
Date of death 
Progressed 
Death after 1 missed assessment 
Date of death 
Progressed 
Progression after 1 missed 
assessment 
Date of progression 
Progressed 
Death or progression after more 
than 1 missed assessment 
Date of last adequate assessment (not NE and not 
missing) 
Censored 
 
Concordance analysis of PFS will consist in a listing of PFS per central and local review by PFS event 
type (PD, death, censored).  
PFS ratio (Cohort 2 only) 
The ratio of PFS observed on the previous regimen to PFS recorded on study treatment. 
For patients in Cohort 2, the number and proportion of any patients with a PFS ratio ≥ 1.3 (Von Hoff 
et al., 2010) will be tabulated together with 90% exact CI, along with descriptive data of the PFS ratio 
for each of these patients. 
Duration of response (DOR) 
DOR applies only to patients with a BOR of confirmed CR or PR (RECIST v1.1).  For RECIST v1.1, DOR is 
defined as the time from the date of the first documented response (CR or PR) to the date of first 
documented progression, or death due to any cause. If a patient has not had an event, time to 
progression is censored at the date of last adequate tumor assessment. 
Time to response (TTR) 
TTR applies only to patients with a BOR of confirmed CR or PR (RECIST v1.1). For RECIST v1.1 TTR is 
defined as the time from the date of the first dose to the first documented response (CR or PR).   
DOR and TTR will be listed for all patients with a response.   
Overall survival (OS) 
OS is defined as the time from the date of the first dose to the date of death due to any cause. For any 
patients still alive at the cut-off date, OS will be censored at the date of last contact. 
Analysis of time to event endpoints 
PFS, DOR, TTR and OS will be listed for all patients.  Kaplan-Meier plots for PFS will be presented by 
cohort and treatment. Median PFS, DOR, OS (in months) with corresponding [90%] CI  (Brookmeyer 
and Crowley 1982) and Kaplan-Meier estimated probabilities (PFS, OS rate) with corresponding 90% 
CIs (Greenwood’s formula, Kalbfleisch and Prentice 2002) at several time points (in months) will be 
presented. For PFS the number (%) of progressions, deaths and patients censored will also be 
summarized. 
Use of alternative cancer therapy 


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For RECIST v1.1, if any alternative cancer therapy is taken, any subsequent assessments will be 
excluded from the analysis of endpoints based on tumor response assessments. 


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6.8 
Other efficacy endpoints 
ECOG performance status 
The ECOG PS scale will be used to assess disease progression, how the disease affects the daily living 
abilities of the patient, and to determine appropriate treatment and prognosis.  
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than  50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Oken, M.M et al (JCO, 1982) 
Listing of collected ECOG scores will be produced. 
 
6.9 
Safety analyses  
All safety analyses will be based on the Safety Set. 
6.9.1 
Adverse events 
AE summaries will include all AEs occurring during the on-treatment period (i.e., TEAEs). All AEs 
collected on the AE eCRF page will be listed along with the information collected on those AEs, e.g. AE 
relationship to study drug, AE outcome etc. AEs with a start date outside of the on-treatment period 
will be flagged in the listings. 
Grading of AEs will be done according to NCI-CTCAE version 4.03.  
AEs will be summarized by number and percentage of patients having at least one AE, having at least 
one AE in each primary system organ class (SOC) and for each preferred term (PT) using MedDRA 
coding. A patient with multiple occurrences of an AE will be counted only once in the respective AE 
category. A patient with multiple CTCAE grades for the same preferred term will be summarized under 
the maximum CTCAE grade recorded for the event. AEs with a missing CTCAE grade will be included 
in the ‘All grades’ column of the summary tables. 
In AE summaries, the primary SOC will be presented alphabetically and the PTs will be sorted within 
primary SOC in descending frequency. Cohort 1 and Cohort 2 will be presented separately. In Cohort 
1, the sort order for the PT will be based on their frequency in the triplet.  
The following AE summaries will be produced by cohort and treatment:  
 
overview of AEs and deaths (number and % of patients who died, who had at least 1 AE, SAE, 
dose reductions/interruptions, AE leading to treatment discontinuation; for all AEs 
irrespective of relationship, severe (grade 3-4), and related AEs);  
 
AEs by SOC and PT, summarized by:  


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 
relationship (all AEs and AEs related to study treatment),  
 
seriousness (SAEs and non-SAEs),  
 
leading to treatment discontinuation,  
 
leading to dose interruption/adjustment,  
 
requiring additional therapy and  
 
leading to a fatal outcome,  
 
infusion-related reactions (IRRs)*.  
  
*Infusion-related reaction (IRR) is defined as an AE developed within 24 hours of the MCLA-128 or 
trastuzumab infusion reported as judged by the investigators as a sign or symptom of IRRs. It includes 
the preferred term of "infusion-related reaction" as well as any other PT marked as such on the AE 
CRF page (e.g. IRR, nausea, vomiting, abdominal pain, headache, hypotension, pyrexia, tremor and 
hypersensitivity). 
Listing of SAEs, AEs leading to treatment discontinuation, and IRRs will also be produced. 
A separate listing of patients with IRRs will include time and grade of IRR onset, infusion status 
(complete or incomplete), recurrence in subsequent cycles.  
Adverse events of special interest (AESI) 
An AESI is a grouping of AEs that are of scientific and medical concern specific to compound MCLA-
128. These groupings are defined using MedDRA terms, SMQs (standardized MedDRA queries), HGLTs 
(high level group terms), HLT (high level terms) and PTs (preferred terms).  
AESIs for MCLA-128 combinations include: 
 
Infusion-related reactions (for any antibodies, known AESI for MCLA-128) 
 
Cardiotoxicity (anti-HER2 therapy) 
 
Diarrhea (anti-HER2 therapy)  
 
Myelosuppression (vinorelbine) 
 
The final scope of AESI related to all components on the combinations will be provided from the case 
retrieval strategy document. 
For each specified AESI, the number and percentage of patients with at least one event of the AESI 
occurring during the on-treatment period will be summarized by AESI, SOC and preferred term. 
Summaries of these AESIs will be provided by cohort and group (specifying grade, SAE, relationship, 
leading to treatment discontinuation, leading to dose adjustment/interruption, hospitalization, death 
etc.). If a sufficient number of events occurred, analysis of time to first occurrence will be applied.  
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI will be 
generated. These listings should be included in section 16 of CSR. 


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6.9.2 
Laboratory data 
In the laboratory data analysis, data from all sources (central and local laboratories, as applicable) will 
be combined. The summaries will include all assessments available for the lab parameter collected no 
later than 30 days after the last study treatment administration date (see Section 6.5). 
The following summaries will be produced for hematology and biochemistry laboratory data (by 
laboratory parameter and treatment): 
 
Worst post-baseline CTC grade (regardless of the baseline status). For each patient, only the 
worst grade observed post-baseline will be counted. 
 
Shift tables using CTC grades to compare baseline to the worst on-treatment value.  
 
For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment  
value. 
 
Trends of lab parameter values over time (baseline and selected on-treatment timepoints) will 
be presented as tables and displayed as boxplots based on time windows for WBC, ANC, 
platelets, hemoglobin, bilirubin, AST, ALT, alkaline phosphatase.  
The following listings will be produced for the laboratory data: 
 
Listings of all laboratory data, with CTC grades and classification relative to the laboratory 
normal range. Lab data collected during the post-treatment period will be flagged.   
 
Listing of all CTC grade 3 or 4 laboratory toxicities. 
Liver function parameters  
Liver function parameters of interest are total bilirubin (TBL), alanine transaminase (ALT), aspartate 
transaminase (AST) and alkaline phosphatase (ALP). The number (%) of patients with worst post-
baseline values will be summarized: 
A table with the following summaries will be produced: 
 
ALT or AST > 3xULN  
 
ALT or AST > 5xULN 
 
ALT or AST > 8xULN 
 
ALT or AST > 10xULN 
 
ALT or AST > 20xULN 
 
TBL > 2xULN 
 
TBL > 3xULN 
 
ALT or AST > 3xULN & TBL > 2xULN 
 
ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  (potential Hy’s law)    
Potential Hy’s law events are defined as those patients with concurrent occurrence of AST or ALT > 
3xULN and TBL > 2xULN and ALP < 2xULN in the same assessment sample during the on-treatment 
period. Further medical review of any identified patients will be conducted to assess potential 
confounding factor such as liver metastases, liver function at baseline etc. 


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6.9.3 
ECG  
The number and percentage of patients with notable ECG values will be presented by treatment 
arm.  
 
QT, QTcF, or QTcB 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 
- 
Increase from Baseline of > 30 ms to ≤  60 ms 
- 
Increase from Baseline of > 60 ms 
 
HR 
- 
Increase from baseline >25% and to a value > 100 bpm 
- 
Decrease from baseline >25% and to a value < 50 bpm 
 
PR 
- 
Increase from baseline >25% and  to a value > 200 ms 
- 
New value of > 200 ms 
 
QRS 
- 
Increase from baseline >25% and  to a value > 120 ms 
A listing of all ECG assessments will be produced by cohort and treatment and notable values will be 
flagged. A separate listing of only the patients with notable ECG values may also be produced. In the 
listing, the assessments collected during the post-treatment period will be flagged. 
6.9.4 
Left ventricular ejection fraction (LVEF) 
Number of patients with LVEF abnormalities on treatment will be summarized as shift tables with 
baseline vs worse post-baseline value according to CTCAE grade below: 
Grade 0: LVEF > 50% and absolute change from baseline > -10% 
Grade 2: LVEF in [40%, 50%] or absolute change from baseline in (-20%, -10%]. 
Grade 3: LVEF in [20%, 40%) or absolute change from baseline ≤ -20%. 
Grade 4: LVEF < 20%. 
Note that there is no grade 1. 
A descriptive summary table will be produced for LVEF at baseline, worst post-baseline value and 
absolute change from baseline. 
Worst post-baseline LVEF value is defined as the lowest value. 
The number (%) of patients with dose delay or infusion interruption will be tabulated by 
presence/absence of LVEF abnormality (grade 2 or above) for patients with at least 1 post-baseline 
LVEF evaluation by ECHO or MUGA. The listing of LVEF will include dose administration information. 
6.9.5 
Vital signs 
Vital sign assessments are performed to characterize basic body function. The following parameters 
were collected: height (cm), weight (kg), body temperature (°C), heart rate (beats per minute), systolic 
and diastolic blood pressure (mmHg). 
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings. 


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For analysis of vital signs, clinically notable vital signs criteria are provided in Table 1 below. 
Table 1: 
Clinically notable changes in vital signs 
Vital sign (units) 
Above normal value  
Below normal value 
Weight (kg) 
increase > 10% from Baseline 
decrease  > 10% from Baseline 
Systolic blood pressure 
(mmHg) 
>=160 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Pulse rate (bpm) 
>=100 with increase from baseline 
of >25% 
<=50 with decrease from baseline of  
> 25% 
 
Body temperature 
>= 39.1  
- 
The number and percentage of patients with notable vital sign values (high/low) will be presented by 
cohort and treatment.  
Maximal changes in vital signs will be summarized in tabular form.  
A listing of all vital sign assessments will be produced by cohort and treatment and notable values 
will be flagged.  
 
6.10 Pharmacokinetic analysis 
Serum concentrations of MCLA-128 will be determined by the bioanalytical lab LGC, UK. Serum 
concentrations of trastuzumab will be determined by the bioanalytical lab QPS, The Netherlands. The 
PK analysis and reporting will be performed by Venn Life Sciences, The Netherlands, using the serum 
concentrations of MCLA-128 and trastuzumab and the actual sampling times and dosing information 
obtained from the eCRF. A separate PK study analysis plan will be prepared by Venn Life Sciences and 
approved by Merus, detailing the data handling, analysis, statistics and reporting of the PK data 
(including the generation of tables, listings and graphs).  
6.10.1 Immunogenicity 
Serum samples will be processed by LGC, UK.  Immunogenicity will be characterized by incidence of 
treatment emergent immunogenicity in IG evaluable patients as described in Shankar et al (2014). 
Among patients with treated emergent immunogenicity the number of patients with treatment-
induced ADA and treatment-boosted ADA will be provided. 
Evaluable subject: a subject with at least one immunogenicity sample taken after drug administration 
during the treatment period with reportable result. 
ADA-positive subject: a subject with at least one treatment-induced or treatment-boosted ADA-
positive sample during the treatment period. 
ADA-negative subject: a subject without a treatment-induced or treatment-boosted ADA-positive 
sample during the treatment period. 


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Treatment-induced ADA: ADA developed de novo (seroconversion) following biologic drug 
administration (i.e., formation of ADA any time after the initial drug administration in a subject 
without pre-existing ADA). 
Treatment-boosted ADA: pre-existing ADA that were boosted to a higher level following biologic drug 
administration. 
Any anti-MCLA-128 antibody samples collected after 30 days of the last dose will not be used for 
summaries or derivations and will only be included in the listing. 
A listing will be provided by patient with supporting information (i.e. ADA sample status at each 
timepoint (including titer for positive samples) and patient ADA status). 
The impact of ADA on the occurrence of safety endpoints will be explored by summary tables for 
incidence of overall and each of the preferred terms of AESIs by subject ADA status, if the number of 
subjects is sufficient (e.g. number of subjects positive for ADA). Otherwise, individual subject’s safety 
profile will be examined and described based on a listing. 
Additional analyses of ADA vs. safety, efficacy, and PK, if conducted, will be defined in a separate SAP 
and the results reported separately from the CSR. 
6.10.2 Cytokines (Safety run-in only) 
A serum cytokine panel (TNFα, IFNγ, IL-1β, IL-6, IL-8, IL-10) will be assessed by LGC, UK.  
For each cytokine descriptive statistics will be tabulated per each scheduled time point after MCLA-
128 and trastuzumab infusions for measured cytokine concentration, absolute and percent change 
from baseline, and fold change from baseline. 
Cytokine levels after MCLA-128 given alone (Cycle 1, Day 1) and trastuzumab given alone (Cycle 1, 
Day 2) will be compared graphically with those obtained after the combination of MCLA-128 and 
trastuzumab (Cycle 2, Day 1). 
 
6.11 Biomarkers 
The Safety set will be used for all biomarker analysis. Unless otherwise specified, all statistical 
analyses of biomarker data will be performed on patients with biomarker data. Assessment of 
associations between biomarker and safety data will be conducted using the safety set. 
For exploratory markers, since the studies are not adequately powered to assess specific biomarker-
related hypotheses, the goal of these exploratory statistical analyses should be considered as the 
generation of new scientific hypotheses. No adjustment for multiple comparisons is usually planned 
for exploratory analyses. Furthermore, additional post hoc exploratory assessments may be 
performed. 
There may be circumstances when a decision is made to stop sample collection, or not perform or 
discontinue their analysis due to either practical or strategic reasons. Under such circumstances, the 
number of samples may be inadequate to perform a rigorous data analysis and the available data 
will only be listed and potentially summarized. 
Additional analyses that may be performed after the completion of the end-of-study CSR will be 
documented in separate reports. The data analysis will be described in a stand-alone analysis plan. 


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The Cycle 1 Day 1 assessment (pre-dose) will be used as the baseline value. For assessments 
performed in tumor biopsies, fresh biopsy results will be used for baseline when both archived and 
fresh tumor samples are available. When more than one biomarker data value are available for a 
patient at any time point, the mean of the replicate values will be used for all statistical analyses. 
Derivation of change and percent change variables 
Absolute and relative change (percent change) and fold change from baseline may be calculated for 
each <patient> <and> </><or> <treatment group>. 
Fold change is calculated as the ratio of biomarker value at ((visit i) / (Baseline biomarker value)), 
while percent change is computed as ((visit i – baseline) / baseline) * 100.  
The average percent change from baseline is computed as the average expression level at each time 
point and then the percent change using the average values.  The number of patients for the average 
of percent change from baseline might vary due to potential missing values at respective time 
points. 
If both the baseline and post baseline values are below LLOQ, absolute change, percent change and 
fold change from baseline will not be imputed and reported as missing. 
Tumor markers 
For patients with measured tumor markers (CA15-3, CEA, and CA27-29) at baseline, descriptive 
statistics will be tabulated by time with observed, change and percent change from baseline following 
rules outlined above. These biomarkers may be summarized by subgroups, e.g. exposure of at least 4 
cycles, CA15-3 positive/negative. 
 
6.12 Exploratory analyses 
The goal of these exploratory analyses is to evaluate potential correlations between biomarkers in 
tumor or blood samples and antitumor activity (including HER2, HER3, HER2:HER3 dimers, heregulin 
and other potential biomarkers measured at baseline only or at baseline and after start of 
treatment).  
HER2 score, NRG1 score, HER2:HER3 dimer score will be summarized at baseline. 
Correlation to “clinical response” plots (scatter plots) will be provided: HER2 score, H-score, NRG1 
score, HER2:HER3 dimer score, sHeregulin level to cycle number, global resp. category, tumour size 
change from baseline. 
Tables will be produced to investigate whether certain categorical parameter is enriched in certain 
patient category (responder/non-responder or other category). 
 
6.13 Interim analysis 
No formal interim analysis is planned.  
 
 
 


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7 
Appendix 
7.1 
Imputation rules 
7.1.1 
Study drug 
The following rule should be used for the imputation of the dose end date for a given study treatment 
component: 
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death date, 
the patient is considered as ongoing:  
The patient should be treated as ongoing and the cut-off date should be used as the dose end date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available: 
Case 1: The dose end date is completely missing, and the EOT completion date is complete, then this 
latter date should be used.   
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:   
            Use Dec31yyyy 
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:  
            Use EOT date 
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the year of EOT 
date and mm < the month of  EOT date:  
            Use last day of the Month (mm) 
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study. 
After imputation, compare the imputed date with start date of treatment, if the imputed date is < 
start date of treatment:  
Use the treatment start date 
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should not 
be imputed. 
For exposure endpoints, the following rule should be used for the imputation of the start date for 
FULVESTRANT: 
Incomplete of start date 
Missing day is defaulted to the 15th of the month.  
7.1.2 
AE, Concomitant medication and safety assessment date imputation 
Rules for imputation of start dates for AEs, concomitant medications as well as for safety assessments 
are outlined in Table 2Table 2. 


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Table 2: 
Imputation of start dates (AE, concomitant medications) and assessments 
(laboratory data, ECG, vital signs) 
Missing 
Element 
Rule 
day, month, 
and year 
No imputation will be done for completely missing dates 
day, month 
If available year = year of study treatment start date then  
If stop date contains a full date and stop date is earlier than study treatment start date 
then set start date = 01JanYYYY  
Else set start date = study treatment start date.  
If available year > year of study treatment start date then 01JanYYYY 
If available year < year of study treatment start date then 01JulYYYY 
day 
If available month and year = month and year of study treatment start date then  
If stop date contains a full date and stop date is earlier than study treatment start date 
then set start date= 01MONYYYY.  
Else set start date = study treatment start date. 
If available month and year > month and year of study treatment start date then 
01MONYYYY   
If available month and year < month year of study treatment start date then 
15MONYYYY   
Any AEs and Concomitant Medications with partial/missing dates will be displayed as such in the data 
listings. 
Any AEs and Concomitant Medications which are continuing as per the data cut-off will be shown as 
‘ongoing’ rather than the end date provided. 
Table 3: 
Imputation of end dates (AE, concomitant medications) 
Missing 
Element 
Rule 
day, month, 
and year 
Completely missing end dates (incl. ongoing events) will be imputed by the end date of 
the on-treatment period*  
day, month 
If partial end date contains year only, set end date = earliest of 31DecYYYY or end date 
of the on-treatment period *  
day 
If partial end date contains month and year, set end date = earliest of last day of the 
month or end date of the on-treatment period* 
*=last treatment date plus 30 days AND prior to min(death date, cut-off date, withdrawal of consent date) 
Note : Imputation of AE end date will be done only for emergent AEs 
7.1.3 
Other imputation rules 
Incomplete date of initial diagnosis of cancer and date of most recent recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-Jan.  
Incomplete assessment dates for tumor assessment 
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. If one or 
more assessment dates are incomplete but other investigation dates are available, this/these 
incomplete date(s) are not considered for calculation of the assessment date and assessment date is 


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calculated as the latest of all investigation dates (e.g. MRI scan, CT scan) if the overall response at that 
assessment is CR/PR/SD/UNK. Otherwise – if overall response is progression – the assessment date is 
calculated as the earliest date of all investigation dates at that evaluation number.  If all measurement 
dates have no day recorded, the 1st of the month is used. If the month is not completed, for any of the 
investigations, the respective assessment will be considered to be at the date which is exactly between 
previous and following assessment. If a previous and following assessment is not available, this 
assessment will not be used for any calculation. 
Applying the cut-off to tumor assessment 
For tumor related assessments, if an evaluation has some assessments done prior to cut-off date and 
others after the cut-off date, then the evaluation is considered post-cut-off date and will be excluded 
from analysis. 
Incomplete of death 
Missing day is defaulted to the 15th of the month. Incomplete date follow-up treatment 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 31-Dec, 
or death date if patient died before.  
 
7.1.4 
Assessment of disease response using RECIST 1.1 
Overall response is calculated for each assessment time point as per Error! Reference source not 
found.. 
Table 4: Overall response in patients with target (+/- non-target) disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable 
The best overall response is determined once all data for a given patient are available and is defined 
as the best response recorded between the start and end of treatment, as described in Error! 
Reference source not found.. 
 


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Table 5: Best overall response 
Overall response 
First time point 
Overall response 
Subsequent time points 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable 
1. If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response 
would depend on whether minimum duration for SD was met. However, sometimes CR may be claimed when subsequent 
scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time point. Under 
these circumstances, the original CR should be changed to PR and the best response is PR. 
 
7.1.5 
CTCAE grading of laboratory parameters 
Toxicity grading will be done for selected laboratory parameters according to CTCAE version 4.03. 
For CTCAE grading of calcium, the corrected calcium derivation is based on total calcium and 
albumin level: 
Imperial units: Corrected Calcium (mg/dL) = 0.8 * [4 - Albumin (g/dL)] + Calcium (mg/dL) 
SI units: Corrected Calcium (mmol/L) = 0.2 * [4 - Albumin (g/dL)] + Calcium (mmol/L) 
The grading for Corrected Calcium (mmol/L) is defined as :  
 
 
 
 
*With LLN & ULN for Calcium 


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Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypocalcemia Corrected serum 
calcium  <LLN* - 2.0 
Corrected serum 
calcium  <2.0 - 1.75 
Corrected serum 
calcium <1.75 - 1.5 
Corrected 
serum calcium  
<1.5 
Hypercalcemia 
Corrected serum 
calcium of >ULN* -
2.9 
Corrected serum 
calcium of >2.9 - 3.1 
Corrected serum 
calcium of >3.1 - 3.4 
Corrected 
serum calcium 
of >3.4 


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8 
References  
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time. Biometrics, 
38, 29 - 41. 
Cheson B, Bennet JM, Kopaeosiecky K, et al (2003) Revised Recommendations of the International 
Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Journal of Clinical Oncology; 
21(24):4642-9 
Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in the case of the 
binomial.  Biometrical, 26, 404-413. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247. 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, May 
2007. 
Kalbfleisch JD and Prentice RL. The Statistical Analysis of Failure Time Data (2002). Wiley Series in 
Probability and Statistics. 
Klein J and Moeschberger M (2003). Survival Analysis: Techniques for Censored and Truncated Data. 
2nd ed. 
Von Hoff DD, Stephenson JJ, Rosen P, Loesch DM, Borad MJ, Anthony S, Jameson G, Brown S, 
Cantafio N, Richards DA, Fitch TR, Wasserman E, et al. 2010. Pilot study using molecular profiling of 
patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin 
Oncol 28:4877–4883. 
 
 
 


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9 
Appendix 1 - Planned CSR outputs 
 
Tables 
Table 14.1.1 
Enrollment by site (All patients) 
Table 14.1.2 
Patient disposition (Safety Set) 
Table 14.1.3 
Analysis sets (Safety Set) 
Table 14.1.4 
Protocol deviations (Safety Set) 
Table 14.1.5. 
Demographics and baseline characteristics (Safety Set) 
Table 14.1.6 
Disease history (Safety Set) 
Table 14.1.7 
Prior anticancer therapy (Safety Set) 
Table 14.1.8 
Relevant medical history (Safety Set) 
Table 14.1.9 
Concomitant medications (Safety Set) 
Table 14.1.10 
Study drug premedications (Safety Set) 
Table 14.1.11 
Study drug premedications by infusion (Safety Set) 
Table 14.9.12 
Post treatment anti-cancer therapy (Safety Set) 
Table 14.1.13 
Duration of exposure and administrations per patient (Safety Set) 
Table 14.1.14 
Dose and dose intensity (Safety Set) 
Table 14.1.15 
Dose adjustments (Safety Set) 
Efficacy  
Table 14.2.1 
CBR at 24 weeks (Efficacy Set) 
Table 14.2.2 
Overall Response Rate (Confirmed/Unconfirmed), Best Overall Response, Disease Control 
Rate (Efficacy Set) 
Table 14.2.3 
Duration of response (Efficacy Set) 
Table 14.2.5 
Progression-free survival (Efficacy Set) 
Table 14.2.7 
Overall survival (Efficacy Set) 
Table 14.2.9 
Progression-free survival ratio (Cohort 2 - Efficacy Set) 
Safety 
Table 14.3.1.1 
General summary of treatment-emergent adverse events (Safety Set) 
Table 14.3.1.2 
Treatment-emergent adverse events irrespective of causality by system organ class and 
preferred term (Safety Set) 
Table 14.3.1.3 
Treatment-emergent adverse events suspected to be study treatment related by system 
organ class and preferred term (Safety Set) 
Table 14.3.1.4 
Treatment-emergent adverse events irrespective of causality by preferred term (Safety Set) 
Table 14.3.1.5 
Treatment-emergent adverse events suspected to be study treatment related by preferred 
term (Safety Set) 
Table 14.3.1.6 
Treatment-emergent serious adverse events irrespective of causality by system organ class 
and preferred term (Safety Set) 
Table 14.3.1.7 
Treatment-emergent serious adverse events suspected to be study treatment related by 
system organ class and preferred term (Safety Set) 
Table 14.3.1.8 
Treatment-emergent adverse events leading to study treatment discontinuation irrespective 
of causality by system organ class and preferred term (Safety Set) 
Table 14.3.1.9 
Treatment-emergent adverse events leading to study treatment discontinuation suspected 
to be study treatment related by system organ class and preferred term (Safety Set) 
Table 14.3.1.10 Treatment-emergent adverse events leading to dose interruption/adjustment by system 
organ class and preferred term (Safety Set) 
Table 14.3.1.11 Treatment-emergent adverse events requiring additional therapy by system organ class and 
preferred term (Safety Set) 


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Table 14.3.1.12 Treatment-emergent adverse events leading to fatal outcome by system organ class and 
preferred term (Safety Set) 
Table 14.3.1.13 Number of patients with adverse events of special interest (Safety Set) 
Table 14.3.1.14 Number of patients with infusion-related reactions (Safety Set) 
 
Table 14.3.2.1 
Hematology shift table based on CTC grades (Safety Set) 
Table 14.3.2.2 
Biochemistry shift table based on CTC grades (Safety Set) 
Table 14.3.2.3 
Hematology shift table based on normal ranges (Safety Set) 
Table 14.3.2.4 
Biochemistry shift table based on normal ranges (Safety Set) 
Table 14.3.2.6 
Liver function test abnormalities (Safety Set) 
Table 14.3.2.7 
ECG abnormalities (Safety Set) 
Table 14.3.2.8 
Vital sign abnormalities (Safety Set) 
Table 14.3.2.9 
LVEF shift table (Safety Set) 
Table 14.3.2.10 Change from baseline in LVEF (Safety Set) 
Immunogenicity 
Table 14.3.3.1 
Number of patients with anti-drug antibodies at baseline and on treatment (Safety Set) 
Cytokines  
Table 14.3.4.1 
Summary of cytokines by visit (Safety Set) 
Biomarkers 
Table 14.3.5.1 
Summary of biomarkers by visit (Safety Set) 
Table 14.3.5.2 
Summary of biomarkers by visit and CA15-3 status at baseline (Safety Set) 
Table 14.3.5.3 
Summary of biomarkers by visit and exposure (Safety Set) 
 
Figures 
Figure 14.2.4 
Kaplan-Meier plot of duration of response (Efficacy Set) 
Figure 14.2.6 
Kaplan-Meier plot of progression-free survival (Efficacy Set) 
Figure 14.2.8 
Kaplan-Meier plot of overall survival (Efficacy Set) 
Figure 14.2.10   Scatterplot of progression-free survival on last prior hormonal therapy and on study in 
cohort 2 patients (Efficacy Set) 
Figure 14.2.11 
Percent change in sum of diameters of target lesions (Efficacy Set) 
Figure 14.2.12 
Swimmer plot (Efficacy Set) 
Figure 14.2.13 
Waterfall plot best percent change from baseline in sum of diameters of target lesions  
(Efficacy Set) 
Figure 14.3.2.5 
Boxplots - Lab parameter values over time (Safety Set) 
Figure 14.3.4.2 
Cytokines values over time (Safety Set) 
 
Listings 
Listing 14.3.1.15 Deaths (Safety Set) 
Listing 14.3.1.6 
Serious adverse events (Safety Set) 
 
Section 16.2 listings not covered in Section 14 
Listing 16.2.1 
Patient disposition and analysis sets  (Safety Set) 
Listing16.2.2 
Protocol deviations (Safety Set) 


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Listing 16.2.4.1 
Demographics and baseline characteristics (Safety Set) 
Listing 16.2.4.2 
Disease history (Safety Set) 
Listing 16.2.4.3 
Prior anticancer therapy - medications (Safety Set) 
Listing 16.2.4.3 
Prior anticancer therapy - surgery (Safety Set) 
Listing 16.2.4.5 
Prior anticancer therapy - radiation (Safety Set) 
Listing 16.2.4.6 
Relevant medical history (Safety Set) 
Listing 16.2.4.7 
Concomitant medications (Safety Set) 
Listing 16.2.5 
Study drug administration (Safety Set) 
 
Listing 16.2.6.1 
Tumor information (RECIST 1.1) per investigator (Efficacy Set) 
Listing 16.2.6.2 
Tumor information (RECIST 1.1) per central review (Efficacy Set) 
Listing 16.2.6.3 
Tumor response (RECIST 1.1) per investigator(Efficacy Set) 
Listing 16.2.6.4 
Tumor response (RECIST 1.1) per central review (Efficacy Set) 
Listing 16.2.6.5 
Best overall response, duration of response (RECIST 1.1) per investigator(Responding 
patients in Efficacy Set) 
Listing 16.2.6.6 
Best overall response, duration of response (RECIST 1.1) per central review (Responding 
patients in Efficacy Set) 
Listing 16.2.6.7 
Concordance between independent radiological review and local assessment of the BOR 
disease (RECIST 1.1) (Safety Set) 
Listing 16.2.6.8 
Progression-free survival per investigator (Efficacy Set) 
Listing 16.2.6.9 
Progression-free survival per central review (Efficacy Set) 
Listing 16.2.6.10 Concordance between independent radiological review and local assessment of the PFS 
(RECIST 1.1) (Safety Set) 
Listing 16.2.6.11 Overall survival (Efficacy Set) 
Listing 16.2.6.12 Cohort 2 - Progression-free survival ratio (RECIST 1.1) (Efficacy Set) 
 
Listing 16.2.7.1 
Adverse events (Safety Set) 
Listing 16.2.7.2 
Infusion-related reactions (Safety Set) 
Listing 16.2.7.3 
Adverse events leading to study treatment discontinuation (Safety Set) 
Listing 16.2.7.4 
Adverse events of special interest (Safety Set) 
Listing 16.2.8.1 
Laboratory listing for patients with abnormalities (liver function test) (Safety Set) 
Listing 16.2.8.2 
Laboratory listing for patients with abnormalities (hematology) (Safety Set) 
Listing 16.2.8.3 
Laboratory listing for patients with grades>=3 (hematology) (Safety Set) 
Listing 16.2.8.4 
Laboratory listing for patients with abnormalities (biochemistry) (Safety Set) 
Listing 16.2.8.5 
Laboratory listing for patients with grades>=3 (biochemistry) (Safety Set) 
Listing 16.2.8.6 
Laboratory listing (urinalysis) (Safety Set) 
Listing 16.2.9.1 
Vital signs abnormalities (Safety Set) 
Listing 16.2.9.2a  ECG assessments (Safety Set) 
Listing 16.2.9.2b  Notable ECG values (Safety Set) 
Listing 16.2.9.3 
Left ventricular ejection fraction (Safety Set) 
Listing 16.2.9.4 
ECOG (Per-protocol Efficacy Set) 
Listing  16.2.9.5 Anti-drug antibodies (Safety set)