Conditions: Oncology MET Gene Amplification NSCLC MET Gene Mutation Non Small Cell Lung Cancer
Keywords: Advanced Solid Tumor Malignancies MET Gene Amplification MET Amplification Wild-type NSCLC METex14del Non-Small Cell Lung Carcinoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 57
Healthy volunteers: no

Brief summary:
This is the first study to test Sym015 in humans. The primary purpose of this study is to see if Sym015 is safe and effective for patients with advanced solid tumor malignancies without available therapeutic options.

Detailed description:
In the first part of the study (Part 1, dose-escalation), Sym015 was evaluated for safety and tolerability. Additionally, the recommended Phase 2 dose (RP2D) was to be determined. Sym015 was given at different dose levels on an every second week (Q2W) dosing schedule. Each patient was given one single weight based dose level.

In the second part of the study (Part 2, dose-expansion), dosing was to be at the RP2D on a Q2W dosing schedule. Three cohorts were included:

* Basket Cohort: Patients with KRAS wild-type (WT) advanced solid tumor malignancies with MET-amplification and without therapeutic options. Patients must have no prior therapy with MET-targeting agents, except a subset of patients having received prior therapy with a MET-targeting tyrosine kinase inhibitor (TKI). As of December 2018, accrual to this cohort was suspended.
* Non-Small Cell Lung Carcinoma (NSCLC) MET-Amplified Cohort: Patients with advanced NSCLC with MET-amplification, and without available therapeutic options. Patients may have received prior therapy with MET-targeting and/or epidermal growth factor receptor (EGFR)-targeting agents.
* NSCLC with MET exon 14 skipping alteration (METex14del) Cohort: Patients with advanced NSCLC METex14del, and without therapeutic options. Tumors need not be MET-amplified, and patients may have received prior therapy with MET-targeting and/or EGFR-targeting agents.

Arms:
arm 1: Sym015 was tested in four dose titration cohorts. Patients in this cohort received 6 mg/kg. A substitute or an additional dose level could potentially be evaluated. arm 2: Sym015 was tested in four dose titration cohorts. Patients in this cohort received 12 mg/kg. A substitute or an additional dose level could potentially be evaluated. arm 3: Sym015 was tested in four dose titration cohorts. Patients in this cohort received 18 mg/kg. A substitute or an additional dose level could potentially be evaluated. arm 4: Sym015 was tested in four dose titration cohorts. Patients in this cohort received 24 mg/kg. A substitute or an additional dose level could potentially be evaluated. arm 5: Patients with KRAS WT advanced solid tumor malignancies with MET-amplification were to receive Sym015 at the RP2D. Included in this group was a subset of patients who have received prior therapy with a MET-targeting TKI. arm 6: Patients with advanced NSCLC with MET-amplification were to receive Sym015 at the RP2D. Patients may have received prior therapy with MET-targeting and/or EGFR-targeting agents. arm 7: Patients with advanced NSCLC with METex14del were to receive Sym015 at the RP2D. Tumors need not be MET-amplified, and patients may have received prior therapy with MET-targeting and/or EGFR-targeting agents. mutation.

Interventions: intervention 1: Sym015
Intervention descriptions: intervention 1: Sym015 is a mixture of two monoclonal antibodies which specifically bind to non-overlapping epitopes in the extracellular domain of MET.

Protocol document:
Prot_000.pdf: 


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Sponsor Declarations 
 
This confidential document is the property of Symphogen A/S. No unpublished information 
contained herein may be passed on, reproduced, published or used without prior written approval 
from Symphogen A/S. Access to this document must be restricted to relevant parties. 
 
The trial will be conducted in compliance with this clinical trial protocol, International Council 
for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use 
E6(R2): Guideline for Good Clinical Practice (GCP) (EMA/CHMP/ICH/135/1995), the 
Declaration of Helsinki, and applicable regulations. 
 
The Sponsor has appointed a Coordinating Investigator for the trial. This Coordinating 
Investigator will provide input to the trial design and act as overall coordinator for Investigators 
across all sites. The Coordinating Investigator will furthermore sign off the Clinical Trial Report 
on behalf of all Investigators. 
 
Lists of Investigators responsible for conducting the trial, medically qualified physicians 
responsible for all site-related medical decisions (if other than the Investigators), monitors, 
clinical laboratories, and other medical and/or technical departments and/or institutions involved 
in the trial are provided as separate documents. 
 


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Principal Investigator Signature Page 
 
I, the undersigned, am responsible for the conduct of the trial at this site and agree: 
 To assume responsibility for the proper conduct of the clinical trial at this Investigational 
Site. 
 Not to implement any changes to the clinical trial protocol without agreement from the 
Sponsor and prior review and written approval from the appropriate Healthy Authority (as 
indicated) and the Institutional Review Board/Ethics Committee, except where necessary to 
eliminate an immediate hazard to the patients. 
 That I am aware of, and will comply with “Good Clinical Practice” (ICH E6(R2) GCP) 
(EMA/CHMP/ICH/135/1995), the Declaration of Helsinki, and all applicable regulatory 
requirements. 
 That all site staff to which I have delegated tasks for this clinical trial are appropriately 
selected and adequately informed about the investigational product(s) and of their trial-
related duties and functions as described in the clinical trial protocol. 
 
________________________________ 
 
____________________ 
Signature 
 
 
 
 
 
Date of Signature 
 
 
Name: ________________________________________ 
 
 
Academic Degree: ______________________________ 
 
 
Function: _____________________________________ 
 
 
Institution: ____________________________________ 


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TABLE OF CONTENTS 
1. 
SYNOPSIS ..............................................................................................................................9 
2. 
LIST OF ABBREVIATIONS AND EXPANDED TERMS ................................................19 
3. 
BACKGROUND AND RATIONALE .................................................................................23 
3.1 
Disease and Treatment .......................................................................................................23 
3.1.1 
Solid Tumor Malignancies ...............................................................................................23 
3.1.2 
MET-Amplified Solid Tumor Malignancies ....................................................................23 
3.1.3 
Current Treatment of MET-Amplified Solid Tumor Malignancies .................................25 
3.2 
Investigational Medicinal Product .....................................................................................26 
3.2.1 
Sym015 .............................................................................................................................26 
3.2.2 
Mechanism of Action .......................................................................................................26 
3.2.3 
Summary of Non-Clinical Findings .................................................................................27 
3.2.4 
Summary of Clinical Findings .........................................................................................28 
3.2.4.1 
Protocol Sym015-01 ......................................................................................................28 
3.2.4.2 
Other Monoclonal Antibodies Targeting MET .............................................................29 
3.3 
Trial Rationale ...................................................................................................................29 
3.4 
Dose Rationale ...................................................................................................................30 
3.4.1 
Rationale for Starting Dose ..............................................................................................30 
3.4.2 
Rationale for Recommended Phase 2 Dose .....................................................................30 
3.5 
Overall Benefits/Risk .........................................................................................................31 
4. 
TRIAL OBJECTIVES ..........................................................................................................33 
4.1 
Objectives of Part 1, Dose-Escalation ...............................................................................33 
4.1.1 
Primary Objective .............................................................................................................33 
4.1.2 
Secondary Objectives .......................................................................................................33 
4.2 
Objectives of Part 2 ............................................................................................................33 
4.2.1 
Primary Objective .............................................................................................................33 
4.2.2 
Secondary Objectives .......................................................................................................33 
5. 
TRIAL DESIGN ...................................................................................................................35 
5.1 
Overall Design and Plan ....................................................................................................35 
5.2 
Discussion of Trial Design.................................................................................................37 
5.2.1 
Rationale for Trial Design ................................................................................................37 
5.2.2 
Rationale for Trial Population ..........................................................................................38 
5.3 
Schedule of Events .............................................................................................................38 
5.3.1 
Prescreening for MET-amplification and METEx14Del Status ............................................39 
5.3.2 
Screening ..........................................................................................................................40 
5.3.3 
Screening Failures ............................................................................................................41 
5.3.4 
Treatment ..........................................................................................................................42 
5.3.5 
End of Treatment and Follow-up Visits ...........................................................................42 
5.3.6 
Flow Chart – Schedule of Assessments ...........................................................................43 
5.4 
Recruitment Period ............................................................................................................48 
5.5 
Number of Patients ............................................................................................................48 
5.6 
End of Trial ........................................................................................................................49 
6. 
PATIENT SELECTION AND WITHDRAWAL ................................................................50 
6.1 
Inclusion Criteria ...............................................................................................................50 
6.2 
Exclusion Criteria ..............................................................................................................52 


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6.3 
Withdrawal .........................................................................................................................55 
6.3.1 
Withdrawal from Treatment with Sym015 ......................................................................55 
6.3.2 
Withdrawal from Trial ......................................................................................................56 
6.4 
Replacement of Patients .....................................................................................................57 
6.4.1 
Part 1, Dose-Escalation ....................................................................................................57 
6.4.2 
Part 2 .................................................................................................................................57 
7. 
TREATMENT ......................................................................................................................58 
7.1 
Investigational Medicinal Product/Sym015 .......................................................................58 
7.1.1 
Packaging and Labeling of Sym015 .................................................................................58 
7.1.2 
Handling, Storage and Preparation of Sym015 ................................................................58 
7.1.3 
Administration of Sym015 ...............................................................................................59 
7.1.3.1 
Treatment Schedule .......................................................................................................59 
7.1.3.2 
Part 1, Dose-Escalation .................................................................................................59 
7.1.3.3 
Part 2 ..............................................................................................................................61 
7.1.3.4 
Duration of Infusion for Administration of Sym015 .....................................................61 
7.1.3.5 
Patient Monitoring During and After Infusion of Sym015 ...........................................61 
7.1.3.6 
Infusion-Related Reactions to Sym015 .........................................................................62 
7.1.3.7 
Handling of Infusion-Related Reactions to Sym015 .....................................................62 
7.1.4 
Dose-Adjustment and Delays of Sym015 ........................................................................63 
7.1.4.1 
Dose-Adjustment for Body Weight ...............................................................................64 
7.1.4.2 
Dose-Delays for Sym015-Related or Disease-Related Toxicities ................................64 
7.1.4.3 
Dose-Reduction for Sym015-Related Toxicities ..........................................................64 
7.2 
Other Drugs to be Used in the Trial ...................................................................................65 
7.2.1 
Premedication for Sym015 Infusions ...............................................................................65 
7.2.2 
Prophylactic and Therapeutic Treatment .........................................................................66 
7.2.2.1 
Mandatory Prophylactic Treatment ...............................................................................66 
7.3 
Blinding..............................................................................................................................66 
7.4 
Drug Accountability and Compliance Check ....................................................................66 
7.5 
Concomitant Medication/Therapy .....................................................................................67 
7.5.1 
Allowed Medication/Therapy and Procedures During the Trial ......................................67 
7.5.2 
Prohibited Medication/Therapy and Procedures During the Trial ...................................67 
7.6 
Medical Care of Patients after End of Trial Participation..................................................69 
8. 
TRIAL ASSESSMENTS ......................................................................................................70 
8.1 
Baseline Characteristics / Eligibility Assessments ............................................................70 
8.1.1 
Signing of Informed Consent ...........................................................................................70 
8.1.2 
Demographics ...................................................................................................................70 
8.1.3 
Medical History ................................................................................................................70 
8.1.4 
Tumor Characteristics and Extent of Disease ..................................................................70 
8.1.5 
Prior Cancer Treatments ...................................................................................................70 
8.2 
Safety Assessments ............................................................................................................71 
8.2.1 
Medication/Procedure Survey ..........................................................................................71 
8.2.2 
Adverse Events Survey ....................................................................................................71 
8.2.3 
Dose-Limiting Toxicities Evaluation (Part 1 Only) .........................................................71 
8.2.4 
Vital Signs and Body Weight ...........................................................................................71 
8.2.5 
Performance Status ...........................................................................................................72 
8.2.6 
Physical Examination .......................................................................................................72 


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8.2.7 
Electrocardiogram ............................................................................................................72 
8.2.8 
Echocardiogram or Multi-Gated Acquisition Scan ..........................................................73 
8.2.9 
Laboratory Assessments and Pregnancy Test ..................................................................73 
8.2.9.1 
Hematology Panel .........................................................................................................74 
8.2.9.2 
Biochemistry Panel ........................................................................................................74 
8.2.9.3 
Coagulation Panel ..........................................................................................................75 
8.2.9.4 
Urinalysis .......................................................................................................................75 
8.2.9.5 
Pregnancy Test ..............................................................................................................76 
8.3 
Disease Assessments ..........................................................................................................76 
8.3.1 
Disease Status Evaluation by CT or MRI ........................................................................76 
8.3.2 
Tumor Marker Evaluation (Part 1 and Part 2 Basket Cohort) ..........................................77 
8.3.3 
Archival Tumor Tissue for MET and KRAS Assessment (Part 1 and Part 2 Basket 
Cohort)  ..........................................................................................................................................77 
8.3.4 
Tumor Biopsy for Eligibility Assessment and Biomarker Analysis (Part 1 and Part 2 
Basket Cohort) ...............................................................................................................................78 
8.3.5 
Tumor Biopsy for MET Status and Biomarker Analysis (Part 2 NSCLC MET-Amplified 
Cohort and NSCLC METEx14Del Cohort) ........................................................................................79 
8.4 
Pharmacokinetic Assessments ...........................................................................................80 
8.5 
Anti-Drug Antibody Testing ..............................................................................................81 
8.6 
Skin Biopsy (Part 1 only) ...................................................................................................82 
8.7 
Blood Sample for Genomic and Biomarker Analyses .......................................................82 
8.8 
Handling of Biological Samples ........................................................................................83 
8.9 
Follow-up Assessments .....................................................................................................83 
8.10 
Appropriateness of Measurements .....................................................................................84 
9. 
ADVERSE EVENTS ............................................................................................................85 
9.1 
Definitions of Adverse Events ...........................................................................................85 
9.1.1 
Adverse Event ..................................................................................................................85 
9.1.2 
Events Not to be Considered as Adverse Events .............................................................85 
9.1.3 
Adverse Events of Medical Interest .................................................................................86 
9.1.4 
Serious Adverse Events ....................................................................................................86 
9.1.5 
Events that Do Not Meet the Definition of Serious Adverse Events ...............................86 
9.2 
Adverse Event Recording and Reporting Instructions.......................................................87 
9.2.1 
Adverse Event Recording Period .....................................................................................87 
9.2.2 
Diagnosis ..........................................................................................................................87 
9.2.3 
Severity .............................................................................................................................87 
9.2.4 
Relationship to Investigational Medicinal Product/Sym015 ............................................88 
9.2.5 
Outcome ...........................................................................................................................89 
9.2.6 
Follow-up of Adverse Events ...........................................................................................89 
9.3 
Serious Adverse Event Recording and Reporting .............................................................90 
9.4 
Safety Reporting to Health Authorities, Institutional Review Boards/Ethics Committees, 
and Investigators ............................................................................................................................90 
9.5 
Dose-Limiting Toxicities (Part 1 Only) .............................................................................91 
9.5.1 
Definition of Dose-Limiting Toxicities ............................................................................91 
9.5.2 
Observation Period for Dose-Limiting Toxicities ............................................................92 
9.5.3 
Reporting of Dose-Limiting Toxicities ............................................................................92 
9.6 
Reporting of Infusion-Related Reactions...........................................................................92 


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9.7 
Pregnancy ...........................................................................................................................92 
10. STATISTICS ........................................................................................................................94 
10.1 
Statistical Considerations and Analysis Plan .....................................................................94 
10.2 
Sample Size Determination................................................................................................94 
10.3 
Analysis Population ...........................................................................................................96 
10.4 
Primary Endpoint and Analysis .........................................................................................96 
10.4.1 Part 1, Dose-Escalation ....................................................................................................96 
10.4.2 Part 2 .................................................................................................................................96 
10.5 
Secondary Endpoint and Analysis .....................................................................................97 
10.5.1 Efficacy Endpoints and Analyses .....................................................................................97 
10.5.2 Other Efficacy Assessments .............................................................................................97 
10.5.3 Safety Endpoints and Analyses ........................................................................................98 
10.5.3.1 Adverse Events ..............................................................................................................98 
10.5.3.2 Clinical Laboratory Values ...........................................................................................99 
10.5.3.3 Other Safety Assessments .............................................................................................99 
10.5.4 Pharmacokinetic Endpoints and Analyses .......................................................................99 
10.5.5 Additional Endpoints and Analyses ...............................................................................100 
10.6 
Interim Analysis ...............................................................................................................101 
10.7 
Deviations from the Statistical Plan .................................................................................101 
11. ETHICS...............................................................................................................................102 
11.1 
Institutional Review Board/Ethics Committee ................................................................102 
11.2 
Patient Information and Informed Consent......................................................................102 
12. SAFETY SURVEILLANCE SET-UP ................................................................................103 
12.1 
Safety Review ..................................................................................................................103 
12.2 
Other Safety Surveillance Activities ................................................................................104 
13. MONITORING AND QUALITY ASSURANCE..............................................................105 
13.1 
Compliance with Good Clinical Practice .........................................................................105 
13.2 
Source Documents ...........................................................................................................105 
13.3 
Monitoring .......................................................................................................................105 
14. DATA HANDLING AND RECORD KEEPING ..............................................................107 
14.1 
Data Protection.................................................................................................................107 
14.2 
Data Transactions and Access .........................................................................................107 
14.3 
Data Processing ................................................................................................................107 
14.4 
Clinical Trial Report ........................................................................................................108 
14.5 
Compliance with the General Data Protection Regulation ..............................................108 
14.6 
Retention of Trial Documents at Site...............................................................................108 
15. REGISTRATION AND COMMUNICATION OF RESULTS .........................................109 
15.1 
Use of Information ...........................................................................................................109 
15.2 
Registration and Publication ............................................................................................109 
16. INSURANCE AND LIABILITY .......................................................................................110 
17. CHANGES TO THE FINAL CLINICAL TRIAL PROTOCOL .......................................111 
18. PREMATURE TERMINATION OF THE TRIAL OR A TRIAL SITE ...........................112 
18.1 
Premature Termination of the Trial .................................................................................112 
18.2 
Premature Termination of a Trial Site .............................................................................112 
19. REFERENCES ...................................................................................................................113 
20. APPENDICES ....................................................................................................................117 


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Appendix 1: Summary of Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ........117 
21. SUMMARY OF CHANGES ..............................................................................................123 
21.1 
Protocol Amendment 1 dated 17-Feb-2016 .....................................................................123 
21.2 
Protocol Amendment 2 dated 22-Feb-2016 .....................................................................124 
21.3 
Protocol Amendment 3 dated 02-May-2016....................................................................125 
21.4 
Protocol Amendment 4 dated 04-Nov-2016 ....................................................................128 
21.5 
Protocol Amendment 5 dated 11-May-2017....................................................................137 
21.6 
Protocol Amendment 6 dated 20-Nov-2017 ....................................................................140 
21.7 
Protocol Amendment 7 dated 07-Dec-2018 ....................................................................152 
 
LIST OF FIGURES 
Figure 1 
Overall Trial Design ................................................................................................... 37 
 
LIST OF TABLES 
Table 1 
Preliminary Sym015 Geometric Mean PK Parameters .............................................. 31 
Table 2 
Overall Trial Plan ....................................................................................................... 39 
Table 3 
Flow Chart: Schedule of Assessments (Part 1 and Part 2 Basket Cohort) ................. 44 
Table 4 
Flow Chart: Schedule of Assessments (Part 2 NSCLC Cohorts) ............................... 46 
Table 5 
Description of Investigational Medicinal Product/Sym015 ....................................... 58 
Table 6 
Infusion-Related Reactions Management Guidelines ................................................ 63 
Table 7 
Sym015 Dose-Reduction Schedule ............................................................................ 65 
Table 8 
Schedule of Safety Blood and Urine Samples ............................................................ 73 
Table 9 
Schedule of Pharmacokinetic Assessments ................................................................ 81 
Table 10 
90% Confidence Intervals for Observed Response Rates for N=20 and N=25.......... 95 
Table 11 
PK Endpoints Definitions and Derivations .............................................................. 100 
Table 12 
Response Criteria for Evaluation of Target Lesions ................................................ 120 
Table 13 
Response Criteria for Evaluation of Non-Target Lesions ........................................ 120 
Table 14 
Overall Response Status for Patients with Baseline Measurable Disease ................ 121 
Table 15 
Best Overall Response when Confirmation of CR and PR Required ....................... 122 
Table 16 
Protocol Amendment 1 ............................................................................................. 123 
Table 17 
Protocol Amendment 2 ............................................................................................. 124 
Table 18 
Protocol Amendment 3 ............................................................................................. 126 
Table 19 
Protocol Amendment 4 ............................................................................................. 129 
Table 20 
Protocol Amendment 5 ............................................................................................. 138 
Table 21 
Protocol Amendment 6 ............................................................................................. 141 
Table 22 
Protocol Amendment 7 ............................................................................................. 153 
 
 


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1. 
SYNOPSIS 
Item 
Summary 
Trial Title 
An Open-label, Multicenter Phase 1a/2a Trial Investigating the Safety, Tolerability 
and Antitumor Activity of Multiple Doses of Sym015, a Monoclonal Antibody 
Mixture Targeting MET, in Patients with Advanced Solid Tumor Malignancies 
Trial ID 
Sym015-01 
Trial Phases 
This is an open-label, multicenter trial composed of 2 parts: 
 
Part 1 is a Phase 1a dose-escalation in patients with KRAS proto-oncogene 
(KRAS) wild-type (WT) advanced solid tumor malignancies without available 
therapeutic options 
 
Part 2 is a Phase 2a dose-expansion in which dosing will be at the 
recommended Phase 2 dose (RP2D) on an every second week (Q2W) 
schedule. Three cohorts will be included: 
o Basket* Cohort: A cohort of approximately 25 patients with KRAS 
WT advanced solid tumor malignancies with MET-amplification, and 
without available therapeutic options.  Included in this group will be a 
subset of approximately 6 patients who have received prior therapy 
with a MET-targeting tyrosine kinase inhibitor (TKI). 
Note:  Effective with protocol version 8.0 (December 2018), accrual to the 
Basket Cohort is suspended. 
o NSCLC MET-Amplified Cohort: A cohort of approximately 20 
patients with advanced non-small cell lung carcinoma (NSCLC) with 
MET-amplification, and without available therapeutic options.  
Patients may have received prior therapy with MET-targeting and/or 
epidermal growth factor receptor (EGFR)-targeting agents. 
o NSCLC METEx14Del Cohort: A cohort of approximately 6-12 patients 
with advanced NSCLC with MET exon 14 skipping alteration      
(METEx14Del), and without available therapeutic options.  Tumors need 
not be MET-amplified, and patients may have received prior therapy 
with MET-targeting and/or EGFR-targeting agents. 
*A basket cohort is designed to evaluate the potential antitumor effects of a targeted 
therapy by enriching for patients with a defined genetic alteration (e.g., mutations in or 
overexpression of a specific gene(s)) regardless of the histotype of the enrolled patients’ 
tumors. 
Trial Sites and 
Countries 
Part 1, Dose-Escalation: 2 to 3 investigational trial sites, located within the United 
States (USA). 
Part 2: 15 to 27 investigational trial sites, located within the USA, Asia Pacific, 
and Europe.  
Planned Trial 
Period 
Part 1 of the trial is expected to begin Q1 2016.  
Patients will be enrolled in dose-escalation cohorts until establishment of a 
maximum tolerated dose (MTD) or until 24 mg/kg has been evaluated, whichever 
comes first, expected by Q1 2017. 
Enrollment to Part 2 of the trial will commence upon establishment of the Q2W 
RP2D. Enrollment is expected to complete by Q4 2019.  
The end of trial will be reached at the latest 1 month (30 +7 days) after the last 
patient has been withdrawn from Sym015. Patients will continue to be followed to 
assess duration of disease stabilization, response, and overall survival (OS). 


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Primary 
Objectives 
Primary objective of Part 1, Dose-Escalation: To assess the safety and tolerability 
of Sym015 when administered by intravenous (IV) infusion on a Q2W schedule to 
patients with KRAS WT advanced solid tumor malignancies without available 
therapeutic options. 
Primary objective of Part 2: To evaluate the antitumor activity of Sym015 when 
administered at the Q2W RP2D to patients in the following cohorts:  
 
Basket Cohort: MET-amplified, KRAS WT solid tumor malignancies 
without available therapeutic options.   
 
NSCLC MET-Amplified Cohort: MET-amplified advanced NSCLC 
without available therapeutic options. 
 
NSCLC METEx14Del Cohort: METEx14Del advanced NSCLC without 
available therapeutic options. 
Primary 
Endpoints 
Primary Endpoint of Part 1, Dose-Escalation: The occurrence of dose-limiting 
toxicities (DLT) measured during Cycle 1 of Sym015 administration on a Q2W 
(28 days equals 1 cycle) dosing schedule. 
Primary Endpoint of Part 2: Documented, confirmed objective response (OR) 
(defined as partial response [PR] or complete response [CR]), assessed by the 
Response Evaluation Criteria in Solid Tumors (Version 1.1) (RECIST v1.1) at any 
time during trial participation by Investigator assessment. 
Overall Trial 
Design  
During Part 1 of the trial, patients with KRAS WT advanced solid tumor 
malignancies will receive increasing doses of Sym015 on a Q2W schedule until 
establishment of the MTD or until 24 mg/kg has been evaluated. Dose-escalation 
will follow a standard 3+3 design with dose-escalation guided by DLTs. Patients 
in Part 1 will receive infusions of Sym015 on a Q2W schedule at the specified 
dose level until the highest planned dose has been evaluated and/or an MTD is 
identified.  
A safety monitoring committee (SMC) will be established and will include 
Investigator(s), Medical Monitor(s), and Sponsor’s medical representatives. The 
SMC will review clinical and laboratory safety data regularly throughout the trial. 
The SMC will select the Q2W RP2D to be used in Part 2 based on safety data and 
available pharmacokinetic (PK) results. 
During Part 2, three cohorts will receive Sym015 at the RP2D on a Q2W dosing 
schedule: 
 
Basket Cohort: A basket cohort of KRAS WT, advanced solid tumor 
malignancy patients with MET-amplification will be evaluated. Patients must 
be MET-targeting TKI-naïve; an exception will be a subset of approximately 
6 patients who have received prior therapy with a MET-targeting TKI. 
Note:  Effective with protocol version 8.0 (December 2018), accrual to the Basket 
Cohort is suspended. 
 
NSCLC MET-Amplified Cohort: A cohort of advanced NSCLC patients with 
MET-amplification will be evaluated.  Patients may have received prior 
therapy with MET-targeting and/or EGFR-targeting agents. 
 
NSCLC METEx14Del Cohort:  A cohort of advanced NSCLC patients with 
METEx14Del will be evaluated. Tumors need not be MET-amplified, and 
patients may have received prior therapy with MET-targeting and/or EGFR-
targeting agents. 
Trial Periods 
Prescreening: Sites may choose to prescreen patients utilizing genomic analysis 


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(e.g., Guardant360 or other similar liquid biopsy methodology) or tumor tissue 
(archival, or recently obtained if acquired outside of the screening process as part 
of the site’s usual practice) to assess MET-amplification status and METEx14Del 
status before entering patients into screening for the treatment portion of the trial. 
In this case, the site will use a separate pre-screening informed consent form. 
Screening Period: After providing informed consent, the eligibility of patients will 
be established according to the protocol-defined inclusion and exclusion criteria. 
Treatment Period: Patients in the trial will receive IV infusions of Sym015 on a 
Q2W schedule until occurrence of any of the following: Unacceptable toxicity or 
other conditions preventing further administration, progressive disease (PD), 
termination of the trial, or patient’s decision to withdraw.  
End of Treatment/Follow-up: Once Sym015 has been discontinued, an End of 
Treatment (EOT) Visit will be performed within 10 days following the decision to 
withdraw treatment. A follow-up visit will be performed 1 month after the last 
administration of Sym015.  
After the 1-Month Follow-up (1M FUP) Visit, the Investigator will make every 
effort to obtain follow-up information on response assessment and/or OS, about 
once every 2 months. Response assessment follow-up is required in the event of an 
ongoing stable disease (SD), PR, or CR at the 1M FUP Visit, until PD or another 
therapeutic intervention is initiated. Survival follow-up is required until death, 
withdrawal of consent, trial site closure, or termination/end of the trial. Occurrence 
of one of these events constitutes the end of trial for the patient.  
Number of 
Patients 
It is planned to enroll approximately 63-72 patients in total.   
Approximately 12-15 patients will receive increasing doses of Sym015 during Part 
1.  
Approximately 51-57 patients will receive Sym015 at the RP2D on a Q2W 
schedule during Part 2.  Three cohorts will be included:  
 
Basket Cohort: Approximately 25 patients with KRAS WT, advanced solid 
tumor malignancies with documented MET-amplification will be enrolled 
and treated.  A subset of approximately 6 patients will have received prior 
therapy with a MET-targeting TKI. 
Note:  Effective with protocol version 8.0 (December 2018), accrual to the Basket 
Cohort is suspended.   
NSCLC MET-Amplified patients entered to the Basket Cohort will be counted 
toward the NSCLC MET-Amplified Cohort; NSCLC METEx14Del patients entered to 
the Basket Cohort will be counted toward the NSCLC METEx14Del Cohort; patients 
with both will be counted as MET-Amplified.   
 
NSCLC MET-Amplified Cohort: approximately 20 patients with advanced 
NSCLC with documented MET-amplification will be enrolled and treated. 
Patients may have received prior therapy with MET-targeting and/or EGFR-
targeting agents. 
 
NSCLC METEx14Del Cohort: approximately 6-12 patients with advanced 
NSCLC with documented METEx14Del will be enrolled and treated. Tumors 
need not be MET-amplified, and patients may have received prior therapy 
with MET-targeting and/or EGFR-targeting agents. 
Note:  NSCLC patients with tumors identified as both MET-Amplified and 
METEx14Del will be enrolled to the MET-Amplified cohort. 
Main Inclusion 
Main inclusion criteria all patients, Part 1 and Part 2: 


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and Exclusion 
Criteria 
 
Male or female, at least 18 years of age at the time of informed consent 
 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 
or 1 
 
Life expectancy >3 months assessed during Screening 
 
Documented (histologically- or cytologically-proven) solid tumor 
malignancy that is locally advanced or metastatic, and that is refractory to 
standard therapy or for which no standard therapy is available or accessible 
(i.e., patients must have recurrent and/or progressive disease and be without 
available therapeutic options) 
Additional main inclusion criteria applicable to Part 1 patients ONLY: 
 
Tumor documented to be KRAS WT by local assessment according to 
institutional standards. If KRAS WT is not previously documented and if 
archival tissue is not available for pretrial assessment, patient must be willing 
to undergo a tumor biopsy to confirm eligibility  
 
Additional main inclusion criteria applicable to Part 2 patients ONLY: 
 
Measurable disease according to RECIST v1.1 that has been confirmed by 
computed tomography (CT) or magnetic resonance imaging (MRI) within 4 
weeks prior to Cycle 1/Day 1 (C1/D1) 
Note: Measurable disease is defined as 1 or more target lesions assessed by CT or MRI. A 
tumor lesion situated in a previously irradiated area is considered measurable only if 
subsequent PD has been documented in the lesion   
 
Basket Cohort ONLY: 
o Confirmed MET-amplification by local assessment; i.e., MET gene 
copy number to control probe ratio [G:CN] >2.2 scored in 50 tumor 
nuclei by fluorescence in situ hybridization (FISH), chromogenic in situ 
hybridization (CISH), silver in situ hybridization (SISH) or similar, or a 
copy number >5 by next-generation sequencing (NGS) or quantitative 
polymerase chain reaction (qPCR) 
Note:  Peripheral blood collection for MET-amplification assessment in ctDNA 
will be allowed as a local pre-screening methodology provided results are 3+ 
by Guardant360* analysis (or equivalent to 3+ by Guardant360 if an 
alternative Sponsor-approved methodology is used), and provided subsequent 
required confirmatory tumor tissue evaluation meets the above inclusion 
criterion.  
*http://guardanthealth.com/ 
o Tumor documented to be KRAS WT by local assessment according to 
institutional standards. If KRAS WT is not previously documented and 
if archival tissue is not available for pretrial assessment, patient must be 
willing to undergo a tumor biopsy to confirm eligibility 
Note:  Peripheral blood collection for KRAS-mutation assessment in circulating 
tumor deoxyribonucleic acid (ctDNA) (also referred to as “liquid biopsy”) will 
be allowed as a local pre-screening methodology by Guardant360* analysis. 
Other liquid biopsy methodologies, except if used to detect METEx14Del, will 
only be allowed if previously approved by the Sponsor. 
o No prior therapy with MET-targeting agents 
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Basket Cohort after having received prior therapy with a MET-targeting TKI. 
o Willingness to undergo a pre- and post-dosing biopsy (maximum of 2 
biopsies) from primary or metastatic tumor site(s) considered safely 
accessible for biopsy 
 
NSCLC MET-Amplified Cohort ONLY: 
o Documented NSCLC meeting disease criteria as defined above 
o Documented MET-amplification by either: 
 Local assessment in a recent* tumor biopsy; i.e.,  G:CN ≥3.0 
scored in 50 tumor nuclei by FISH, CISH, SISH or similar assay, 
or a copy number >5 by NGS or qPCR (subsequent central 
confirmation required; however, patient may be enrolled and 
treated based on local assessment, before central confirmation 
results have been obtained) 
*Tissue for local assessment may be from a recent tumor biopsy, defined 
as one performed since last documented disease progression as part of the 
site’s usual practice, and where no intervening antineoplastic therapy has 
been administered; otherwise tissue from a newly performed biopsy must 
be obtained and submitted.       
 Central confirmation** in a newly performed pre-dosing tumor 
biopsy; i.e.,  G:CN ≥3.0 scored in 50 tumor nuclei by FISH 
**If central confirmation of MET-amplification status cannot be assessed 
in tumor due to assay failure/technical error, the Sponsor may decide to 
enroll based on MET-amplification detected by Guardant360 on a case 
per case basis (see Note below regarding Guardant360 analysis). 
o May have received prior therapy with MET-targeting and/or EGFR-
targeting agents (antibodies or TKIs) 
o Willingness to undergo a pre-dosing biopsy (mandatory unless a 
recent* tumor biopsy as defined above is available), and potentially a 
biopsy at the End of Cycle 2 (EOC2) (optional), from a primary or 
metastatic tumor site considered safely accessible for biopsy 
Note: Peripheral blood for ctDNA analysis by Guardant360 will be obtained for 
assessment of MET-amplification status.  As data are acquired on concordance 
between findings in tumor tissue versus ctDNA, the Sponsor may decide to 
transition to screening for MET-amplification using Guardant360 analysis only 
(e.g., 2+ or 3+ amplification score) without requiring confirmation in a recent or 
newly performed tumor biopsy. 
 
NSCLC METEx14Del Cohort ONLY:  
o Documented NSCLC meeting disease criteria as defined above 
o Documented METEx14Del (tumors need not be MET-amplified) 
Note:  METEx14Del status to be documented according to local institutional 
standards.  Assessment in ctDNA by Guardant360 technology or equivalent is 
allowed.  Tissue from a recent* or newly performed pre-dosing tumor biopsy 
must be submitted for central assessment. 
*Recent tumor biopsy, defined as one performed since last documented disease 
progression as part of the site’s usual practice, and where no intervening 
antineoplastic therapy has been administered; otherwise tissue from a newly 


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performed biopsy must be obtained and submitted. 
o May have received prior therapy with MET-targeting agents and/or 
EGFR-targeting agents (antibodies or TKIs)  
o Willingness to undergo a pre-dosing biopsy (mandatory unless a 
recent* tumor biopsy as defined above is available), and potentially a 
biopsy at the EOC2 (optional), from a primary or metastatic tumor site 
considered safely accessible for biopsy 
Note: Peripheral blood for ctDNA analysis by Guardant360 will be obtained for 
assessment of METEX14Del status. 
Main exclusion criteria all patients, Part 1 and Part 2: 
 
Any antineoplastic agent for the primary malignancy (standard or 
investigational) without delayed toxicity within 4 weeks or 5 plasma half-
lives, whichever is shortest, prior to C1/D1, except:  
o Nitrosoureas and mitomycin C within 6 weeks prior to C1/D1  
 
Immunosuppressive or systemic hormonal therapy within 2 weeks prior to 
C1/D1 with specified allowed exceptions 
 
Use of hematopoietic growth factors within 2 weeks prior to C1/D1 
 
Active second malignancy or history of another malignancy within the last 3 
years, with specified allowed exceptions 
 
Central nervous system (CNS) malignancy including primary malignancies 
of the CNS and/or known, untreated CNS or leptomeningeal metastases, or 
spinal cord compression; patients with any of these not controlled by prior 
surgery or radiotherapy, or symptoms suggesting CNS involvement for 
which treatment is required 
 
Inadequate recovery from an acute toxicity associated with any prior 
antineoplastic therapy 
 
Major surgical procedure within 4 weeks prior to C1/D1 or inadequate 
recovery from any prior surgical procedure 
 
Active thrombosis, or a history of deep vein thrombosis or pulmonary 
embolism, within 1 month prior to C1/D1, unless adequately treated and 
stable 
 
Active uncontrolled bleeding or a known bleeding diathesis 
 
Significant cardiovascular disease or condition 
 
Abnormal hematologic, renal or hepatic function as defined by the following 
criteria: 
o Absolute neutrophil count (ANC) <1.5 ×109/L (1500/mm3) 
o Hemoglobin ≤9 g/dL 
o Platelet count <75 ×109/L (75,000/mm3)  
o Serum creatinine >1.5 × upper limit of normal (ULN) for the institution 
o Aspartate aminotransferase (AST) >3.5 × ULN for the institution or 
AST >5 × ULN for the institution in case of known liver metastases 
o Alanine aminotransferase (ALT) >3.5 × ULN for the institution or ALT 
>5 × ULN for the institution in case of known liver metastases  
o Total bilirubin >1.5 × ULN for the institution 
o Prothrombin time as assessed by International Normalized Ratio (INR) 
>1.5 × ULN for the institution* 


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o Partial thromboplastin time (PTT) >1.5 × ULN for the institution* 
*Unless on a stable dose of anticoagulant therapy for a prior thrombotic 
event 
 
Any of the following within 2 weeks prior to C1/D1: 
o Any serious or uncontrolled infection 
o Any infection requiring parenteral antibiotics 
o Unexplained fever >38.0 °C 
Additional main exclusion criteria applicable to Part 2 patients ONLY: 
 
Basket Cohort ONLY:  
o Prior therapy with MET-inhibiting agents 
Note:  Exceptions will be a subset of approximately 6 patients entered to the 
Basket Cohort after having received prior therapy with a MET-targeting TKI. 
o Prior therapy with antibody to hepatocyte growth factor (HGF) 
 
Basket Cohort and NSCLC MET-Amplified Cohort ONLY: Tumor status 
demonstrating MET-polysomy in the absence of MET-amplification, as 
specified 
Note: Patients in the NSCLC METEx14Del Cohort with polysomy are eligible 
 
Radiotherapy against target lesions within 4 weeks prior to C1/D1, unless 
there is documented progression of the lesion following the radiotherapy 
Investigational 
Medicinal 
Product, Dose(s) 
and Treatment 
Schedule 
The Investigational Medicinal Product (IMP) is Sym015. 
Sym015 is a recombinant antibody mixture containing 2 humanized 
immunoglobulin G1 (IgG1) monoclonal antibodies (mAbs), designated Hu9006 
and Hu9338, which bind specifically to MET, the receptor for HGF. Preclinical 
studies have shown that Sym015 effectively down-regulates the target and has a 
superior tumor growth inhibitory activity compared to other antibodies targeting 
this receptor. Sym015 is intended for the treatment of solid tumor malignancies 
with amplification of the gene encoding MET. 
 
Sym015 will be administered on a Q2W schedule by IV infusion.  
 
Q2W dosing: Day 1 and Day 15 of each 28-day cycle (± 2 days) 
Sym015 will be administered over a 1.5-hour (+10 minutes) period for doses ≥18 
mg/kg and over a 1-hour (+10 minutes) period for doses <18 mg/kg, following 
delivery of premedication prior to each infusion. In Part 2, if the patient is without 
evidence of infusion related reactions (IRRs) after Cycle 1, the Investigator may 
opt to withdraw premedication on a patient-by-patient basis with subsequent 
dosing. 
 
Part 1/Dose-Escalation 
During the dose-escalation part of the trial, the following dose levels of Sym015 
administered Q2W will potentially be evaluated in a standard 3+3 dose-escalation 
design: 
 
Dose Level 1: 6 mg/kg  
 
Dose Level 2: 12 mg/kg  
 
Dose Level 3: 18 mg/kg  


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 
Dose Level 4: 24 mg/kg  
A substitute or additional dose level, within the dose levels listed above, could 
potentially be evaluated.  
Enrollment will be staggered between the first and second patient in each new 
higher dose level tested. The first patient must have completed and tolerated the 
first dose of Sym015, including follow-up until Day 8 of Cycle 1 (C1/D8), in order 
to allow for review of clinical and laboratory assessments. Thereafter patients 
within a cohort may be added concurrently. 
 
Part 2 
Once the Q2W RP2D has been established during dose-escalation, the enrollment 
into Part 2 will commence.  
Note:  Effective with protocol version 5.0 (November 2016), following review of available 
safety and PK data, the decision has been made to choose the following as the Q2W RP2D 
of Sym015: Loading dose of 18 mg/kg infused over 1.5 hours on C1/D1, followed by Q2W 
maintenance doses of 12 mg/kg infused over 1 hour beginning on C1/D15. As the MTD 
has not yet been reached, dose-escalation will continue in Part 1 of the trial to 24 mg/kg. 
Trial 
Assessments 
All assessments will be repeated throughout the trial at protocol-specified 
intervals, unless otherwise stated. 
 
Safety Assessments 
 
Medication/Procedure survey 
 
(Serious) Adverse Event ([S]AE) survey 
 
DLT evaluation (Part 1, dose-escalation only) during Cycle 1 with a final 
assessment 14 (±2) days after the last dose of Cycle 1 or prior to dosing on 
Cycle 2/Day 1 (C2/D1) 
 
Vital signs and body weight 
 
ECOG PS 
 
Physical examination 
 
Electrocardiogram (ECG) at screening, EOT and as clinically indicated 
during trial participation 
 
Transthoracic echocardiogram (ECHO) or multi-gated acquisition (MUGA) 
scan at screening and in the event of cardiac symptoms and as otherwise 
clinically indicated during trial participation 
 
Safety blood samples 
 
Urinalysis 
 
Pregnancy test at screening, EOT, and if clinically indicated during trial 
participation 
 
Disease Assessments 
 
Disease status evaluation by CT or MRI at screening, at the EOC2 and every 
second cycle thereafter. Further potential timepoints are in the event of 
suspected PD, in the event of CR/PR and at EOT/1M FUP 
 
Tumor marker evaluation as indicated by tumor type, if applicable  
 
Archival tumor tissue for MET and KRAS assessment (Part 1 and Part 2 
Basket Cohort):  


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o For patients in Part 1, local eligibility assessment for KRAS mutational 
status will be done using archival tissue, whenever possible. If archival 
tissue is not available, a tumor biopsy will be performed for eligibility 
assessment. Assessment of MET-amplification status is not required 
for patients in Part 1, but tissue should be assessed if available 
o For patients in Part 2, local eligibility assessment for KRAS mutational 
status may be done using archival tumor tissue. If archival tissue is not 
available, tissue from the tumor biopsy performed during screening 
will be used. 
 
It is preferred that the eligibility assessment for MET-amplification 
will be done using tissue from a tumor biopsy performed during 
screening, however archival tumor tissue may be used at the 
Investigator’s discretion. 
Note:  During Part 2 ONLY, peripheral blood collection for KRAS-
mutation assessment and for MET-amplification assessment in ctDNA is 
allowed as a local pre-screening methodology by Guardant360 analysis.  
Other liquid biopsy methodologies, except if used to detect METEx14Del, 
will only be allowed if previously approved by the Sponsor. Subsequent 
required tumor tissue evaluation to confirm MET-amplification must 
meet the protocol-specified inclusion criteria. 
 
NSCLC METEx14Del Cohort (pre-protocol v8.0): Eligibility 
assessment for METEx14Del status will be done according to local 
institutional standards.  Assessment in ctDNA by Guardant360 
technology or equivalent is allowed.  Subsequent confirmation in 
tumor tissue is preferred but not required, however, archival tissue 
to be submitted for central testing, if available (applies only to 
patients with METEx14Del tumors entered prior to suspension of the 
Basket Cohort and establishment of NSCLC METEx14Del Cohort). 
 
Tumor biopsy for MET status and biomarker analysis (Part 2 NSCLC MET-
Amplified Cohort and NSCLC METEx14Del Cohort):  
o Screening (Mandatory) 
 NSCLC MET-Amplified Cohort: Required; tissue from a newly 
performed pre-dosing tumor biopsy must be submitted for central 
confirmation of MET-amplification  
(Patients may be entered and treated based on local assessment of 
a recent tumor biopsy [if available and performed outside of the 
screening process as part of the site’s usual practice] provided no 
intervening antineoplastic therapy has been administered; 
otherwise tissue from a newly performed pre-dosing biopsy must 
be obtained and submitted) 
 NSCLC METEx14Del Cohort: Required; tissue from a recent or 
newly performed pre-dosing tumor biopsy must be submitted for 
central assessment of METEx14Del  
(Patients may be entered and treated based on local institutional 
standards; alternatively, assessment in ctDNA by Guardant360 
technology or equivalent is allowed; a recent [as defined above] or 
newly performed pre-dosing biopsy must still be submitted) 
o Post-Dosing (Optional) 


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EOC2 (i.e., coinciding with time of first response assessment) or upon 
PD, whichever occurs first. 
Additional Assessments 
 
PK sampling with extended PK-profiling after the first infusion 
 
Anti-drug antibody (ADA) testing 
 
Part 1 only: Skin biopsy for biomarker analysis at screening, at the EOC2 or 
upon PD, whichever comes first 
 
Blood sample for genomic/biomarker analyses at screening, at the EOC2 or 
upon PD, whichever comes first, and at EOT 
Statistical 
Methods and 
Sample Size 
Calculation 
The primary endpoint of Part 1 of the trial is the occurrence of DLTs measured 
during Cycle 1 of Sym015 administration. The number of enrolled patients will 
depend on the extent of observed DLTs independently in each cohort. Based on a 
3+3 design, it is planned to enroll between 12 and 15 patients during dose-
escalation. 
All DLT events will be listed by dose cohort and patient. A summary table of 
DLTs by System Organ Class (SOC) and Preferred Term will be presented for 
each dose cohort, if applicable. The summaries will include number of DLTs and 
number and percentages of patients experiencing a DLT.  
The MTD is defined as the highest dose with a maximum of 1 out of 6 patients 
experiencing a DLT. The MTD may or may not be found within the dose levels 
tested. Based on an overall evaluation of the dose-escalation part, the Q2W RP2D 
and highest safe dose tested will be selected.  
In Part 2 of the trial, the primary endpoint is documented, confirmed OR, assessed 
by RECIST v1.1 at any time during trial participation by Investigator assessment. 
It is planned to include approximately 25 patients with advanced solid tumor 
malignancies, documented and confirmed as MET-amplified in the Basket Cohort, 
20 patients in the NSCLC MET-Amplified Cohort, and 6-12 patients in the 
NSCLC METEx14Del Cohort, for a total of approximately 51-57 patients in Part 2.  
The expected (target) range of OR in any of the three cohorts is in the range of 
20%-50%, depending on histology, previous therapies, and other prognostic 
factors defining the enrolled patient population.  
Number and percentages of patients with documented OR will be presented 
including corresponding 90% exact Confidence Intervals (CI). 


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2. 
LIST OF ABBREVIATIONS AND EXPANDED TERMS 
1M FUP 
1-Month Follow-up 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody-Dependent Cellular Cytotoxicity  
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST  
Aspartate Aminotransferase 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
C#/D# 
Cycle # / Day # 
CAP 
College of American Pathologists 
CEC 
Central Ethical Committee 
CI 
Confidence Interval 
CISH 
Chromogenic In Situ Hybridization 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
CTCAE v4.03 Common Terminology Criteria for Adverse Events (Version 4.03) 
CTR 
Clinical Trial Report 
DLT 
Dose-Limiting Toxicity 
DMP 
Data Management Plan 
DR 
Duration of Response 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


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EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EGFR 
Epidermal Growth Factor Receptor 
EOC 
End of Cycle 
EOI 
End of Infusion 
EOS 
End of Study 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FISH 
Fluorescence In Situ Hybridization 
FUP 
Follow-up 
G:CN 
Gene Copy Number to Control Probe Ratio 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GTP 
Gamma-Glutamyl Transpeptidase 
hCG 
Human Chorionic Gonadotropin 
HGF 
Hepatocyte Growth Factor 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormone Replacement Therapy 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IgG1 
Immunoglobulin G1 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-Related Reaction 
ISF 
Investigator Site File 
IV 
Intravenous 
KRAS 
KRAS proto-oncogene 
mAb 
Monoclonal Antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
MET proto-oncogene tyrosine kinase, hepatocyte growth factor receptor 


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MET 
MET proto-oncogene, hepatocyte growth factor receptor gene 
METEx14Del 
MET exon 14 skipping alteration 
MRI 
Magnetic Resonance Image/Imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multi-Gated Acquisition 
NE 
Not Evaluable 
NGS 
Next-Generation Sequencing 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
NSCLC 
Non-Small Cell Lung Cancer 
NYHA 
New York Heart Association 
OR 
Objective Response 
OS 
Overall Survival 
PD 
Progressive Disease 
PDF 
Portable Document Format 
PDX 
Patient-Derived Xenograft 
PFS 
Progression-free Survival 
PK 
Pharmacokinetic(s) 
PO 
Orally, by mouth 
PR 
Partial Response 
PS 
Performance Status 
PSA 
Prostate-Specific Antigen 
PTT 
Partial Thromboplastin Time 
qPCR 
Quantitative Polymerase Chain Reaction 
Q2W 
Every Second Week 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors (Version 1.1) 
RP2D 
Recommended Phase 2 Dose 
RTK 
Receptor Tyrosine Kinase 
TKI 
Tyrosine Kinase Inhibitor 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SISH 
Silver In Situ Hybridization 


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SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SOI 
Start of Infusion 
SOP 
Standard Operating Procedure(s) 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
USA 
United States 
WHO 
World Health Organization 
WT 
Wild-Type 
 
PHARMACOKINETIC TERMS 
AUC τ 
Area under the concentration-time curve in a dosing interval 
AUCNorm, τ 
Dose-normalized area under the concentration-time curve in a dosing interval 
CL 
Clearance 
Cmax 
Maximum Concentration 
Ctrough 
Trough Concentration 
Cz 
Last Quantifiable Concentration 
T½ 
Elimination Half-Life 
Tmax 
Time of Maximum Concentration 
Vz 
Volume of Distribution 
λz 
Terminal Rate Constant


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3. 
BACKGROUND AND RATIONALE  
3.1 
Disease and Treatment 
3.1.1 Solid Tumor Malignancies 
Cancers are malignant tumors formed by an abnormal growth of cells and tissue leading to organ 
failure. They fall into two categories: solid and hematological cancers. Solid tumors are formed 
by an abnormal growth of body tissue cells other than blood, bone marrow or lymphatic cells. A 
solid tumor consists of an abnormal mass of cells, which may stem from different tissue types 
such as lung, breast, colon, prostate, stomach and liver, and which initially grows in the organ of 
its cellular origin. In advanced stages of the disease, solid tumors may spread to other organs 
through metastatic tumor growth.   
Cancer is the second-leading cause of death and disability in the world, only surpassed by heart 
disease. In 2012, 14.1 million people were diagnosed with cancer worldwide. An estimated 8.2 
million people died from the disease. The World Health Organization (WHO) projected that by 
2035, these figures could increase to 24 million new cases and 14.6 million cancer deaths 
worldwide. Lung, breast, colorectal, prostate and stomach cancer are the most common 
malignancies (1). Non-small cell lung cancer (NSCLC) is the leading cause of death due to 
malignancy globally (31).  
3.1.2 MET-Amplified Solid Tumor Malignancies 
MET (MET proto-oncogene tyrosine kinase, hepatocyte growth factor receptor, also known as c-
MET) is a receptor tyrosine kinase (RTK) containing an extracellular ligand-binding domain, a 
transmembrane domain, and an intracellular domain with tyrosine kinase activity. The 
hepatocyte growth factor (HGF), also known as scatter factor, is the only known ligand for MET. 
Binding of HGF to MET leads to receptor dimerization and autophosphorylation, which activates 
downstream signaling pathways and ultimately leads to increased cell proliferation, survival, and 
motility (2).   
Dysregulation of MET or HGF activity may occur through overexpression, gene-amplification, 
mutation, or alternative splicing of MET, or through HGF ligand-induced autocrine/paracrine 
loop signaling. Such dysregulation plays a role in many cancers by facilitating cancer 
invasiveness, angiogenesis, metastasis, and tumor growth, thus leading to a more aggressive 
cancer phenotype and a poorer prognosis. Recent preclinical and clinical results have indicated 
that MET (MET proto-oncogene, hepatocyte growth factor receptor gene)-amplification confers 


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addiction to this receptor in cancer cells and make them susceptible to treatment with MET-
targeted therapeutics (3,4). 
Depending on the methodology used for detection, varying frequencies of MET amplification 
have been reported in solid tumor malignancies over the past few years. Fluorescence in situ 
hybridization (FISH) is currently considered the gold standard for detection of MET-
amplification, as this methodology makes it possible to distinguish between polysomy and true 
gene-amplification (3). In accordance with the American Society of Clinical Oncology (ASCO) 
and the College of American Pathologists (CAP) guidelines for testing of HER2 amplification 
(5), MET-amplification may be defined as positive with a MET/CEP7 ratio (CEP7 being the 
centromeric region of chromosome 7) of >2.2 (occasionally 2.0), equivocal with a ratio between 
1.8 and 2.2, and negative with a ratio of <1.8. Polysomy tends to yield a ratio in the equivocal 
range. 
In a recent study, MET-amplification (MET/CEP7 ratio >2 by FISH) was detected in 29 out of 
1,115 (2.6%) patients with advanced solid tumor malignancies (6). Tumor types where MET-
amplification was detected included adrenocortical, renal cell, gastro-esophageal, breast, ovarian, 
colorectal, biliary, bladder, salivary gland and lung carcinomas, as well as malignant melanoma. 
This study also reported MET-amplification frequencies above 10% for certain tumors, albeit 
based on a limited number of patients. Based on FISH analysis in larger cohorts of patients, 
MET-amplification has been shown to occur in 3%-4% of NSCLC (7,8,9,10) and in 4%-6% of 
gastric cancers (11,12,13). A number of studies have also demonstrated a correlation between 
MET-expression by immunohistochemistry (IHC) and MET-amplification by FISH (10,11). 
Mutations leading to skipping of MET exon 14 (METEx14Del) result in the deletion of the 
juxtamembrane domain of MET, which stabilizes and accumulates receptor on the cell surface 
and leads to enhanced signaling through the MET receptor pathway (13). MET alterations that 
result in exon 14 skipping are found in 3%-4% of lung adenocarcinomas, both in the presence 
and absence of MET-amplification and studies have demonstrated clinical benefit of targeting 
patients with tumors harboring METEx14Del (14-17). Over 100 mutations in MET-mutated cancers 
resulting in exon 14 skipping have been described (15). KRAS proto-oncogene (KRAS) mutation 
appears to be a cause of resistance to MET inhibition both in preclinical models (19) and in the 
clinic (20). According to the single study published to date that deals with the prevalence of 
KRAS mutation in MET-amplified tumors, 25% (4/16) of MET-amplified lung adenocarcinomas 
were found to harbor KRAS mutations, and alterations of both MET and KRAS were found in 
0.8% (4/519) of treatment-naïve lung adenocarcinomas (10). Because these two molecular 


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alterations are rare in NSCLC patients, testing of KRAS status in clinical trials involving anti-
MET therapy may not be warranted (10,19). 
NSCLC patients with either MET-amplification or METEx14Del have been documented to have a 
poor prognosis (32). MET-amplification was observed in 0.7% of all patients with NSCLC and 
MET mutations were observed in 2.6% of patients in this population. 
3.1.3 Current Treatment of MET-Amplified Solid Tumor Malignancies 
There are currently no approved therapeutics for targeted treatment of MET-amplified solid 
tumor malignancies. However, multiple compounds targeting the MET/HGF pathway are being 
evaluated in the clinic. These include both small-molecule tyrosine-kinase inhibitors, such as 
crizotinib, cabozantinib, tivantinib, tepotinib, and capmatinib as well as single monoclonal 
antibodies (mAbs). The small-molecule inhibitors are generally promiscuous in their target 
specificity and may have activity on additional RTKs besides MET. The activity of MET 
inhibitors in patients with NSCLC has recently been reviewed (33), and more recent data are 
cited below with respect to additional inhibitors. 
Crizotinib is an inhibitor of MET, ALK, and ROS1. Crizotinib has been approved for treatment 
of advanced NSCLC harboring ALK translocations and has shown promising results in an 
ongoing Phase 1 clinical trial in MET-amplified NSCLC patients (21). The degree of MET-
amplification, determined by FISH, correlated closely with the observed response rate; there 
were no responses in patients with tumors classed as low-level amplified, and response rates of 
20% and 50% were observed in tumors classed as having medium or high levels of MET-
amplification, respectively. 
Tepotinib is another MET tyrosine kinase inhibitor (TKI) that has been studied in Phase 1 and 
Phase 2 clinical studies.  A recent study was reported showing evidence of antitumor activity in 
patients with METEx14Del. The preliminary data documented that 60% of patients treated with 
tepotinib in this study had confirmed partial responses (PR) (34). 
Capmatinib (INC280), a MET TKI, is also in Phase 2 studies enrolling NSCLC patients with 
METEx14Del as well as in combination with gefitinib in patients with epidermal growth factor 
receptor (EGFR)-mutated MET dysregulated NSCLC. An overall response rate of 72% was 
observed in treatment-naïve patients compared to a 39% objective response rate in previously 
treated patients with advanced METEx14Del-positive NSCLC (35). 


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AMG 337 is an investigational selective MET inhibitor that has shown promising clinical 
activity. An objective response (OR) was observed in 8 out of 13 patients with MET-amplified 
gastroesophageal junction, gastric, or esophageal cancer (22). 
LY2875358 (emibetuzumab) is a humanized IgG4 anti-MET mAb that is reported to block 
ligand binding and induce target internalization. LY2875358 has demonstrated preliminary 
evidence of antitumor activity (durable PR in 2 of 13 patients) in combination with erlotinib in 
patients with tumors positive for MET-expression and is currently being evaluated in Phase 2 
trials (23).  
ABT-700 is a humanized immunoglobulin G1 (IgG1) mAb with an engineered hinge region that 
inhibits MET receptor dimerization and induces receptor internalization and antibody-dependent 
cellular cytotoxicity (ADCC) in tumor cell lines in vitro. ABT-700 has demonstrated potent 
activity as a single agent in patients with MET-amplified tumors (tumor regression in 5/8 
patients) (24).  
ARGX-111 is a third mAb that has recently entered clinical trials. ARGX-111 is a human IgG1 
mAb, which has been glyco-engineered to enhance ADCC activity. In the Phase 1 dose-
escalation trial, the only patient with a MET-amplified tumor maintained stable disease during 6 
months of treatment (25).  
3.2 
Investigational Medicinal Product 
3.2.1 Sym015 
The investigational medicinal product (IMP) tested in this trial is Sym015.  
Sym015 is a recombinant antibody mixture containing 2 humanized IgG1 mAbs, designated 
Hu9006 and Hu9338, which bind specifically to MET, the receptor for HGF. Preclinical studies 
have shown that Sym015 effectively down-regulates the target and has superior tumor growth 
inhibitory activity compared to other antibodies targeting this receptor. Sym015 is intended for 
the treatment of solid tumor malignancies with amplification of the gene encoding MET. 
Sym015 is a clear to opalescent, colorless to slightly yellow liquid to be administered as an 
intravenous (IV) infusion through a peripheral line or indwelling catheter. 
3.2.2 Mechanism of Action 
The two antibodies of Sym015 bind to non-overlapping epitopes on the SEMA-α domain of 
MET. This allows the antibodies to bind simultaneously to the receptor and effectively induce 


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receptor internalization and degradation. Through this mechanism, Sym015 effectively inhibits 
cell-proliferation and tumor growth in models where MET is constitutively activated. Moreover, 
Sym015 blocks HGF-binding to the receptor and is thus also capable of inhibiting HGF-induced 
MET phosphorylation and cell-proliferation. In addition, Sym015 induces effector functions, 
including ADCC, which may contribute to the activity observed in vivo. 
3.2.3 Summary of Non-Clinical Findings 
Sym015 demonstrates potent antitumor activity in a number of MET-dependent cell line and 
patient-derived xenograft (PDX) tumor models, including esophagogastric and NSCLC models. 
Response to Sym015 was observed in models with MET-amplification, METEx14Del, and 
autocrine HGF-expression. Sym015 also retains full efficacy in MET-amplified models in human 
HGF transgenic mice. Sym015 is in many cases superior to a LY2875358 (emibetuzumab) 
analogue and is also active in tumor models that escape treatment with this antibody. Based on 
the preclinical models, KRAS mutation appears to predict resistance to Sym015 treatment 
(25,26).  
In vivo safety and pharmacokinetics (PK) of Sym015 were evaluated in non-human primates. 
MET is evolutionarily conserved between cynomolgus monkeys and humans and Sym015 
recognizes both human and cynomolgus MET with the same, high affinity. Thus, the 
cynomolgus monkey is considered a pharmacologically relevant model in which to study toxicity 
and PK. 
In the pivotal repeat-dose toxicity study, the toxicity of Sym015 was determined following 
weekly IV infusions (30 minutes infusion time) at 15 mg/kg, 50 mg/kg, or 100 mg/kg to 
cynomolgus monkeys for 4 weeks followed by a 6-week treatment-free period in the high dose 
group. 
No unscheduled deaths occurred during the course of the study. Sym015 did not exert effects on 
cardiovascular functions and was overall well tolerated in the monkeys. However, soft, liquid, or 
loose feces were observed in treated animals, with a higher incidence in high dose males. At the 
end of the recovery period, there was no evidence of delayed onset toxicity in previously treated 
animals. 
No in vivo agonistic activity of Sym015 was observed as judged by Ki67 expression 
(proliferation marker) in liver, kidney, duodenum, and heart at study termination. Toxicokinetic 
profiles showed that all treated animals were exposed to Sym015 throughout the entire duration 


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of the study. Target engagement, documented by reduced MET expression in tissues, was 
observed for all dose levels tested. 
In the initial elimination phase, the serum half-life (T½) of Sym015 after a single dose of 15 
mg/kg ranged from 8-23 days, while in the terminal elimination phase the T½ ranged from 5-8 
days. Upon repeat, once-weekly dosing of Sym015 at 15 mg/kg, 50 mg/kg, or 100 mg/kg 
produced a 2-fold accumulation of Sym015 over a period of four weeks. 
In conclusion, the 100 mg/kg dose level is considered the no observed adverse effect level 
(NOAEL) of Sym015 in monkeys. 
For further information, refer to the Investigator’s Brochure. 
3.2.4 Summary of Clinical Findings 
3.2.4.1 
Protocol Sym015-01 
This is the first clinical trial to study Sym015. As of Amendment 5, a total of 12 patients were 
enrolled in the completed Part 1 of this trial: 3 patients at each of 4 dose levels (6 mg/kg, 12 
mg/kg, 18 mg/kg, and 24 mg/kg, dosed every second week [Q2W]). All 4 dose levels were 
considered well tolerated, no DLTs or trial drug-associated serious adverse events (SAEs) were 
reported. A total of 2 of 3 patients entered to the 18 mg/kg cohort experienced infusion-related 
reactions (IRRs) with the first dose of trial drug.  Reactions were characterized in one patient by 
nausea, a “cotton-mouth” sensation, and wheezing, and characterized in the second patient by 
cough, shortness of breath, and a transient oxygen saturation decrease to 87% that did not require 
delivery of supplemental oxygen.  In each case, the infusion was interrupted for approximately 
30 minutes while the patient was treated with a glucocorticoid and an antihistamine; upon 
resolution of symptoms, the infusion was restarted at a slower rate and completed without further 
incident.  As a result of these two events, the duration of Sym015 infusion was extended from 1 
hour to 2 hours for the affected patients, and the duration of Sym015 infusion was extended per 
protocol from 1 hour to 1.5 hours for subsequent patients entered at this dose and higher doses.  
No additional IRRs were reported with the longer duration of infusion in the remaining patients 
treated during Part 1 of the trial.  While data in this ongoing clinical trial have not been fully 
monitored, other observed trial drug-associated adverse events (AEs) noted have included fatigue 
in 2 patients, and single episodes of nausea, dyspepsia, vomiting, diarrhea, peripheral edema, 
weight decrease, and hypokalemia; all AEs were Grade 1 or Grade 2 in severity.  Part 2 of the 
study is open to accrual.   


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As of September 2018, a total of 21 MET-amplified patients and 2 METEx14Del patients have been 
enrolled in the ongoing Part 2 portion of this trial to receive Sym015 at a loading dose of 18 
mg/kg delivered over 1.5 hours, followed by Q2W maintenance doses of 12 mg/kg delivered 
over 1 hour.  In a single patient, the SAEs of Grade 3 colitis which resulted in Grade 3 septic 
shock (both possibly-related) have been reported; these 2 events occurred in a patient with 
metastatic gastric carcinoma and a history of total gastrectomy with esophagojejunostomy whose 
diarrhea present at baseline worsened after administration of 3 doses of Sym015.  In another 
patient, the SAEs of Grade 3 anasarca and Grade 3 hypoalbuminemia (both possibly related) 
have been reported. Other study drug-related AEs have been limited to Grade 2 fatigue and 
mouth sores, and Grade 1 asthenia, anorexia, gastric pain, abdominal cramping, abdominal gas, 
nausea, diarrhea, constipation, xerosis, pruritus, and voice change.  In addition to the Grade 3 
hypoalbuminemia noted, other laboratory abnormalities reported as study drug-related AEs have 
been Grade 1 in severity and have included: anemia; prolongations in prothrombin time and 
international normalized ratio (INR); and elevations in aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl transpeptidase (GTP), and blood bilirubin.  Accrual to 
the Part 2 portion of the trial continues. 
Note:  Effective with protocol version 8.0 (December 2018), accrual to the Part 2 Basket Cohort comprised of 
patients with MET-amplified solid tumor malignancies is suspended; accrual will continue to cohorts of patients 
with MET-amplified NSCLC or METEx14Del NSCLC. 
3.2.4.2 
Other Monoclonal Antibodies Targeting MET 
Based on available literature/reports, mAbs targeting MET appear to be generally well tolerated. 
No dose-limiting toxicities (DLTs) or SAEs were observed in the Phase 1 trials with LY2875358 
or ABT-700. The most frequent treatment-related AEs were nausea, vomiting, and diarrhea for 
LY2875358 and constipation, fatigue and decreased appetite for ABT-700 (23,24). Two DLTs of 
infusion-related reactions (IRRs) have been reported with the glyco-engineered ARGX-111. 
IRRs were the overall most common adverse event with this drug (likely a class effect of glyco-
engineered antibodies), followed by fatigue and nausea (25). Based on nonclinical results, 
Sym015 appears to have a safety profile similar to that of LY2875358 and ABT-700. 
3.3 
Trial Rationale 
As outlined in the sections above, recent results suggest that MET-amplification and METEx14Del 
identify small but clinically important subgroups of patients who are likely to respond to MET 
targeted therapies. The potent tumor inhibitory activity, observed in preclinical studies in models 
with MET-amplification and/or METEx14Del, suggests that Sym015 may provide a clinically 


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relevant effect in these patient populations. Based on the nonclinical pharmacology and toxicity 
testing, Sym015 is expected to continue to be well tolerated and the benefit-risk ratio for patients 
enrolled is considered to be favorable. 
3.4 
Dose Rationale 
3.4.1 Rationale for Starting Dose 
The starting dose of 6 mg/kg Sym015 has been selected based on demonstrated safety of 
Sym015 in nonclinical studies in cynomolgus monkeys (refer to Section 3.2.3). In these studies, 
dose levels that are multiples (2.5- to 17-fold) of the anticipated clinical starting dose of 6 mg/kg 
were tested to provide a safety margin. All dose levels resulted in high levels of exposure to 
Sym015. The NOAEL was determined as 100 mg/kg in cynomolgus monkeys. In addition, the 
results of nonclinical pharmacology, pharmacodynamic, PK, and toxicology studies provide 
guidance with respect to potential target serum levels of Sym015 to down-regulate MET in 
tissues and that correlate with efficacy in animal models. 
The dosing schedule to be explored in this clinical trial is based on nonclinical data documenting 
the concentrations of Sym015 required for downregulation of MET, inhibition of cancer cell 
lines in vitro, and in vivo activity in murine models. PK data (long terminal T½ and accumulation 
with weekly dosing) support the selection of the dosing schedule, dosing every second week 
(Q2W), to be evaluated in this trial. 
IV dosing is being pursued to maximize exposure to Sym015 while minimizing the potential for 
adverse effects and immunogenicity. Based on the anticipated doses required, neither 
subcutaneous nor intramuscular dosing have been considered for initial evaluation of Sym015. 
3.4.2 Rationale for Recommended Phase 2 Dose 
As of Amendment 4, following review of available safety (refer to Section 3.2.4.1) and PK data, 
the decision has been made to choose the following as the recommended Phase 2 dose (RP2D) 
on a Q2W schedule of Sym015 (referenced as the Q2W RP2D):   
 Loading dose of 18 mg/kg infused over 1.5 hours on Cycle 1/Day 1 (C1/D1) 
 Followed by Q2W maintenance doses of 12 mg/kg infused over 1 hour beginning on 
Cycle 1/Day 15 (C1/D15) 


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The rational for this choice is based upon preliminary PK data from the initial 6 mg/kg Q2W 
(N=3, 2-3 cycles) and 12 mg/kg Q2W (N=3, up to Cycle 2/Day 1) cohorts treated in the dose-
escalation phase of this trial.  These data were used to establish a population PK model.  
The summary PK parameters for these data, based on non-compartmental analysis, are listed in 
Table 1. 
Table 1 
Preliminary Sym015 Geometric Mean PK Parameters 
Dose 
Q2W 
N 
AUC0-336h 
1st dose 
(h x μg/mL) 
Cmax 
1st dose 
(μg/mL) 
Ctrough 
2nd dose 
(μg/mL) 
Cmax 
3rd dose 
(μg/mL) 
t½ 
1st dose 
(h) 
6 mg/kg 
3 
19400 
146 
35.9 
196 
158 
12 mg/kg 
3 
40000 
294 
119 
396 
213 (n=1) 
Abbreviations: AUC, area under the concentration-time curve in a dosing interval; Cmax, maximum concentration; Ctrough, trough 
concentration; h, hour; N, number of patients; Q2W, dosing every second week; t½, elimination half-life 
 
The model was used to simulate average and 90% confidence intervals for Sym015 PK profiles 
for the 18+12 mg/kg Q2W regimen, and demonstrated that pre-dose serum concentrations, 
Ctrough, are likely to be above 100 μg/mL for the vast majority of patients for all dose 
administrations. The serum concentration of 100 μg/mL has been defined as an approximate 
threshold for clinical efficacy. This has been deduced from the 750 mg Q2W dose regimen of 
another anti-MET monoclonal antibody, emibetuzumab, which has shown signs of efficacy in 
patients with MET-amplified tumors (23,28).  It is assumed that similar serum concentrations of 
Sym015 and emibetuzumab will result in similar clinical efficacy because similar potencies 
between the two compounds have been observed in preclinical in vitro and in vivo studies (refer 
to Investigator’s Brochure). In vivo studies also support that efficacy can be expected at 
concentrations above 100 μg/mL for both compounds.  
3.5 
Overall Benefits/Risk 
It is not possible to quantify the potential benefit to individual patients entering this Phase 1 trial. 
Definite, but sometimes limited, antitumor activity has been reported in many Phase 1 trials, 
including other trials of MET-targeted agents.   
In this trial there will be an ongoing assessment of the risks with periodic evaluation of safety 
data. The trial will be discontinued in the event of any new finding indicating a risk that would 
render continuation of the trial unjustifiable. 
In order to mitigate potential risks, the trial is designed to detect DLTs, if any, and to define a 
maximum tolerated dose (MTD), if this is observed in the range of doses planned for the trial. 


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Enrollment will be staggered between the first and second patient in each new higher dose level 
tested in order to ensure safety, before allowing concurrent enrollment of further patients at the 
given dose level. If the dose administered in a cohort is safe and well-tolerated, dose-escalation 
may proceed, and enrollment of subsequent cohorts may occur in order to establish a Q2W 
RP2D and to define an MTD or highest safe dose. The potential to slow infusions, interrupt 
dosing, decrease the dose administered, and discontinue administration of Sym015 in the event 
of specific AEs is outlined. In addition, steps to prevent IRRs, and measures to intervene in the 
event of their occurrence are specified.  


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4. 
TRIAL OBJECTIVES  
4.1 
Objectives of Part 1, Dose-Escalation 
4.1.1 Primary Objective 
To assess the safety and tolerability of Sym015 when administered by IV infusion on a Q2W 
schedule to patients with KRAS wild-type (WT) advanced solid tumor malignancies without 
available therapeutic options.   
4.1.2 Secondary Objectives 
1. To determine a Q2W RP2D of Sym015 
2. To evaluate the PK profile of Sym015 
3. To evaluate target-engagement in skin biopsy tissue 
4. To evaluate the immunogenicity of Sym015 
5. To evaluate potential pharmacodynamic biomarkers of Sym015 action, and estimate, if 
feasible, the magnitude of biological activity 
6. To make a preliminary evaluation of the antitumor activity of Sym015  
4.2 
Objectives of Part 2 
4.2.1 Primary Objective 
To evaluate the antitumor activity of Sym015 when administered at the Q2W RP2D to patients 
in the following cohorts:  
1. Basket Cohort: MET-amplified, KRAS WT solid tumor malignancies without available 
therapeutic options; patients may not have received prior therapy with a MET-targeting 
TKI  
2. NSCLC MET-Amplified Cohort: MET-amplified advanced NSCLC without available 
therapeutic options; patients may have received prior therapy with MET-targeting and/or 
EGFR-targeting agents   
3. NSCLC METEx14Del Cohort: METEx14Del advanced NSCLC without available therapeutic 
options; patients may have received prior therapy with MET-targeting and/or EGFR-
targeting agents 
4.2.2 Secondary Objectives 
1. To further evaluate the safety and tolerability of Sym015 when administered at the Q2W 
RP2D  
2. To further evaluate the PK profile of Sym015 when administered at the Q2W RP2D 


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3. To further evaluate the immunogenicity of Sym015 when administered at the Q2W RP2D 
4. To further evaluate potential pharmacodynamic biomarkers of Sym015 action, and 
estimate, if feasible, the magnitude of biological activity when administered at the Q2W 
RP2D 
5. Basket Cohort: To make a preliminary assessment of the antitumor activity of Sym015, 
and to evaluate all of the above secondary objectives, in a subset of approximately 6 
patients with solid tumor malignancies administered Sym015 at the Q2W RP2D after 
having received prior therapy with a MET-targeting TKI 
 


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5. 
TRIAL DESIGN 
5.1 
Overall Design and Plan 
This is an open-label, multicenter trial composed of 2 parts: 
 Part 1 is a Phase 1a dose-escalation in patients with KRAS WT advanced solid tumor 
malignancies without available therapeutic options. 
 Part 2 is a Phase 2a dose-expansion in which dosing will be at the RP2D on an every 
second week (Q2W) schedule.  Three cohorts will be included: 
o Basket* Cohort: A cohort of approximately 25 patients with KRAS WT advanced 
solid tumor malignancies with MET-amplification, and without available 
therapeutic options. Included in this group will be a subset of approximately 6 
patients who have received prior therapy with a MET-targeting TKI.   
Note:  Effective with protocol version 8.0 (December 2018), accrual to the Basket Cohort is 
suspended.  
o NSCLC MET-Amplified Cohort: A cohort of approximately 20 patients with 
advanced NSCLC with MET-amplification, and without available therapeutic 
options.  Patients may have received prior therapy with MET-targeting and/or 
EGFR-targeting agents. 
o NSCLC METEx14Del Cohort: A cohort of approximately 6-12 patients with advanced 
NSCLC with METEx14Del, and without available therapeutic options.  Tumors need 
not be MET-amplified, and patients may have received prior therapy with MET-
targeting and/or EGFR-targeting agents. 
*A basket cohort is designed to evaluate the potential antitumor effects of a targeted 
therapy by enriching for patients with a defined genetic alteration (e.g., mutations in or 
overexpression of a specific gene(s)) regardless of the histotype of the enrolled 
patients’ tumors.  
During Part 1, dose-escalation, cohorts of patients with KRAS WT advanced solid tumor 
malignancies will receive increasing doses of Sym015 on a Q2W schedule until establishment of 
the MTD or until 24 mg/kg has been evaluated. Dose-escalation will follow a standard 3+3 
design with escalation dependent upon the occurrence of DLTs. The following dose levels of 
Sym015 will potentially be evaluated: 
 Dose Level 1: 6 mg/kg  


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 Dose Level 2: 12 mg/kg  
 Dose Level 3: 18 mg/kg  
 Dose Level 4: 24 mg/kg  
An MTD may or may not be reached in the range of doses tested. 
A safety monitoring committee (SMC) will be established and will include Investigator(s), 
Medical Monitor(s), and Sponsor’s medical representatives. The SMC will review clinical and 
laboratory safety data regularly throughout the trial. The SMC will select the Q2W RP2D to be 
used in Part 2 based on safety data and available PK results.  
Note:  Effective with protocol version 5.0 (November 2016), following review of available safety and PK 
data, the decision has been made to choose the following as the Q2W RP2D of Sym015:  Loading dose of 
18 mg/kg infused over 1.5 hours on C1/D1, followed by Q2W maintenance doses of 12 mg/kg infused 
over 1 hour beginning on C1/D15. As the MTD has not yet been reached, dose-escalation will continue in 
Part 1 of the trial to 24 mg/kg. 
During Part 2, three cohorts will receive Sym015 at the RP2D on a Q2W dosing schedule: 
 Basket Cohort: A basket cohort of KRAS WT, advanced solid tumor malignancy patients 
with MET-amplification will be evaluated. Patients must be MET-targeting TKI-naïve; an 
exception will be a subset of approximately 6 patients entered who have received prior 
therapy with a MET-targeting TKI. 
Note:  Effective with protocol version 8.0 (December 2018), accrual to the Basket Cohort is suspended. 
 NSCLC MET-Amplified Cohort: A cohort of advanced NSCLC patients with MET-
amplification will be evaluated.  Patients may have received prior therapy with MET-
targeting and/or EGFR-targeting agents. 
 NSCLC METEx14Del Cohort: A cohort of advanced NSCLC patients with METEx14Del will 
be evaluated. Tumors need not be MET-amplified, and patients may have received prior 
therapy with MET-targeting and/or EGFR-targeting agents.  
The trial design is shown in Figure 1. 


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Figure 1 
Overall Trial Design  
 
 
Abbreviations: EGFR, epidermal growth factor receptor; Dec, December; KRAS, KRAS proto-oncogene; MET, MET proto-oncogene; 
METEx14Del, MET exon 14 skipping alteration; N, number of patients; NSCLC, non-small cell lung carcinoma; Q2W, dosing every second 
week; RP2D, recommended Phase 2 dose; TKI, tyrosine kinase inhibitor; WT, wild-type 
 
Part 1 will be conducted in the United States (USA). Part 2 will be conducted in the USA and 
countries within the Asia Pacific and European regions. The number of investigational trial sites, 
hereafter called “trial sites”, expected to participate, will be approximately 2 to 3 in Part 1 and 15 
to 27 in Part 2.  
5.2 
Discussion of Trial Design 
5.2.1 Rationale for Trial Design 
Part 1 of this trial utilizes a standard dose-cohort escalation with groups of a minimum of three 
patients evaluated for safety and tolerability of Sym015 in each cohort.  In the event of a DLT, a 
cohort will be expanded to six patients.  If tolerability is demonstrated (0/3 DLT, 1/6 DLT) in 
any cohort, escalation to the next dose level will be permitted. This part of the trial is designed to 
select a safe and well-tolerated dose of Sym015 on a Q2W schedule. Part 2 of this trial is 


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designed to evaluate the antitumor activity of Sym015 administered at the selected RP2D on a 
Q2W schedule.  
The choice of a basket cohort (i.e., patients with MET-amplified, KRAS WT, advanced solid 
tumor malignancies of any tissue origin) for Part 2 is expected to allow for effective recruitment 
of patients with this relatively rare molecular alteration within a reasonable period of time. 
Emerging literature allowed for the identification of specific tumor types that are more likely to 
respond to Sym015 treatment (e.g., NSCLC).  
Note:  Effective with protocol version 8.0 (December 2018), accrual to the Basket Cohort is suspended. 
5.2.2 Rationale for Trial Population 
In Part 1, patients with KRAS WT advanced solid tumor malignancies without other treatment 
options will be entered in order to evaluate the safety and tolerability of Sym015.  
In Part 2, patients with MET-amplified, KRAS WT, advanced solid tumor malignancies of any 
tissue origin will be entered to evaluate the antitumor activity of Sym015 in the Basket Cohort. 
In addition, a cohort of NSCLC patients with MET-amplification and a cohort of NSCLC 
patients with METEx14Del will be entered to evaluate the antitumor activity of Sym015 in these 
populations.  
Nonclinical studies have documented that the activity of Sym015 is greater in tumors with MET-
amplification and/or METEx14Del, suggesting that Sym015 may provide a clinically relevant effect 
in these patient populations.  Similar findings have been observed in preliminary studies in 
patients with MET-amplified tumors with other anti-MET mAbs in early clinical trials. 
5.3 
Schedule of Events 
The overall trial plan is introduced in Table 2 and further defined in the following sections. 


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Table 2 
Overall Trial Plan 
Screening Period 
Screening 
Within 14 days prior to the first dose of Sym015 
Treatment Period 
Treatment Allocation 
The allocated dose and dosing schedule of Sym015 will depend upon cohort 
assignment and will be confirmed in writing by the Sponsor or designee on 
the Screening and Allocation Form. 
Sym015 
Sym015 will be initiated on C1/D1 and will be administered by IV infusion 
in cycles of treatment: 
 
Q2W dosing 
o 
Day 1 and Day 15 of each 28-day cycle (± 2 days) 
Sym015 will be administered following delivery of premedication prior to 
each infusion. In Part 2, if the patient is without evidence of IRRs after 
Cycle 1, the Investigator may opt to withdraw premedication on a patient-
by-patient basis with subsequent dosing. 
Discontinuation of Sym015 
Treatment will continue until unacceptable toxicity or other conditions 
preventing further treatment, PD, termination of the trial, or patient’s 
decision to withdraw. 
End of Treatment 
End of Treatment Visit 
Within 10 days following the decision to discontinue Sym015, an EOT Visit 
must be performed. 
Follow-up 
1-Month Follow-up Visit 
Follow-up continues until 1 month (30 + 7 days) after the last dose of 
Sym015. At that time, a 1M FUP Visit must be performed.  
Continued follow-up for 
response and/or for OS 
After the 1M FUP Visit, the Investigator will make every effort to obtain 
follow-up information on response assessment and/or OS about once every 2 
months. Response assessment follow-up is required in the event of an 
ongoing SD, PR or CR at the 1M FUP Visit, until PD or another therapeutic 
intervention is initiated. Survival follow-up is required until death, 
withdrawal of consent, trial site closure, or termination/end of the trial.  
Occurrence of one of these events constitutes the end of study (EOS) for the 
patient. 
The continued follow-up does not require an in-person visit at the trial site, 
but may be obtained by collection of data/documentation. 
Abbreviations (in alphabetical order): C1/D1, Cycle 1/Day 1; CR, complete response; EOS, End of Study; EOT, End of Treatment Visit; 
IRR, infusion-related reaction; 1M FUP, 1-Month Follow-up Visit; OS, overall survival; PD, progressive disease, PR, partial response; Q2W, 
every second week; SD, stable disease 
 
5.3.1 Prescreening for MET-amplification and METEx14Del Status 
The trial site may choose to prescreen patients utilizing genomic analysis (e.g., Guardant360 or 
other similar liquid biopsy methodology) or tumor tissue (archival, or recently obtained if 
acquired outside of the screening process as part of the site’s usual practice) to assess MET-
amplification status and METEx14Del status before entering patients into screening for the 
treatment portion of the trial. In this case, the site will use a separate pre-screening informed 
consent form.   


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Peripheral blood collection for assessment in circulating tumor deoxyribonucleic acid (ctDNA) 
(also referred to as “liquid biopsy”) may be used as a local pre-screening methodology by 
Guardant360 analysis (http://guardanthealth.com).  Other liquid biopsy methodologies, if used to 
detect METEx14Del, are acceptable alternatives.     
All patients giving informed consent for prescreening will receive a unique prescreening number. 
This number is composed of the prefix “PS”, followed by a three-digit number, allocated 
sequentially starting from 001, i.e.. PS001, PS002, PS003, etc. The trial site must maintain a 
prescreening log detailing the results for prescreened patients. This log will list the patient’s 
prescreening number, and if the patient continues into full screening, the patient’s unique patient 
number as defined in the following section.  
5.3.2 Screening 
When the trial site identifies a patient suitable for screening, the Sponsor or designee should be 
contacted to ensure that a cohort is open for inclusion (applies to Part 1 only). With this 
assurance, the patient may be approached for informed consent. Screening activities may begin 
only once written informed consent has been obtained. 
All patients giving informed consent to participate in the trial will receive a unique patient 
number. This number will identify the patient throughout the trial and will be composed of: a 
five-digit prefix, which identifies the country and site; a three-digit number, allocated 
sequentially starting from 001 for the first patient screened at the site, 002 for the second patient 
screened, etc. 
The trial site staff must complete a Screening and Allocation Form, stating the allocated patient 
number along with the planned dates of screening and the day of first scheduled Sym015 
administration (C1/D1). The planned date of C1/D1 will be agreed upon in collaboration with 
Sponsor or designee for the dose-escalation cohorts in order to ensure adequate time between 
dosing of the first patient and dosing of subsequent patients within each cohort (applies to Part 1 
only). The completed Screening and Allocation Form will then be sent to the Sponsor or 
designee prior to or on the day of Screening. 
Once eligibility has been confirmed in accordance with the inclusion and exclusion criteria, the 
Screening and Allocation Form will be fully completed and signed by the Investigator and resent 
to the Sponsor or designee. Sponsor or designee will approve each patient for start of treatment. 
A copy of the fully executed Screening and Allocation Form will be returned to the trial site for 
archiving. This form documents the allocated dose and dosing schedule of Sym015. 


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 Part 1: Patients in Part 1 with known MET-amplification who consent to optional biopsies 
will have a biopsy performed for biomarker analysis (archival tissue or tissue from a 
biopsy performed during screening as part of eligibility assessment may be submitted) 
 Basket Cohort: All patients in the Part 2 Basket Cohort will have a tumor biopsy 
performed for biomarker analysis (tissue from a biopsy performed during screening as 
part of eligibility assessment is preferred, however archival tissue may be submitted at 
the Investigator’s discretion).   
 NSCLC MET-Amplified Cohort: All patients in the Part 2 NSCLC MET-Amplified 
Cohort will have a tumor biopsy performed and submitted for central confirmation of 
MET-amplification status, and for biomarker analysis.   
Note: Peripheral blood for ctDNA analysis by Guardant 360 will be obtained for assessment of 
MET-amplification status. If central confirmation of MET-amplification status cannot be assessed 
in tumor due to assay failure/technical error, the Sponsor may decide to enroll based on MET-
amplification detected by Guardant360 on a case per case basis. As data are acquired on 
concordance between findings in tumor tissue versus ctDNA, the Sponsor may decide to 
transition to screening for MET-amplification using Guardant360 analysis only (e.g., 2+ or 3+ 
amplification score) without requiring confirmation in a recent or newly performed tumor biopsy. 
 NSCLC METEx14Del Cohort: All patients in the Part 2 NSCLC METEx14Del Cohort will 
have a tumor biopsy performed and submitted for central assessment of METEx14Del 
status, and for biomarker analysis.   
 All patients in Part 1 will have a skin biopsy performed for biomarker analysis 
 All patients in Part 1 and Part 2 will have a blood sample taken for biomarker analysis 
All safety screening activities must be performed within 14 days prior to C1/D1, unless 
otherwise specified. Individual safety screening assessments may be repeated prior to C1/D1, if 
justified and documented by the Investigator. 
5.3.3 Screening Failures 
A patient found not eligible after giving informed consent to the trial is considered a screening 
failure. The Screening and Allocation Form must be completed and sent to the Sponsor or 
designee to confirm the outcome of the screening process. 
Re-screening of a patient will be allowed, if justified and documented by the Investigator. 


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5.3.4 Treatment 
On the day of the first scheduled Sym015 infusion (C1/D1) and prior to the start of infusion 
(SOI), the Investigator must assess whether any changes have occurred in the clinical state of the 
patient, which would exclude the patient from the trial.  
Sym015 will be administered on a Q2W schedule by IV infusion: 
 Q2W dosing: Day 1 and Day 15 of each 28-day cycle (± 2 days) 
There will be no intra-patient dose-escalation.  
For all patients, the dose to be administered and the dosing schedule will be documented on the 
Screening and Allocation Form.  
In the event of toxicity due to Sym015, dosing may be delayed, and/or the dose may be reduced, 
as described in Section 7.1.4. 
Treatment will continue until unacceptable toxicity or other conditions preventing further 
treatment, progressive disease (PD), termination of the trial, or patient’s decision to withdraw. 
5.3.5 End of Treatment and Follow-up Visits 
An End of Treatment (EOT) Visit will be performed for all patients within 10 days following the 
decision to discontinue treatment. 
The patient will return for a 1-Month Follow-up Visit (1M FUP) 30 (+7) days after the last dose 
of Sym015.  
After the 1M FUP Visit, the Investigator will make every effort to obtain follow-up information 
on response assessment and/or overall survival (OS) about once every 2 months. Response 
assessment follow-up is required in the event of an ongoing stable disease (SD) or objective 
response (OR, defined as PR or complete response [CR]), as per the Response Evaluation 
Criteria in Solid Tumors (Version 1.1) (RECIST v1.1) (29) at the 1M FUP Visit, until PD or 
another therapeutic intervention is initiated. Survival follow-up is required until death, 
withdrawal of consent, trial site closure, or termination/end of the trial.  Occurrence of one of 
these events constitutes the EOS for the patient.  This continued follow-up does not require an 
in-person visit at the trial site, but may be obtained by collection of data/documentation. 


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5.3.6 Flow Chart – Schedule of Assessments 
Schedules of assessments are provided in the trial flow charts in Table 3 (Part 1 and Part 2 
Basket Cohort) and Table 4 (Part 2 NSCLC Cohorts). 
All efforts should be made to perform assessments as close as possible to the scheduled time 
points. Visit windows are included in the flow chart.  
The projection of visit days within each cycle must be made from Day 1 of the respective cycle. 
Furthermore, each new cycle must be initiated as soon as possible after completion of the 
previous cycle in order to achieve the Q2W dosing schedule.


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Table 3 
Flow Chart: Schedule of Assessments (Part 1 and Part 2 Basket Cohort) 
Pre-Treatment Period 
Treatment Period1 
Post-Treatment Period2 
 
Screening 
Cycle 1 
Cycle 2, 4, 6 etc. 
Cycle 3, 5, 7 
etc. 
EOT 
1M FUP2 
Day within Cycle 
Visit Window (± days) 
D-14 to D-1 
D1 
D3 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D1 
(±2) 
D15 
(±2) 
 
End of 
Cycle 
D1 
(±2) 
D15 
(±2) 
≤ 10 d 
following the 
decision of trial 
treatment 
withdrawal 
1 month after last 
dose of trial 
treatment 
(30+7d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Characteristics/Eligibility3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Medication/Procedure Survey 
X 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
(S)AE Survey and Reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLT Evaluation4 
Part 1/Dose-Escalation only 
 
X 
X 
X 
X 
X 
C2 only 
 
 
 
 
 
 
Vital Signs and Body Weight 
X 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
ECOG PS5 
X 
X5 
 
 
 
 
X 
 
 
X 
 
X 
X 
Physical Examination5 
X 
X5 
 
 
 
 
X 
 
 
X 
 
X 
X 
ECG6 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
ECHO or MUGA scan7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Safety blood samples5,8 
X 
X5 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urinalysis5,8 
X 
X5 
 
 
X 
 
X 
 
 
X 
 
X 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Disease Assessments 
Disease Status Evaluation by CT/ MRI9 
X 
 
 
 
 
 
 
 
X 
 
 
X10 
X10 
Tumor Marker Evaluation11 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Archival Tumor Tissue (may include pre-
screening by liquid bx)12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsy13 
X13 
 
 
 
 
 
 
 
C2 only13 
 
 
 
 
Additional Assessments 
PK Samples14 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
ADA Sample15 
 
X 
 
 
 
 
C2 
only15 
 
 
X 
 
X 
X 
Skin Biopsy16 
Part 1/Dose-Escalation only 
X 
 
 
 
 
 
 
 
C2 only16 
 
 
 
 
Biomarker Blood Sample17 
X 
 
 
 
 
 
 
 
C2 only17 
 
 
X 
 
Trial Treatment 
Sym015 Premedication18 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Sym015 Infusion 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Post-Infusion Monitoring 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 


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Abbreviations (in alphabetical order): ADA, anti-drug antibody; Bx, biopsy; C, Cycle; CT, computed tomography scan; D/d, day(s); DLT, dose-limiting toxicity; EOT, End of Treatment Visit; ECG, 
electrocardiogram; ECHO, transthoracic echocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; MRI, magnetic resonance imaging; MUGA, multi-gated acquisition scan; 
1M FUP, 1-Month Follow-up Visit; PK, pharmacokinetic; Q2W, every second week; (S)AE, (serious) adverse event; TX, therapy 
 
1) 
The treatment period continues until the patient is withdrawn from Sym015. 
2) 
After the 1M FUP Visit, the Investigator will make every effort to obtain follow-up information on response assessment and/or OS about once every 2 months. Response assessment follow-up is 
required in the event of an ongoing SD, PR or CR at the 1M FUP Visit, until PD or another therapeutic intervention is initiated. Survival follow-up is required until death, withdrawal of consent, 
trial site closure, or termination/end of the trial. This continued follow-up does not require an in-person visit at the trial site, but may be obtained by collection of data/documentation. 
3) 
Screening assessments include demographics, medical history, tumor histology, mutation status, extent of disease, prior anti-cancer treatment, etc. 
4) 
DLT evaluation, applicable for Part 1/dose-escalation cohorts only: DLTs are reported during Cycle 1 with a final assessment 14 (±2) days after the last dose of Cycle 1 or prior to dosing on 
C2/D1.  
5) 
Does not need to be performed prior to C1/D1 if performed during screening ≤ 7 days from C1/D1. 
6) 
In addition to the scheduled timepoints, an ECG should be performed if clinically indicated.  
7) 
In addition to the scheduled timepoint, an ECHO/MUGA should be performed in the event of cardiac symptoms and as otherwise clinically indicated. 
8) 
Local laboratory results must be available and assessed prior to each Sym015 infusion. Refer to Section 8.2.9 for details. 
9) 
CT or MRI imaging schedule and conditions, applying to all cohorts: 
 
A CT/MRI performed within 28 days prior to C1/D1 can be used for evaluation of eligibility and as baseline scan, provided that the CT/MRI has been performed according to the protocol 
requirements. 
 
The first CT/MRI assessment for response is done at the end of Cycle 2 and thereafter repeated at the end of every second cycle (in the week prior to Day 1 of the next cycle) 
 
In the event of suspected PD, a CT/MRI is to be performed as soon as possible.  
 
In the event of CR/PR, a confirmatory CT/MRI is to be performed no earlier than 28 days after the first assessment of CR/PR.   
10) A CT/MRI at EOT should only be performed if the previous CT/MRI has been performed >3 weeks before. A CT/MRI scan at 1M FUP should only be performed if no CT/MRI documents PD 
before or at EOT. 
11) Tumor maker evaluation to include tumor markers that are part of the trial site standard practices as indicated by tumor type, if applicable. 
12) Archival tumor tissue: To be assessed locally. Does not need to be repeated if MET-amplification and KRAS mutational status have been assessed previously and the pathology report is available to 
document findings.   
For Part 2-Basket Cohort: It is preferred that the local eligibility assessment for MET-amplification will be done using tissue from a tumor biopsy performed during screening, however archival 
tumor tissue may be used at the Investigator’s discretion. If archival tissue is not available, tissue from a tumor biopsy performed during screening will be used.  Peripheral blood collection for 
KRAS-mutation assessment and for MET-amplification assessment in ctDNA (liquid biopsy) is allowed as a local pre-screening methodology by Guardant360 analysis. Other liquid biopsy 
methodologies, except if used to detect METex14 mutation, will only be allowed if previously approved by the Sponsor. 
For Part 2-NSCLC Cohort: Archival tissue to be submitted, if available       
13) Tumor biopsy: To be assessed locally as part of eligibility assessment in Part 1 and Part 2, if applicable. Optional for patients with known MET-amplification enrolled in Part 1  
For Part 2-Basket Cohort: Required, to be assessed centrally. Tissue from a tumor biopsy performed during screening is preferred, however archival tissue may be submitted for central analysis 
at the Investigator’s discretion, provided the archival tissue is suitable for central analysis. Sampling for central analysis to be repeated at the end of Cycle 2 or upon PD, whichever occurs first. 
Refer to Section 8.3.4 for details. 
For Part 2-NSCLC Cohort: Biopsies are optional at the timepoints specified 
14) Extended PK sampling for PK profiling will be done starting C1/D1. Refer to Table 9 for details.  
15) Only applicable for Part 2: ADA sample on first day of Cycle 2, prior to dosing. 
16) Only applicable for Part 1: Skin biopsy is obtained during screening after patient eligibility has been confirmed. Sampling is repeated at the end of Cycle 2 or upon PD, whichever occurs first.  
17) Biomarker blood sample is taken during screening after patient eligibility has been confirmed. Sampling is repeated at the end of Cycle 2 or upon PD, whichever occurs first, and at EOT. If a tumor 
biopsy is collected at the same time point as the biomarker blood sample, the biomarker blood sample should be collected prior to collecting the tumor biopsy.  
18) For Part 1 of the trial, premedication is mandatory prior to each dose of Sym015.  For Part 2 of the trial, premedication is mandatory prior to each dose of Sym015 during Cycle 1. In Part 2, 
premedication may be withdrawn after Cycle 1 on a patient-by-patient basis if the patient is without evidence of infusion related reactions. Refer to Section 7.2.1 for details. 
 


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Table 4 
Flow Chart: Schedule of Assessments (Part 2 NSCLC Cohorts) 
Pre-Treatment Period 
Treatment Period1 
Post-Treatment Period2 
 
Screening 
Cycle 1 
Cycle 2, 4, 6 etc. 
Cycle 3, 5, 7 etc. 
EOT 
1M FUP 
Day within Cycle 
Visit Window (± days) 
D-14 to D-1 
D1 
D3 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D1 
(±2) 
D15 
(±2) 
 
 
EOC 
D1 
(±2) 
D15 
(±2) 
≤ 10 d 
following the 
decision of trial 
treatment 
withdrawal 
1 month after last 
dose of trial 
treatment 
(30+7d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Characteristics/Eligibility3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Medication/Procedure Survey 
X 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
(S)AE Survey and Reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Body Weight 
X 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
ECOG PS4 
X 
X4 
 
 
 
 
X 
 
 
X 
 
X 
X 
Physical Examination4 
X 
X4 
 
 
 
 
X 
 
 
X 
 
X 
X 
ECG5 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
ECHO or MUGA scan6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Safety blood samples4,7 
X 
X4 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urinalysis4,7 
X 
X4 
 
 
X 
 
X 
 
 
X 
 
X 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Disease Assessments 
Disease Status Evaluation by CT/MRI8 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Tumor Biopsy9 
X 
 
 
 
 
 
 
 
EOC2 only 
optional 
 
 
 
 
Additional Assessments 
PK Samples10 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
ADA Sample 
 
X 
 
 
 
 
C2 only 
 
 
X 
 
X 
X 
Genomic/Biomarker Blood Sample11 
X 
 
 
 
 
 
 
 
EOC2 only 
 
 
X 
 
Trial Treatment 
Sym015 Premedication12 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Sym015 Infusion 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Post-Infusion Monitoring 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Abbreviations (in alphabetical order): ADA, anti-drug antibody; Bx, biopsy; C, Cycle; CT, computed tomography scan; D/d, day(s); DLT, dose-limiting toxicity; EOC, End of Cycle; EOT, End of 
Treatment Visit; ECG, electrocardiogram; ECHO, transthoracic echocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; MRI, magnetic resonance imaging; MUGA, 
multi-gated acquisition scan; 1M FUP, 1-Month Follow-up Visit; PK, pharmacokinetic; Q2W, every second week; (S)AE, (serious) adverse event; TX, therapy 
 
1) 
Treatment Period: The treatment period continues until the patient is withdrawn from Sym015. 
2) 
Post-treatment Period: After the 1M FUP Visit, the Investigator will make every effort to obtain follow-up information on response assessment and/or OS about once every 2 months. Response 
assessment follow-up is required in the event of an ongoing SD, PR or CR at the 1M FUP Visit, until PD or another therapeutic intervention is initiated. Survival follow-up is required until death, 
withdrawal of consent, trial site closure, or termination/end of the trial. This continued follow-up does not require an in-person visit at the trial site, but may be obtained by collection of 
data/documentation. 


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3) 
Baseline Characteristics/Eligibility: Screening assessments include demographics, medical history, tumor histology, mutation status, extent of disease, prior anti-cancer treatment, etc. 
4) 
Safety Assessments: Does not need to be performed prior to C1/D1 if performed during screening ≤ 7 days from C1/D1. 
5) 
ECG: In addition to the scheduled timepoints, an ECG should be performed if clinically indicated.  
6) 
ECHO/MUGA: In addition to the scheduled timepoint, an ECHO/MUGA should be performed in the event of cardiac symptoms and as otherwise clinically indicated. 
7) 
Blood Safety Samples/Urinalysis: Local laboratory results must be available and assessed prior to each Sym015 infusion. Refer to Section 8.2.9 for details. 
8) 
Disease Status Evaluation: CT or MRI imaging schedule and conditions: 
 
A CT/MRI performed within 28 days prior to C1/D1 can be used for evaluation of eligibility and as baseline scan, provided that the CT/MRI has been performed according to the protocol 
requirements. 
 
The first CT/MRI assessment for response is done at the EOC2 and thereafter repeated at the end of every second cycle (EOC assessments may be performed at any time during the week 
prior to Day 1 of the next cycle, including Day 1 of the next cycle prior to dosing, provided results are available prior to study drug administration) 
 
In the event of suspected PD, a CT/MRI is to be performed as soon as possible.  
 
In the event of CR/PR, a confirmatory CT/MRI is to be performed no earlier than 28 days after the first assessment of CR/PR.   
 
A CT/MRI at EOT should only be performed if the previous CT/MRI has been performed >3 weeks before. A CT/MRI scan at 1M FUP should only be performed if no CT/MRI documents 
PD before or at EOT. 
9) 
Tumor Biopsy: Recent or newly performed biopsies are mandatory at screening; it is permissible to perform the screening procedure outside the 14-day screening period provided informed consent 
for the trial has been obtained.  EOC2 tumor biopsies (coinciding with time of first response assessment) or upon PD, whichever occurs first, are optional.   
10) PK Samples: Extended PK sampling for PK profiling will be done starting C1/D1. Refer to Table 9 for details. 
11) Genomic/Biomarker Blood Sample: It is permissible to obtain the screening sample outside the 14-day screening period provided informed consent for the trial has been obtained. Subsequent 
samples to be obtained: EOC2 (coinciding with time of first response assessment) or upon PD, whichever occurs first; EOT (if after EOC2; need not repeat if patient is discontinuing at the EOC2 
or if a sample was obtained upon PD).  If a tumor biopsy is collected at the same time point as the biomarker blood sample, the biomarker blood sample should be collected prior to collecting the 
tumor biopsy.  
12) Premedication: Mandatory prior to each dose of Sym015 during Cycle 1; may be withdrawn after Cycle 1 on a patient-by-patient basis if the patient is without evidence of infusion related 
reactions. Refer to Section 7.2.1 for details. 


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5.4 
Recruitment Period 
Part 1 of the trial is expected to begin Q1 2016.  
Patients will be sequentially enrolled to dose-escalation cohorts until completion of Dose Level 4 
or establishment of an MTD, whichever comes first, expected by Q1 2017. 
Enrollment to Part 2 of the trial will commence upon establishment of the Q2W RP2D. 
Enrollment is expected to complete by Q4 2019. 
5.5 
Number of Patients 
In total, approximately 63-72 patients will be included in this trial. 
It is estimated that approximately 12-15 patients will be enrolled to receive increasing doses of 
Sym015 during Part 1. The exact number of patients will depend upon the observed tolerability 
of Sym015 and the potential for adding additional patients to a cohort to assure a sufficient 
number of evaluable patients per cohort. For details, refer to Section 7.1.3.2. 
It is estimated that approximately 51-57 patients will be enrolled to receive Sym015 at the RP2D 
on a Q2W schedule during Part 2. Three cohorts will be included: 
 Basket Cohort: Approximately 25 patients with KRAS WT, advanced solid tumor 
malignancies with documented MET-amplification will be enrolled and treated. A subset 
of approximately 6 patients will have received prior therapy with a MET-targeting TKI.  
Note:  Effective with protocol version 8.0 (December 2018), accrual to the Basket Cohort is 
suspended. 
NSCLC MET-Amplified patients entered to the Basket Cohort will be counted toward the 
NSCLC MET-Amplified Cohort; NSCLC METEx14Del patients entered to the Basket Cohort will be 
counted toward the NSCLC METEx14Del Cohort; patients with both will be counted as MET-
Amplified. 
 NSCLC MET-Amplified Cohort: approximately 20 patients with advanced NSCLC with 
documented MET-amplification will be enrolled and treated. Patients may have received 
prior therapy with MET-targeting agents and/or EGFR-targeting agents. 
 NSCLC METEx14Del Cohort: approximately 6-12 patients with advanced NSCLC with 
documented METEx14Del will be enrolled and treated. Tumors need not be MET-amplified, 
and patients may have received prior therapy with MET-targeting and/or EGFR-targeting 
agents.   
Note:  NSCLC patients with tumors identified as both MET-Amplified and METEx14Del will be 
enrolled to the MET-Amplified cohort. 


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For details regarding the sample size considerations, refer to Section 10.1. 
5.6 
End of Trial 
The end of trial will be reached at the latest 1 month (30 +7 days) after the last patient has been 
withdrawn from Sym015.  


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6. 
PATIENT SELECTION AND WITHDRAWAL 
Questions regarding patient eligibility must be addressed and resolved by the Investigator in 
consultation with the Sponsor or designee prior to enrollment. 
6.1 
Inclusion Criteria 
For inclusion in the trial, all of the following criteria must be fulfilled: 
1. Written informed consent given before any trial-specific procedure is initiated 
2. Male or female, at least 18 years of age at the time of informed consent 
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 
4. Life expectancy >3 months assessed during Screening 
5. Documented (histologically- or cytologically-proven) solid tumor malignancy that is 
locally advanced or metastatic, and that is refractory to standard therapy or for which no 
standard therapy is available or accessible (i.e., patients must have recurrent and/or 
progressive disease and be without available therapeutic options) 
6. Part 1 ONLY: Tumor documented to be KRAS WT by local assessment according to 
institutional standards. If KRAS WT is not previously documented and if archival tissue is 
not available for pretrial assessment, patient must be willing to undergo a tumor biopsy to 
confirm eligibility 
7. Part 2 ONLY: 
a. Measurable disease according to the RECIST v1.1 that has been confirmed by 
computed tomography (CT) or magnetic resonance imaging (MRI) within 4 weeks 
prior to C1/D1 
Note: Measurable disease is defined as 1 or more target lesions assessed by CT or MRI. A 
tumor lesion situated in a previously irradiated area is considered measurable only if 
subsequent PD has been documented in the lesion 
b. Basket Cohort ONLY: 
 Tumor documented to be KRAS WT by local assessment according to 
institutional standards. If KRAS WT is not previously documented and if 
archival tissue is not available for pretrial assessment, patient must be willing to 
undergo a tumor biopsy to confirm eligibility.   
Note:  Peripheral blood collection for KRAS-mutation assessment in ctDNA will be 
allowed as a local pre-screening methodology by Guardant360* analysis.  Other liquid 
biopsy methodologies, if used to detect METEx14Del, are acceptable alternatives. 
*<http://guardanthealth.com> 
 Confirmed MET-amplification by local assessment; i.e., MET gene copy 
number to control probe ratio [G:CN] >2.2 scored in 50 tumor nuclei by FISH, 
chromogenic in situ hybridization (CISH), silver in situ hybridization (SISH) or 


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similar (5), or a copy number >5 by next-generation sequencing (NGS) or 
quantitative polymerase chain reaction (qPCR) 
Note:  Peripheral blood collection for MET-amplification assessment in ctDNA will be 
allowed as a local pre-screening methodology provided results are 3+ by Guardant360* 
analysis (or equivalent to 3+ by Guardant360 if an alternative Sponsor-approved 
methodology is used), and provided subsequent required confirmatory tumor tissue 
evaluation results meet the above inclusion criterion.   
*<http://guardanthealth.com> 
 No prior therapy with MET-targeting agents 
Note:  An exception will be a subset of approximately 6 patients entered to the Basket 
Cohort after having received prior therapy with a MET-targeting TKI. 
 Willingness to undergo a pre- and post-dosing biopsy (maximum of 2 biopsies) 
from primary or metastatic tumor site(s) considered safely accessible for biopsy 
 
c. 
NSCLC MET-Amplified Cohort ONLY: 
 Documented NSCLC meeting disease criteria as defined above   
 Documented MET-amplification by either: 
o Local assessment in a recent* tumor biopsy; i.e.,  G:CN ≥3.0 scored in 50 
tumor nuclei by FISH, CISH, SISH or similar assay, or a copy number >5 
by NGS or qPCR (subsequent central confirmation required, however 
patient may be enrolled and treated based on local assessment, before 
central confirmation results have been obtained) 
*Tissue for local assessment may be from a recent tumor biopsy, defined as one 
performed since last documented disease progression as part of the site’s usual 
practice, and where no intervening antineoplastic therapy has been 
administered; otherwise tissue from a newly performed biopsy must be obtained 
and submitted.       
o Central confirmation** in a newly performed pre-dosing tumor biopsy; 
i.e.,  G:CN ≥3.0 scored in 50 tumor nuclei by FISH 
**If central confirmation of MET-amplification status cannot be assessed in 
tumor due to assay failure/technical error, the Sponsor may decide to enroll 
based on MET-amplification detected by Guardant360 on a case per case basis 
(see Note below regarding Guardant360 analysis). 
 May have received prior therapy with MET-targeting and/or EGFR-targeting 
agents (antibodies or TKIs) 
 Willingness to undergo a pre-dosing biopsy (mandatory unless a recent* tumor 
biopsy as defined above is available), and potentially a biopsy at the End of 
Cycle 2 (EOC2) (optional), from a primary or metastatic tumor site considered 
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Note: Peripheral blood for ctDNA analysis by Guardant 360 will be obtained for 
assessment of MET-amplification status. As data are acquired on concordance between 
findings in tumor tissue versus ctDNA, the Sponsor may decide to transition to screening 
for MET-amplification using Guardant360 analysis only (e.g., 2+ or 3+ amplification 
score) without requiring confirmation in a recent or newly performed tumor biopsy. 
d. NSCLC METEx14Del Cohort ONLY:  
 Documented NSCLC meeting disease criteria as defined above   
 Documented METEx14Del (tumors need not be MET-amplified) 
Note: METEx14Del status to be documented according to local institutional standards.  
Assessment in ctDNA by Guardant360 technology or equivalent is allowed. Tissue 
from a recent* or newly performed pre-dosing tumor biopsy must be submitted for 
central assessment.  
*Recent tumor biopsy, defined as one performed since last documented disease 
progression as part of the site’s usual practice, and where no intervening antineoplastic 
therapy has been administered; otherwise tissue from a newly performed biopsy must 
be obtained and submitted. 
 May have received prior therapy with MET-targeting and/or EGFR-targeting 
agents (antibodies or TKIs) 
 Willingness to undergo a pre-dosing biopsy (mandatory unless a recent* tumor 
biopsy as defined above is available), and potentially a biopsy at the EOC2 
(optional), from a primary or metastatic tumor site considered safely accessible 
for biopsy 
Note: Peripheral blood for ctDNA analysis by Guardant 360 will be obtained for 
assessment of METEX14Del status.   
8. If female and of childbearing potential, a negative pregnancy test 
9. Male or female, either not of childbearing potential or agreeing to use a medically 
effective method of contraception as per institutional standards during the trial and for 4 
months after the last dose of trial drug 
6.2 
Exclusion Criteria 
Patients meeting any of the following criteria will not be permitted to enter the trial: 
1. Any antineoplastic agent for the primary malignancy (standard or investigational) without 
delayed toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest, prior to 
C1/D1 except:  
 Nitrosoureas and mitomycin C within 6 weeks prior to C1/D1 
2. Part 2 ONLY:  
a. Basket Cohort:  
 Prior therapy with MET-inhibiting agents  


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Note:  Exceptions will be a subset of approximately 6 patients entered to the Basket Cohort 
after having received prior therapy with a MET-targeting TKI  
 Prior therapy with antibody to HGF 
b. Basket Cohort and NSCLC MET-Amplified Cohort: Tumor status demonstrating 
MET-polysomy in the absence of MET-amplification, as specified 
Note: Patients in the NSCLC METEx14Del Cohort with polysomy are eligible.   
c. Radiotherapy against target lesions within 4 weeks prior to C1/D1, unless there is 
documented progression of the lesion following the radiotherapy 
Note: Radiotherapy for pain control against non-target lesions is allowed, as long as it does 
not influence bone marrow function 
3. Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone equivalent) 
within 2 weeks prior to C1/D1 (for exceptions, see Section 7.5.2)  
4. Use of hematopoietic growth factors within 2 weeks prior to C1/D1 
5. Active second malignancy or history of another malignancy within the last 3 years, with 
the exception of: 
a. Treated, non-melanoma skin cancers 
b. Treated carcinoma in situ of the breast or cervix 
c. Controlled, superficial carcinoma of the urinary bladder 
d. T1a or b carcinoma of the prostate treated according to local standard of care, with 
prostate-specific antigen (PSA) within normal limits for the institution 
6. Central nervous system (CNS) malignancy including: 
a. Primary malignancies of the CNS 
b. Known, untreated CNS or leptomeningeal metastases, or spinal cord compression; 
patients with any of these not controlled by prior surgery or radiotherapy, or 
symptoms suggesting CNS metastatic involvement for which treatment is required 
Note: Patients with treated CNS metastases will be eligible if they are asymptomatic, do not 
require corticosteroids or anticonvulsants, and have confirmation of at least stable brain 
disease status as assessed by 2 imaging studies performed > 4 weeks apart with the most 
recent performed within 4 weeks prior to first trial drug administration 
Patients with newly identified CNS metastases during study treatment will be considered to 
have PD and will be discontinued from treatment 
7. Inadequate recovery from an acute toxicity associated with any prior antineoplastic 
therapy 
Note: With the exception of persistent Grade 2 alopecia and/or peripheral neuropathy, patients 
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8. Major surgical procedure within 4 weeks prior to C1/D1 or inadequate recovery from any 
prior surgical procedure 
9. Non-healing wounds on any part of the body 
10. Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 1 
month prior to C1/D1, unless adequately treated and stable 
11. Active uncontrolled bleeding or a known bleeding diathesis 
12. Significant cardiovascular disease or condition, including: 
a. Congestive heart failure currently requiring therapy 
b. Class III or IV cardiovascular disease according to the New York Heart 
Association's (NYHA) functional criteria (30) 
c. Need for antiarrhythmic medical therapy for a ventricular arrhythmia 
d. Severe conduction disturbance (e.g., 3rd degree heart block) 
e. Unstable angina pectoris (last episode at least 6 months prior to C1/D1)  
f. Uncontrolled hypertension (per the Investigator's discretion) 
g. Myocardial infarction within 6 months prior to C1/D1 
13. Abnormal hematologic, renal or hepatic function as defined by the following criteria: 
a. Absolute neutrophil count (ANC) <1.5 ×109/L (1500/mm3) 
b. Hemoglobin ≤9 g/dL 
c. Platelet count <75 ×109/L (75,000/mm3)  
d. Serum creatinine >1.5 × upper limit of normal (ULN) for the institution 
e. Aspartate aminotransferase (AST) >3.5 × ULN for the institution or AST >5 × 
ULN for the institution in case of known liver metastases 
f. Alanine aminotransferase (ALT) >3.5 × ULN for the institution or ALT >5 × ULN 
for the institution in case of known liver metastases 
g. Total bilirubin >1.5 × ULN for the institution 
h. Prothrombin time as assessed by International Normalized Ratio (INR) >1.5 × ULN 
for the institution*  
i. Partial thromboplastin time (PTT) >1.5 × ULN for the institution* 
* unless the patient is on a stable dose of anticoagulant therapy for a prior 
thrombotic event 
14. Any of the following within 2 weeks prior to C1/D1: 


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a. Any serious or uncontrolled infection 
b. Any infection requiring parenteral antibiotics 
c. Unexplained fever >38.0 °C 
15. Known or suspected hypersensitivity to any of the excipients of the Sym015 drug product 
16. Any other life-threatening illness, significant organ system dysfunction, or clinically 
significant laboratory abnormality, which in the opinion of the Investigator, would either 
compromise the patient’s safety or interfere with the evaluation of the safety of the trial 
drug 
17. Any kind of disorder that compromises the ability of the patient to give written informed 
consent and/or to comply with trial procedures or is unwilling or unable to comply with 
trial requirements at the discretion of the Investigator  
18. Breast feeding, or plans by the patient (or the patient’s partner) to become pregnant 
during treatment or within 4 months after the end of treatment 
6.3 
Withdrawal  
The visit schedule for the treatment period will apply until Sym015 has been discontinued. Once 
this has occurred, an EOT Visit will be performed within 10 days following the decision to 
discontinue Sym015. 
After EOT, the patient will continue to be followed for safety until 1 month (30 +7 days) after 
the last dose of Sym015, when the 1M FUP Visit must be completed. 
6.3.1 Withdrawal from Treatment with Sym015 
The patient must be withdrawn from treatment with Sym015 in the event of any of the following: 
 A DLT considered by the Investigator to require treatment discontinuation. Refer to 
Section 9.5 for DLT definition (dose-escalation cohorts only) 
 Occurrence of an AE considered by the Investigator to require treatment discontinuation 
 Basket Cohort ONLY: Results from archival tumor tissue or a tumor biopsy submitted to 
confirm MET-amplification status that do not meet study eligibility criteria.   
Note:  Such patients may remain on study if there is evidence of an OR, SD, or other clinical 
benefit, but will not be included in the Evaluable for Response Population. 
 PD, verified by CT/MRI according to RECIST v1.1 
 Treatment failure not meeting the criteria for PD, but considered by the Investigator to 
require treatment discontinuation 
 Requirement for a significant surgical procedure  


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Note: Patients requiring a minor surgical procedure (e.g., port placement, skin abscess drainage) 
may continue at the Investigator's discretion following discussion with the Sponsor or designee.  
A brief interruption in therapy may be considered 
 An intercurrent illness which, in the opinion of the Investigator, would prevent 
completion of trial-related evaluations 
 Use of prohibited concomitant medication, as defined in Section 7.5.2 
 Pregnancy 
 Significant deviation from the eligibility criteria may require discontinuation after 
discussion with the Sponsor 
 Noncompliance with trial procedures may require discontinuation after discussion with 
the Sponsor 
 Patient withdrawal of consent and election to discontinue treatment. (Patients may leave 
the trial at any time for any reason if they wish to do so, without any consequences) 
 Termination of the trial by the Sponsor 
 Patients who meet Hy’s Law criteria that cannot be explained by factors not related to 
Sym015. 
Note: Patients meeting all three of the following are considered to have met Hy’s Law criteria:  
o The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above ULN of ALT or AST 
o Among trial subjects showing such aminotransferase elevations, often much greater than 
3xULN, one or more show elevation of serum total bilirubin to ≥2xULN, without initial 
findings of cholestasis (elevated serum alkaline phosphatase [ALP]). 
o No other reason can be found to explain the combination of increased aminotransferase and 
serum total bilirubin, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or 
another drug capable of causing the observed injury. 
6.3.2 Withdrawal from Trial 
The patient must be withdrawn from trial in the event of any of the following: 
 The patient withdraws consent to participate 
 The Investigator judges it necessary due to medical reasons 
The EOT and the 1M FUP visits should be performed to the extent possible and the Investigator 
should ensure any SAE is followed as described in Section 9.3. 
After the 1M FUP Visit, the Investigator will make every effort to obtain follow-up information 
on response assessment and/or OS every 2 months. Response assessment follow-up is required in 


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the event of an ongoing SD, PR or CR, as per RECIST v1.1 at the 1M FUP Visit, until PD or 
another therapeutic intervention is initiated. Survival follow-up is required until death, 
withdrawal of consent, or termination of the trial. This continued follow-up does not require an 
in-person visit at the trial site, but may be obtained by collection of data/documentation. 
6.4 
Replacement of Patients 
6.4.1 Part 1, Dose-Escalation 
Patients who do not complete Cycle 1 as defined in Section 9.5.2, for reasons other than drug 
toxicity, will be replaced.  
Data from these patients will be included in the safety analysis, but will not contribute to the 
determination of the Q2W RP2D. 
6.4.2 Part 2 
Basket Cohort ONLY: Patients enrolled to the study based on local MET-amplification 
assessments conducted in ctDNA, but with subsequent confirmatory tumor tissue evaluation 
results not meeting the protocol-specified inclusion criteria, will be replaced (patients may 
remain on study if there is evidence of an OR, SD, or other clinical benefit, but will not be 
included in the Evaluable for Response Population).




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7.1.3 Administration of Sym015 
7.1.3.1 
Treatment Schedule 
All patients will be administered IV infusions of Sym015, dosed according to body weight, 
through a peripheral line or indwelling catheter, and with the use of an infusion pump and an 
inline filter. Sym015 will be administered Q2W (Day 1 and Day 15 of each 28-day cycle [±2 
days]).   
For all Sym015 infusions, a complete dosing history will be recorded, i.e.,: 
 Total dose and volume administered 
 Start and stop time of infusion 
 Infusion interruption or termination and reason for such actions 
7.1.3.2 
Part 1, Dose-Escalation 
During the dose-escalation part of the trial, the following dose levels of Sym015 administered 
Q2W will potentially be evaluated in a standard 3+3 dose-escalation design: 
 Dose Level 1: 6 mg/kg  
 Dose Level 2: 12 mg/kg  
 Dose Level 3: 18 mg/kg  
 Dose Level 4: 24 mg/kg  
A substitute or additional dose level, within the dose levels listed above, could potentially be 
evaluated. Any decision to add or replace a dose to be tested will be guided by PK data and/or 
data on target occupancy in skin biopsy samples. This substitute or additional dose level would 
be chosen between the currently listed dose levels, and a dose higher than 24 mg/kg will not be 
evaluated without a formal amendment to this protocol. 
Cohorts will be filled sequentially until establishment of the highest safe dose. Patients will be 
allocated to the next available treatment slot within the current or next cohort, as appropriate and 
depending on the ongoing observation of DLTs and other safety parameters. 
Enrollment will be staggered between the first and second patient in each new higher dose level 
tested. The first patient must have completed and tolerated the first dose of Sym015, including 
follow-up until Day 8 of Cycle 1 (C1/D8), in order to allow for review of clinical and laboratory 
assessments. Thereafter patients within a cohort may be added concurrently. 


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There is potential for entry of additional patients in the dose-escalation portion of the trial to 
assure a sufficient number of evaluable patients per cohort by entering an additional patient to a 
cohort (e.g., increase a 3 patient cohort to 4 patients, or a 6 patient cohort to 7 patients).  
Note: Should this action be taken, cohort tolerability assessment and subsequent dose-escalation will 
occur when the minimum number of patients required to evaluate tolerability have completed Cycle 1. 
However, if any additional patient experiences an event that would, per protocol, result in either cohort 
expansion or the halting of dose-escalation, protocol rules as outlined herein will be followed. 
Progression from a current dose level to the next will only proceed following evaluation of 
tolerability of the current dose level. Thus, dosing of the first patient at Dose Level 2 will 
commence only once all patients to be treated at Dose Level 1 have completed Cycle 1, and Dose 
Level 1 has been found to be tolerable. Similarly, dosing in Dose Level 3 will only commence 
once all patients to be treated at Dose Level 2 have completed Cycle 1, and Dose Level 2 has 
been found to be tolerable. The dose-escalation decision points are listed below: 
 If no DLTs are encountered in any of the first 3 patients completing Cycle 1 within a 
dose level, dose-escalation may continue to the next level 
 If 1 of 3 patients within a dose level experiences a DLT, 3 more patients will be enrolled 
at the same dose level. If no DLTs are encountered in the 3 additional patients, dose-
escalation may continue to the next level  
 If  ≥ 2 patients within a dose level (of up to 6 patients) experience a DLT, then that dose 
will be considered to have exceeded the MTD and the dose level just below this dose 
level will be considered to be the MTD 
 If no DLTs are encountered in any of the first 3 patients at Dose Level 4, 24 mg/kg will 
be considered the highest safe dose tested 
The SMC will review safety data throughout the trial. During Part 1, the SMC will make 
decisions regarding the advisability of: continuing accrual to a particular dose cohort; dose-
escalation and accrual of patients to a higher dose cohort; and the dose(s) to be used in Part 2 
(i.e., Q2W RP2D to be evaluated). 
Each patient enrolled will receive Sym015 at the allocated dose until treatment withdrawal, 
unless dose-reduction is necessary as specified in Section 7.1.4. There will be no intra-patient 
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7.1.3.3 
Part 2 
During Part 2 of this trial, patients will receive the RP2D of Sym015 on a Q2W dosing schedule. 
The SMC will continue to review safety data and assess the tolerability of Sym015 during Part 2 
of the trial. 
7.1.3.4 
Duration of Infusion for Administration of Sym015 
Sym015 will be administered over a 1.5-hour (+10 minutes) period for doses ≥18 mg/kg, and 
over a 1 hour (+10 minutes) period for doses <18 mg/kg, following delivery of premedication as 
specified in section 7.2.1.  
Note:  Effective with protocol version 5.0 (November 2016), the duration of infusion has been extended 
to 1.5 hours for all patients receiving doses ≥18 mg/kg due to the occurrence of Grade 2 IRRs in 2 of 3 
patients treated in the 18 mg/kg cohort during Part 1 (This action was implemented 13Sep2016). 
Administration should be at a constant rate using a programmable volumetric infusion pump in 
order to assure accuracy of delivery. The times of infusion initiation and completion must be 
recorded.  
The duration of Sym015-infusion will be prolonged for all subsequent patients entered to the trial 
in the following situations: 
 In the event of a Grade 2 IRR in ≥ two thirds of the patients entered to a cohort, the 
duration of infusion for subsequent patients entered at that dose and higher doses will be 
extended from 1 hour (+10 minutes) to 1.5 hours (+10 minutes) (or longer, if indicated) 
Note: This action was implemented 13Sep2016 and applies to doses ≥18 mg/kg.  
 In the event of a Grade 3 or greater IRR in any patient within a cohort, the duration of 
infusion for subsequent patients entered at that dose and higher doses will be extended 
from 1 hour (+10 minutes) to 1.5 hours (+10 minutes) (or longer, if indicated). Such a 
case will also be considered to have met the protocol criteria for a DLT, thus requiring 
expansion of the cohort 
These same criteria will be applied in the event IRRs occur on the extended 1.5 hours infusion 
schedule. In such a case, the duration of infusion for subsequent patients entered at that dose and 
higher doses will be extended to 2 hours (or longer, if indicated).  
Recommendations for management of an IRR in individual patients can be found in Section 
7.1.3.7. 
7.1.3.5 
Patient Monitoring During and After Infusion of Sym015 
Patients will be treated on an outpatient basis. 


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Sym015 infusions must be administered under the close supervision of an experienced physician 
in an environment where full resuscitation facilities are immediately available.  
Patients will be carefully observed for a minimum of 2 hours following completion of the first 
administration of Sym015 and a minimum of 1 hour following completion of subsequent 
administrations. At the end of each infusion, the IV line must remain in place for at least 1 hour 
to allow administration of IV drugs, if necessary. 
7.1.3.6 
Infusion-Related Reactions to Sym015 
An IRR is defined as an AE occurring during the Sym015 infusion and up to 2 hours after the 
end of infusion (EOI), which is assessed by the Investigator to be related to the infusion of 
Sym015. Signs of IRRs may include but are not limited to facial flushing and swelling, shortness 
of breath, headache, diaphoresis, tachycardia, hypotension, chills, rigors, chest and throat 
tightness, as well as chest, back and/or abdominal discomfort. 
7.1.3.7 
Handling of Infusion-Related Reactions to Sym015 
The risk of an IRR is highest for the first administration of a mAb and diminishes with 
subsequent infusions. 
If an IRR occurs, it should be classified according to the Common Terminology Criteria for 
Adverse Events (Version 4.03) (CTCAE v4.03). Recommended management guidelines are 
shown in Table 6. In all cases, the Investigator should use best clinical judgment in managing 
such reactions. 


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Table 6 
Infusion-Related Reactions Management Guidelines 
CTCAE Grade 
Management/Treatment 
Grade 1 
Mild transient reaction; 
infusion interruption not indicated; 
intervention not indicated 
 
Continue infusion; consider slowing to 50% of the prior rate 
 
Monitor closely 
 
If infusion is extended, administer subsequent infusions during 
Cycle 1 at the prolonged rate 
 
Thereafter, if vital signs remain stable and symptoms do not 
recur, at the discretion of the Investigator an attempt may be 
made to slowly increase the rate of infusion. Final infusion 
duration should not be briefer than the initial rate attempted in 
the patient 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for 
≤ 24 h 
 
Interrupt infusion for a minimum of 30 minutes 
 
Administer symptomatic treatment (e.g., antihistamines, 
NSAIDs, etc.) and appropriate supportive care (e.g., 
bronchodilator, oxygen, etc.), as indicated 
 
When symptoms have resolved or decreased to Grade 1, restart 
infusion at 50% of the prior rate  
 
Monitor closely 
 
If symptoms recur, stop the infusion, institute remedial therapy, 
monitor closely and evaluate whether the patient can continue 
the trial 
 
Administer subsequent infusions during Cycle 1 at the 
prolonged rate 
 
Thereafter, if vital signs remain stable and symptoms do not 
recur, at the discretion of the Investigator an attempt may be 
made to slowly increase the rate of infusion. Final infusion 
duration should not be briefer than the initial rate attempted in 
the patient 
Grade 3 
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
 
Discontinue the infusion 
 
Administer symptomatic treatment (e.g., antihistamines, 
NSAIDs, glucocorticoid etc.) and appropriate supportive care 
(e.g., bronchodilator, oxygen, IV fluid etc.), as indicated 
 
Do not resume infusion 
 
Patient will either be discontinued from further treatment or 
receive subsequent treatments at a reduced dose; if treatment is 
continued administer subsequent infusions during Cycle 1 at 
50% of the prior rate 
 
Thereafter, if vital signs remain stable and symptoms do not 
recur, at the discretion of the Investigator an attempt may be 
made to slowly increase the rate of infusion. Final infusion 
duration should not be briefer than the initial rate attempted in 
the patient. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
 
Discontinue infusion 
 
Administer necessary life-support measures, as indicated 
 
Discontinue from further treatment 
Abbreviations (in alphabetical order): CTCAE, Common Terminology Criteria for Adverse Events v4.03; h, hours; IRR, infusion-related 
reaction; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug 
 
7.1.4 Dose-Adjustment and Delays of Sym015 
The dose of Sym015 in mg/kg assigned to the individual patient will be confirmed by the 
Sponsor or designee prior to C1/D1 on the Screening and Allocation Form. 


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Based on the body weight of the patient, the site will calculate the nominal dose of Sym015 to be 
administered in mg.  
Weight changes (> ±10%) for a patient during trial will require recalculation of the dose. Refer 
to Section 7.1.4.1. 
Furthermore, dose-delays of Sym015 and intra-patient dose-reduction(s) may also be required 
upon occurrence of specific toxicities. Refer to Section 7.1.4.2. 
7.1.4.1 
Dose-Adjustment for Body Weight 
Sym015 is dosed in mg/kg and the dose to be administered will be calculated based on the actual 
body weight of the patient. The dose calculated may be used for subsequent infusions, unless 
body weight changes of ≥ ± 10%, in which case the dose should be adjusted according to the 
change in body weight. Recalculation for lower weight changes is allowed. 
7.1.4.2 
Dose-Delays for Sym015-Related or Disease-Related Toxicities 
Clinical judgment will be used when determining whether it is advisable to continue a patient on 
to the next dosing.  In order to dose a patient, the following criteria must be met: 
 ANC >1.0 ×109/L (1000/mm3) 
 Platelet count >60 ×109/L (60,000/mm3) 
 Any ongoing AEs should NOT meet the criteria for DLT, during the DLT observation 
period 
 Any ongoing AEs, assessed as possibly, probably, or related to Sym015, should have 
either ameliorated to ≤ Grade 1 severity, returned to baseline status, or resolved with the 
exception of Grade 2 clinical events that are being adequately controlled with best 
supportive care (e.g., nausea, vomiting, diarrhea, fatigue) and asymptomatic laboratory 
abnormalities that are considered clinically insignificant or that are resolving with 
medical therapy 
Should any one of the criteria above not be met, dosing of Sym015 must be delayed until the 
patient meets the above criteria. All per protocol assessments must be done. 
7.1.4.3 
Dose-Reduction for Sym015-Related Toxicities 
Patients experiencing any of the following toxicities, assessed as possibly, probably, or related to 
Sym015, will have their dose reduced in accordance with the reduction schedule outlined in 
Table 7. 


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1. Grade 3 non-hematologic toxicity regardless of duration, with the exceptions of:  
a. Grade 3 nausea, vomiting, diarrhea, or fatigue lasting ≤ 2 days with best supportive 
care  
b. Grade 3 asymptomatic electrolyte abnormalities lasting ≤ 3 days that are not 
considered clinically relevant by the Investigator and that resolve with medical 
therapy without requiring hospitalization 
2. Any Grade 4 non-hematologic toxicity, with the exception of: 
a. Grade 4 asymptomatic electrolyte abnormalities lasting ≤ 3 days that are not 
considered clinically relevant by the Investigator and that resolve with medical 
therapy 
3. Neutropenia that is: 
a. Grade 3-4 febrile neutropenia 
b. Grade 4 and sustained (i.e., ANC <500 per mm3, duration >5 days) 
4. Thrombocytopenia that is: 
a. Grade 3 with clinically significant hemorrhage 
b. Grade 4 (platelets <25,000 per mm3) 
5. AST/ALT elevation > 3×ULN with bilirubin elevation >2×ULN that cannot be explained 
by factors not related to study drug 
 
Table 7 
Sym015 Dose-Reduction Schedule 
Allocated Dose 
First Reduction 
Second Reduction 
Subsequent Reductions 
6 mg/kg 
3 mg/kg 
1.5 mg/kg 
Reduce by 50% 
12 mg/kg 
6 mg/kg 
3 mg/kg 
Reduce by 50% 
18 mg/kg 
12 mg/kg 
6 mg/kg 
Reduce by 50% 
24 mg/kg 
18 mg/kg 
12 mg/kg 
Reduce to 6 mg/kg, then 
by 50% 
Note: In the event that an intermediate dose is explored in this study, dose-reductions in such cases will be to the next lower established 
tolerated dose level(s). If further dose-reductions are indicated, proceed as outlined above. 
 
7.2 
Other Drugs to be Used in the Trial 
7.2.1 Premedication for Sym015 Infusions 
There is an inherent risk for IRRs with the administration of mAbs. A premedication schedule 
will therefore be implemented for all patients treated. 
For Part 1 of the trial, premedication is mandatory prior to each dose of Sym015. 
 
For Part 2 of the trial, premedication is mandatory prior to each dose of Sym015 during Cycle 1. 
 


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All patients must be premedicated as described with standard therapies that include a 
glucocorticoid and an H1 antagonist.  Where indicated, consideration may be given to including 
an H2 antagonist and/or acetaminophen.  The recommended premedication doses are as follows:  
 Glucocorticoid therapy equivalent to 80-100 mg IV methylprednisolone, approx. 0.5 to 2 
hours prior to the start of Sym015 infusion 
 Antihistamine (H1 antagonist) equivalent to 25-50 mg IV diphenhydramine, approx. 0.5 
hours prior to the start of Sym015 infusion 
 Antihistamine (H2) antagonist (optional) such as 50 mg IV ranitidine or 30 mg 
famotidine, approx. 0.5 hours prior to the start of Sym015 infusion 
 Acetaminophen (optional) such as 1000 mg IV or PO (orally), approx. 0.5 hours prior to 
the start of Sym015 infusion 
In Part 2, if a patient is without evidence of IRRs after Cycle 1, the Investigator may opt to 
withdraw premedication on a patient-by-patient basis with subsequent dosing in order to 
determine whether such continued therapy is necessary in that patient. Where practical, it is 
recommended that withdrawal of premedication be done in a gradual fashion. 
For those patients who experienced symptoms suggestive of an IRR after Cycle 1, consideration 
should be given to continuing premedication for at minimum 1 to 2 additional doses before any 
future attempt to withdraw. 
7.2.2 Prophylactic and Therapeutic Treatment 
7.2.2.1 
Mandatory Prophylactic Treatment 
Mandatory prophylactic treatment will be implemented for all patients treated in this trial should 
an increased incidence begin to occur of mild-to-moderate Sym015-related reactions that are 
amenable to prophylaxis with standard agents. Such actions will occur following discussions 
within the SMC. 
7.3 
Blinding 
Not applicable as this is an open-label trial. 
7.4 
Drug Accountability and Compliance Check 
The Investigator is responsible for ensuring accountability for the IMP, including maintenance of 
IMP accountability records. 
IMP accountability records will include a full inventory of the IMP including: 


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 Confirmation of IMP delivery to the trial site 
 Record of each dose dispensed 
 The return of unused IMP to the Sponsor or designee 
 Record of any on-site destruction of unused IMP, as agreed with the Sponsor or designee  
Records will specify dates, quantities, batch numbers, use-by dates and patient numbers, as 
applicable. 
The Investigator, or designee, should maintain records that adequately document: 
 That the patients were provided the doses specified by the protocol, and 
 That all IMP provided by the Sponsor was fully reconciled 
7.5 
Concomitant Medication/Therapy 
7.5.1 Allowed Medication/Therapy and Procedures During the Trial 
Patients may receive their current concomitant medication and any medication considered 
necessary for the welfare of the patient during trial, except if listed in Section 7.5.2.  
Furthermore, the following are permitted during the trial: 
 Premedication with standard therapies prior to Sym015 administration to reduce the risk 
of IRRs 
 Prophylaxis and treatment of Sym015-related toxicities 
 Radiotherapy for pain control against non-target lesions, as long as it does not influence 
bone marrow function 
 Bisphosphonates and denosumab:  Bisphosphonates and denosumab for bone metastases 
and other skeletal conditions provided the patient is on a stable dose for at least 2 months 
prior to study start and remains on the stable dose while receiving study treatment 
7.5.2 Prohibited Medication/Therapy and Procedures During the Trial 
The following medications and procedures are not allowed from C1/D1, or as specified in the 
inclusion/exclusion criteria, until the EOT Visit: 
 Anti-cancer treatment, including cytotoxic or cytostatic agents, hormonal therapy (except 
as physiologic hormone replacement)  


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 Basket Cohort ONLY: MET-targeting therapies, except in subset of approximately 6 
patients 
 Radiotherapy against target lesion(s) (Part 2 only) 
 Systemic immunosuppressive or systemic hormonal therapy with the exception of the 
following allowed therapies: 
o Hormonal therapy (e.g., Megace) for appetite stimulation 
o Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
o Oral replacement glucocorticoid therapy for adrenal insufficiency 
o Low-dose maintenance steroid therapy for other conditions (excluding steroid tapers 
for brain edema/metastases/radiation) 
o Steroid therapy as prophylaxis for contrast reactions 
o Stable hormonal therapy for ovarian suppression for non-malignant conditions, 
hormonal contraceptive therapy, or post-menopausal HRT*  
o GnRH analogs in patients with prostate cancer 
o Intra-articular steroid injections 
o Higher dose steroid therapy for treatment of an acute intercurrent illness in patients 
with stable disease or an ongoing response. In such situations, protocol therapy 
treatment should be interrupted. 
*Prior or concomitant therapies are permitted; however, patients must have been on a stable dose for at 
least 6 months prior to study start, and if continuing must remain on the stable dose while receiving study 
treatment (i.e., such treatment will not be considered as systemic hormonal therapy for the purpose of study 
eligibility). 
 Prophylactic use of hematopoietic growth factors during Cycle 1 
 Major surgery that would preclude the patient from complying with the requirements of 
the protocol 
If any one of the above listed medications/procedures becomes necessary during the trial, the 
patient must be withdrawn from Sym015 and the EOT Visit should be performed. The 1M FUP 
Visit should then be performed, no less than 1 month (30 +7 days) after the last dose of Sym015. 


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7.6 
Medical Care of Patients after End of Trial Participation 
After completing treatment in this trial, patients will be offered standard of care treatment in 
accordance with generally accepted medical practice and depending on the patient’s individual 
medical need. Patients will continue to be followed for survival. 


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8. 
TRIAL ASSESSMENTS 
All trial assessments are considered mandatory for all patients included in the trial, unless 
otherwise stated. All assessments are to be performed on or about the indicated visit day, i.e., ±2 
days, unless otherwise stated. A slightly longer allowance for routine assessments is permissible 
in the event of scheduling difficulties associated with weekends, holidays, etc. 
8.1 
Baseline Characteristics / Eligibility Assessments 
8.1.1 Signing of Informed Consent 
Prior to any protocol-related procedure, unless such testing was performed previously as part of 
the routine clinical management of the patient. 
 Screening 
Note: Informed consent may be obtained outside the 14-day screening period prior to C1/D1 
8.1.2 Demographics 
To include date of birth, sex, race and ethnicity (as allowed by country) 
 Screening 
8.1.3 Medical History 
To include prior and ongoing medical illnesses and conditions and prior surgical procedures not 
related to the primary diagnosis. 
 Screening 
 C1/D1 (prior to dosing) 
8.1.4 Tumor Characteristics and Extent of Disease 
To include diagnosis and date of initial diagnosis, staging at time of initial diagnosis and at 
screening, tumor histology, current location of metastases, and date of most recent disease 
progression, and mutation status. 
 Screening 
8.1.5 Prior Cancer Treatments 
To include prior surgical procedures for the primary diagnosis, as well as prior radiotherapy, 
chemotherapy and/or biological targeted therapy, investigational treatment, and/or procedures.  
Include dates of treatments, numbers of cycles, and best response to such treatments.  


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 Screening 
 C1/D1 (prior to dosing) 
8.2 
Safety Assessments 
To be performed within 14 days of C1/D1, unless otherwise specified. 
8.2.1 Medication/Procedure Survey 
To include all medications taken other than Sym015 and all procedures performed during trial.  
For medications: Include generic name or brand name, indication for use, dose and frequency, 
route of administration, start and stop dates or if ongoing at 1M FUP Visit. For procedures: 
Include date and reason for procedure. 
 Starting from the date of Screening 
 Until the date of the 1M FUP 
8.2.2 Adverse Events Survey  
For details about (S)AEs and (S)AE reporting, refer to Section 9. 
 Starting from signing of informed consent for participation in the trial 
 Until the date of the 1M FUP 
Note: Patients who sign informed consent and are subsequently deemed to be screening failures 
will be followed for the occurrence of SAEs/AEs until it is determined that they will not be 
participating in the trial 
8.2.3 Dose-Limiting Toxicities Evaluation (Part 1 Only) 
For details about AEs meeting DLT criteria, refer to Section 9.5. 
 Starting from the first dose of trial drug (C1/D1) 
 Reported during Cycle 1 with a final assessment 14 (±2) days after the last dose of Cycle 
1 or prior to dosing on C2/D1 
8.2.4 Vital Signs and Body Weight 
To include temperature, heart rate, blood pressure, and body weight   
 Screening 
 Prior to each dosing 
 EOT 
 1M FUP  


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 As clinically indicated 
8.2.5 Performance Status 
To be assessed by ECOG PS score. 
 Screening 
 Day 1 of each cycle (prior to dosing)  
o Does not need to be assessed prior to C1/D1 if assessed during screening ≤ 7 days 
from C1/D1 
 EOT 
 1M FUP 
 As clinically indicated 
8.2.6 Physical Examination 
To include evaluation of the following at Screening: General appearance, skin, head, ears, eyes, 
nose, throat, neck/thyroid, chest, cardiovascular system, abdomen, musculoskeletal system, 
lymph nodes, neurologic status, and mental status; include height (without shoes, rounded to 
nearest centimeter). Thereafter, a targeted physical examination may be performed as indicated. 
 Screening 
 Day 1 of each cycle (prior to dosing)  
o Does not need to be performed prior to C1/D1 if performed during screening ≤ 7 days 
from C1/D1 
 EOT 
 1M FUP 
 As clinically indicated 
8.2.7 Electrocardiogram 
To include standard 12-lead electrocardiogram (ECG). The Investigator, or qualified designee, 
should document the evaluation of the ECG, including specification of any abnormality as 
clinically significant or not clinically significant. 
 Screening 
 EOT 
 As clinically indicated 


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8.2.8 Echocardiogram or Multi-Gated Acquisition Scan 
Patients will be scheduled for a transthoracic echocardiogram (ECHO) at baseline to exclude 
enrollment of patients with insufficient heart function; alternatively, a radionuclide angiography 
(Multi-Gated Acquisition [MUGA] scan) of the heart may be performed.  
 Screening 
 In the event of cardiac symptoms (e.g., shortness of breath, edema) an ECHO or MUGA 
is to be scheduled as soon as possible  
 As otherwise clinically indicated 
8.2.9 Laboratory Assessments and Pregnancy Test 
All routine laboratory analyses will be performed at a laboratory facility local to the trial site. 
Results must be available and assessed prior to each dosing of Sym015. 
Sponsor or designee must be provided with a list of trial site laboratory normal ranges for all 
required parameters prior to screening of the first patient at the site. Likewise, any change in 
laboratory normal ranges during the trial should be forwarded to the Sponsor or designee 
promptly during the trial. 
Blood samples will be taken at all scheduled visits and will be analyzed for the following 
parameters as per Table 8 and as clinically indicated: 
Table 8 
Schedule of Safety Blood and Urine Samples 
Sample Analysis 
Screening 
Cycle 1 
Cycles 
Thereafter 
EOT 
IM 
FUP 
Day within Cycle 
 
D1 
D3 
D8 
D15 
D22 
D1 
D15 
 
 
Hematology Panel 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
Biochemistry Panel 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X1 
 
X 
 
X 
 
X 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
X 
 
Abbreviations (in alphabetical order): D, day; EOT, End of Treatment Visit; 1M FUP, 1-Month Follow-up Visit 
1) Does not need to be performed prior to C1/D1 if performed during screening ≤7 days from C1/D1 
 


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8.2.9.1 
Hematology Panel 
To include complete blood count with differential, ANC, and platelet count. 
 Screening 
 Cycle 1 
o Weekly (prior to Sym015 administration on days of dosing) 
 Does not need to be performed prior to C1/D1 if performed during screening ≤7 
days from C1/D1 
o Day 3 
 Each cycle thereafter 
o Prior to each dosing 
 EOT 
 1M FUP 
 As clinically indicated  
In the event of hematologic toxicity, the evaluation frequency should be increased to include 
additional evaluations between scheduled assessments, as clinically indicated. 
8.2.9.2 
Biochemistry Panel  
To include sodium, potassium, chloride, bicarbonate or carbon dioxide, blood urea nitrogen 
(BUN), creatinine, glucose, bilirubin [total and direct], AST, ALT, ALP, calcium, magnesium, 
phosphorus, albumin, total protein, uric acid, amylase, lipase, and creatine kinase (fasting not 
required). Clinically significant electrolyte abnormalities should be corrected prior to dosing. 
 Screening 
 Cycle 1 
o Weekly (prior to Sym015 administration on days of dosing) 
 Does not need to be performed prior to C1/D1 if performed during screening 
≤7 days from C1/D1 
o Day 3 
 Each cycle thereafter 
o Prior to each dosing 
 EOT 


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 1M FUP 
 As clinically indicated  
In the event of significant biochemistry abnormalities, the evaluation frequency should be 
increased to include additional evaluations between the scheduled assessments, as clinically 
indicated.  In the event of creatine kinase abnormalities, isoenzyme analysis should be 
performed. 
8.2.9.3 
Coagulation Panel 
To include prothrombin time, PTT and INR. 
 Screening 
 Cycle 1 
o Weekly (prior to Sym015 administration on days of dosing) 
 Does not need to be performed prior to C1/D1 if performed during screening 
≤7 days from C1/D1 
o Day 3 
 Each cycle thereafter 
o Prior to each dosing 
 EOT 
 1M FUP 
 As clinically indicated 
8.2.9.4 
Urinalysis 
Multi-parameter chemical test strips are acceptable and should include assessment of: specific 
gravity, pH, protein, glucose, ketones, occult blood, leukocyte esterase, nitrite, bilirubin, and 
urobilinogen. 
 Screening 
 Cycle 1 
o Prior to each dosing 
 Does not need to be performed prior to C1/D1 if performed during screening 
≤7 days from C1/D1 
o Day 1 of each cycle thereafter (prior to dosing) 


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 EOT 
 1M FUP 
 As clinically indicated 
8.2.9.5 
Pregnancy Test 
Serum human Chorionic Gonadotropin (β-hCG) at screening, urine β-hCG thereafter, in women 
of childbearing potential. 
 Screening 
 EOT 
 As clinically indicated 
Women are considered of childbearing potential unless they have been hysterectomized, have 
undergone tubal ligation or have been postmenopausal for at least one year. 
8.3 
Disease Assessments 
8.3.1 Disease Status Evaluation by CT or MRI 
The anti-tumor activity of Sym015 will be assessed by the Investigator, or qualified designee, 
according to RECIST v1.1 (29). Refer to Appendix 1. 
Patients will undergo imaging by CT or MRI of neck, chest, abdomen and pelvis as indicated 
based on tumor type and clinical judgment in order to follow the underlying malignancy. The use 
of CT or MRI must be consistent per patient throughout the trial.  Use of contrast is preferred but 
is at the discretion of the Investigator, as medically indicated.  
 Screening 
Note: A CT/MRI performed within 28 days prior to Day 1 may be used for evaluation of 
eligibility and as baseline scan, provided that the CT/MRI has been performed according to the 
protocol requirements 
 EOC2 and end of every second cycle thereafter, i.e., EOC4, EOC6, EOC8, etc. 
Note: May be performed at any time during the week prior to Day 1 of the next cycle, including 
Day 1 of the next cycle, prior to dosing (provided results are available prior to study drug 
administration) 
 Suspected PD (as soon as possible) 
 At least 28 days following an OR (PR, CR) 
 EOT (if >3 weeks since previous CT/MRI)  


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 At 1M FUP (if PD was not documented before or at EOT) 
If PD is documented at any time, no further disease assessments will be required. Patients with 
documented PD will be discontinued from Sym015 so that alternative management of their 
malignancy may be considered. 
To be assigned a status of PR or CR, changes in disease status must be confirmed by repeat 
imaging studies performed no less than 28 days (4 weeks) after the criteria for response are first 
met.  In the case of SD, follow-up measurements must have met the SD criteria at least once after 
trial entry at a minimal interval in general no less than 6-8 weeks from first dose of Sym015. 
Imaging data (imaging studies and derived assessments) will be stored by the sites and will be 
available upon request for potential review by the Sponsor or an independent radiology reviewer. 
For Part 2 only: In addition, imaging studies will be sent to an imaging facility for storage in 
order to ensure central availability and readiness for read at a future time upon Sponsor or Health 
Authority request. 
For all imaging time points, the following will be recorded as per RECIST v1.1: Target lesions 
including size, location, and type (nodal/non-nodal); sum of diameters of target lesions; any new 
lesions noted during trial, including size, location, and type (nodal/non-nodal); final response 
assessment at each visit (PD, SD, PR, CR or Not Evaluable [NE]). 
8.3.2 Tumor Marker Evaluation (Part 1 and Part 2 Basket Cohort)  
To include tumor markers that are part of the trial site standard practices as indicated by tumor 
type, if applicable. 
It is recommended that tumor markers are evaluated at timepoints coinciding with the CT/MRI 
imaging studies as listed in Section 8.3.1. 
8.3.3 Archival Tumor Tissue for MET and KRAS Assessment (Part 1 and Part 2 Basket 
Cohort) 
To be assessed locally. Does not need to be repeated if MET-amplification and KRAS mutational 
status have been assessed previously and the pathology report is available to document findings. 
May be performed as part of prescreening outside the 14-day screening period, provided separate 
informed consent has been obtained. 
 Screening 


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o Part 1: Eligibility assessment for KRAS mutational status will be done using archival 
tumor tissue, whenever possible. If archival tissue is not available, tissue from a 
tumor biopsy performed during screening will be used.  
Assessment of MET-amplification status is not required, but tissue should be assessed 
if feasible. 
o Part 2:  
Eligibility assessment for KRAS mutational status may be done using archival tumor 
tissue. If archival tissue is not available, tissue from the tumor biopsy performed 
during screening will be used. Refer to Section 8.3.4. 
It is preferred that the eligibility assessment for MET-amplification be done using 
tissue from a tumor biopsy performed during screening, however archival tumor 
tissue may be used at the investigator’s discretion. 
Note: If a new biopsy is performed for MET-amplification testing, tissue from this biopsy 
may be used for KRAS mutation testing as well.  
During Part 2 ONLY, peripheral blood collection for KRAS-mutation assessment and for 
MET-amplification assessment in ctDNA is allowed as a local pre-screening methodology by 
Guardant360 analysis. Other liquid biopsy methodologies, except if used to detect METEx14Del, 
will only be allowed if previously approved by the Sponsor. Subsequent required tumor tissue 
evaluation to confirm MET-amplification must meet the protocol-specified inclusion criteria.   
NSCLC METEx14Del Cohort (pre-protocol v8.0): Eligibility assessment for METEx14Del 
status will be done according to local institutional standards.  Assessment in ctDNA 
by Guardant360 technology or equivalent is allowed.  Subsequent confirmation in 
tumor tissue is preferred but not required, however, archival tissue to be submitted, if 
available (applies only to patients with METEx14Del tumors entered prior to suspension 
of the Basket Cohort and establishment of NSCLC METEx14Del Cohort). 
8.3.4 Tumor Biopsy for Eligibility Assessment and Biomarker Analysis (Part 1 and Part 2 
Basket Cohort) 
To be assessed locally for eligibility:  
 Screening; Part 1 and Part 2, if applicable as per Section 8.3.3 (i.e., Basket Cohort) 
Note: It will be permissible to perform this procedure outside the 14-day screening period, 
provided informed consent for the trial has been obtained 
To be assessed centrally for biomarker analysis:  
 Screening 
o Part 1: Optional; only applicable for patients with known MET-amplification who 
consent to this optional procedure; to be performed after confirmation of eligibility 
o Part 2:  


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Basket Cohort: Required, if archival tissue is unavailable or insufficient for central 
analysis; to be performed after confirmation of eligibility  
 
Note: Tissue from a tumor biopsy performed during screening is preferred, however archival 
tissue may be submitted for central analysis at the Investigator’s discretion, provided the 
archival tissue is suitable as specified in the laboratory manual. It must be ensured that the 
archival tissue can be made available to the central laboratory prior to deciding to omit the 
tumor biopsy procedure at time of screening 
NSCLC METEx14Del Cohort:  Optional 
 Post-dosing 
If feasible, it is preferred that the second biopsy is taken from the same tumor site from 
which the first biopsy was taken. 
o Part 1: Optional; only applicable for patients with known MET-amplification who 
consent specifically to this optional procedure; to be performed as specified below for 
Part 2 patients 
o Part 2:  
Basket Cohort: Required; EOC2 (i.e., coinciding with time of first response 
assessment) or upon PD, whichever occurs first 
Note: EOC assessments may be performed at any time during the week prior to Day 1 of the 
next cycle, including Day 1 of the next cycle, prior to dosing   
NSCLC METEx14Del Cohort: Optional, at the timepoint specified above 
 
8.3.5 Tumor Biopsy for MET Status and Biomarker Analysis (Part 2 NSCLC MET-
Amplified Cohort and NSCLC METEx14Del Cohort) 
To be assessed centrally:  
 Screening (Mandatory) 
Note: It will be permissible to perform this procedure outside the 14-day screening period, 
provided informed consent for the trial has been obtained 
o NSCLC MET-Amplified Cohort: Required; tissue from a newly performed pre-dosing 
tumor biopsy must be submitted for central confirmation of MET-amplification  
(Patients may be entered and treated based on local assessment of a recent tumor 
biopsy [if available and performed outside of the screening process as part of the 
site’s usual practice] provided no intervening antineoplastic therapy has been 
administered; otherwise tissue from a newly performed biopsy must be obtained and 
submitted) 
o NSCLC METEx14Del Cohort:  Required; tissue from a recent or newly performed pre-
dosing tumor biopsy must be submitted for central assessment of METEx14Del  


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(Patients may be entered and treated based on local institutional standards; 
alternatively, assessment in ctDNA by Guardant360 technology or equivalent is 
allowed; a recent [as defined above] or newly performed pre-dosing biopsy must still 
be submitted) 
 Post-dosing (Optional) 
EOC2 (i.e., coinciding with time of first response assessment) or upon PD, whichever 
occurs first 
Note: EOC assessments may be performed at any time during the week prior to Day 1 of the 
next cycle, including Day 1 of the next cycle, prior to dosing   
To include a tumor biopsy performed by a core biopsy of a locally recurrent or metastatic lesion. 
This procedure will take place prior to the first Sym015 administration. The tumor biopsy must 
be performed with minimal morbidity to the patient by a percutaneous core needle biopsy either 
with or without the aid of an imaging modality chosen at the discretion of the physician 
performing the biopsy.  
Biopsy specimens will be obtained using standard sterile surgical techniques and formalin-fixed, 
paraffin-embedded according to standard laboratory techniques. All tumor tissue samples should 
be reviewed by a pathologist to confirm the presence of tumor cells before the tissue sample 
(blocks or slides) is sent to the central laboratory for analysis. A detailed laboratory manual 
specifying sample collection, handling, storage, and shipment will be provided to the trial sites.  
Analysis of tumor biopsies may include genes and/or proteins that are unknown or have not been 
included in the scientific hypotheses of this trial, but that, during the collection of data from this 
trial, may evolve as new candidate genes and markers related to Sym015 safety, efficacy, or 
mechanism of action.  
All analyses will be related to and used only in connection with the data collected in the present 
trial and future development of Sym015, and the identity of the patient will remain confidential. 
The analyses will not have any medical consequences for the patient or their relatives. 
Tumor biopsy samples will be stored for up to 15 years after completion of the trial, where after 
all samples will be destroyed.  
8.4 
Pharmacokinetic Assessments 
PK samples will be taken according to the schedules shown in Table 9.  
Analysis of PK will be performed at a central laboratory. A detailed laboratory manual 
specifying sample collection, handling, storage, and shipment will be provided to the trial sites. 


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In the event that a collected serum sample is inadequate or insufficient for PK analysis, the 
analysis of PK can be done using an anti-drug antibody (ADA) serum sample from the same time 
point, if available. 
Note:  Comprehensive collection of clinical samples is critical to the conduct of this study.  In situations 
where collection of EOI + 8h samples is logistically difficult due to clinic staff availability, the 
observation period may be shortened and an "end of day" sample may be obtained at the latest practical 
time.  Such an option (if to be routinely employed) is available only after previous discussion with and 
approval by the Sponsor. 
Table 9 
Schedule of Pharmacokinetic Assessments 
 
Cycle 1 
Cycles Thereafter 
EOT 
IM FUP 
Sampling Time Window 
D1-D3 
D8 
D15 
D1 
D15 
 
 
Part 1 / Part 2 Basket Cohort 
Prior to SOI 
- 4 h 
X 
 
X1 
X1 
X1 
 
 
EOI 
+ 10 min 
X 
 
X1 
X1 
X1 
 
 
EOI + 1 h 
±15 min 
X 
 
 
 
 
 
 
EOI + 2 h 
±30 min 
X 
 
 
 
 
 
 
EOI + 4 h 
±30 min 
X 
 
 
 
 
 
 
EOI + 8 h 
±90 min 
X 
 
 
 
 
 
 
EOI + 24 h 
±6 h 
X 
 
 
 
 
 
 
EOI + 48 h 
±12 h 
X 
 
 
 
 
 
 
During Visit 
NA 
 
X 
 
 
 
X 
X 
Part 2 NSCLC Cohorts (effective with protocol v8.0; December 2018) 
Prior to SOI 
- 4 h 
X 
 
X1 
X1 
X1 
 
 
EOI 
+ 10 min 
X 
 
X1 
X1 
X1 
 
 
EOI + 4 h 
±30 min 
X 
 
 
 
 
 
 
EOI + 48 h 
±12 h 
X 
 
 
 
 
 
 
During Visit 
NA 
 
X 
 
 
 
X 
X 
Abbreviations (in alphabetical order): D, day; EOI, End of Infusion, EOT, End of Treatment Visit; NA, Not Applicable; h, hour; min, minutes; 
1M FUP, 1-Month Follow-up Visit; SOI, Start of Infusion 
1) 
If Sym015 is paused, only one PK sample should be taken during the visit 
 
 
8.5 
Anti-Drug Antibody Testing 
To assess formation of ADA. All samples must be taken prior to the Sym015 infusion of that 
visit. Analysis of ADA and residual serum levels of Sym015 will be performed at a central 
laboratory. A detailed laboratory manual specifying sample collection, handling, storage, and 
shipment will be provided to the trial sites. In the event that a collected serum sample is 
inadequate or insufficient for ADA analysis, the analysis of ADA can be done using a PK serum 
sample from the same time point, if available. 


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 C1/D1 
 C2/D1 (Part 2 only) 
 Day 1 of to every second cycle thereafter, i.e., Cycle 3, 5, 7 etc. (prior to dosing)  
 EOT 
 1M FUP 
8.6 
Skin Biopsy (Part 1 only) 
To be performed only after eligibility has been confirmed  
Analysis of skin biopsy samples will be performed at a central laboratory. Biopsy specimens will 
be obtained using standard techniques and formalin-fixed, paraffin-embedded according to 
standard laboratory techniques. A detailed laboratory manual specifying sample collection, 
handling, storage, and shipment will be provided to trial sites.  
Skin biopsies are requested from a rash-free area. 
 Screening, after confirmation of eligibility 
 EOC2 (i.e., coinciding with time of first response assessment) or upon PD, whichever 
occurs first  
Note: EOC assessments may be performed at any time during the week prior to Day 1 of the next 
cycle, including Day 1 of the next cycle, prior to dosing  
8.7 
Blood Sample for Genomic and Biomarker Analyses 
To include assessment of MET-amplification and METEx14Del status; analysis of all samples taken 
will be performed at a central laboratory. A detailed laboratory manual specifying sample 
collection, handling, storage, and shipment will be provided to the trial sites.  
 Screening (it will be permissible to perform this procedure outside the 14-day screening 
period, provided informed consent for the trial has been obtained) 
 EOC2 (coinciding with time of first response assessment or upon PD, whichever occurs 
first)  
Note: EOC assessments may be performed at any time during the week prior to Day 1 of the next 
cycle, including Day 1 of the next cycle, prior to dosing  
 EOT (if after EOC2; need not repeat if patient is discontinuing at the EOC2 or if a sample 
was obtained upon PD) 
Note:  If a tumor biopsy is collected at the same time point as the biomarker blood sample, 
the biomarker blood sample should be collected prior to collecting the tumor biopsy. 


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The purpose of the pharmacodynamic biomarker assessments is to develop an approach for the 
identification and validation of genes or proteins that may predict which patients are likely to 
respond to Sym015, and that may change with the possible development of acquired resistance to 
Sym015. Potential biomarkers of interest include genes, gene transcripts and proteins of the 
RTKs and molecules of the MET signaling pathway, including MET, HGF, EGFR, HER2, 
HER3, IGF1R, ROS1, RET, PIK3CA, PTEN, cMYC, KRAS, NRAS, BRAF, AKT1, FGFR, and 
RON. 
Analysis of biomarker blood samples may include genes and/or proteins that are unknown or 
have not been included in the scientific hypotheses of this trial, but that, during the collection of 
data from this trial, may evolve as new candidate genes and markers related to Sym015 safety, 
efficacy, or mechanism of action.  
All analyses will be related to and used only in connection with the data collected in the present 
trial and future development of Sym015, and the identity of the patient will remain confidential. 
The analyses will not have any medical consequences for the patient or their relatives. 
Biomarker samples will be stored for up to 15 years after completion of the trial, where after all 
samples will be destroyed. 
8.8 
Handling of Biological Samples  
All biological samples to be analyzed locally will be collected and handled according to 
institutional practices. 
All biological samples to be analyzed centrally will be collected and handled according to a 
detailed laboratory manual. 
Retention time for biologic specimens will be specified in the laboratory manual. 
8.9 
Follow-up Assessments 
Assessments at the 1M FUP Visit include disease status and subsequent cancer therapy. 
After the 1M FUP Visit, the Investigator will make every effort to obtain follow-up information 
on response assessment and/or OS every 2 months. Response assessment follow-up is required in 
the event of an ongoing SD, PR or CR, as per RECIST v1.1 at the 1M FUP Visit, until PD or 
another therapeutic intervention is initiated. Survival follow-up is required until death, 
withdrawal of consent, or termination of the trial. This continued follow-up does not require an 
in-person visit at the trial site, but may be obtained by collection of data/documentation. 


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8.10 Appropriateness of Measurements 
Standardized methods for assessments of efficacy and safety variables will be used. 


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9. 
ADVERSE EVENTS 
9.1 
Definitions of Adverse Events 
9.1.1 Adverse Event 
An AE is any untoward medical occurrence in a patient or a clinical investigation subject 
administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IMP, whether or not considered related to the IMP.  
Causality for the above-mentioned AE will be assessed appropriately as: Related to IMP, 
Possibly Related to IMP, Probably Related to IMP, Unlikely Related to IMP, or Not Related to 
IMP. In addition, any AE, regardless of causality, that also meets the seriousness criteria, will be 
reported on an SAE form. 
9.1.2 Events Not to be Considered as Adverse Events 
A pre-existing condition (i.e., a disorder that is present before the AE recording period starts and 
is noted on the medical history/physical examination form) should not be recorded as an AE 
unless the condition worsens, or episodes increase in frequency during the AE recording period. 
PD will not be captured as an AE unless the nature of the PD is different than expected (i.e., 
other diagnosis and/or signs/symptoms that are not typical of PD).  
Note:  PD may be reported as an AE in the case of patient death, with death being the outcome of the event. 
An abnormal laboratory value or an abnormality in physiological testing (such as ECGs) need 
not be reported as an AE unless one of the following applies: 
 The Investigator considers the abnormality clinically significant  
 The event meets the definition of an SAE 
 The event requires an intervention 
 The event results in an action taken with Sym015 (dose-reduction and/or withdrawal) 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
recorded as AEs. A medical condition for which an unscheduled procedure was performed, 
should however be recorded if it meets the definition of an AE. For example, an acute 
appendicitis should be recorded as the AE and not the appendectomy. 


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Procedures to support the treatment regimens, such as insertion of central venous catheters, etc. 
should not be recorded as AEs, unless the procedures result in complications. 
9.1.3 Adverse Events of Medical Interest 
Not applicable. 
9.1.4 Serious Adverse Events 
An SAE is an AE that meets one or more of the following outcome criteria: 
 Results in death 
Note: In the case of deaths, the event(s) leading to the death should be recorded and reported as 
SAE(s) with the outcome “Fatal”. The death itself will not be reported as an event (SAE), unless 
the cause of the death is unknown (e.g., in case of unexplained or sudden death)  
 Is life-threatening 
Note: The term "life-threatening" in this definition refers to an event in which the patient is at 
immediate risk of death at the time of the event; it does not refer to an event which hypothetically 
might cause death if it was more severe 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is medically important  
Note: Medical and scientific judgment must be exercised in deciding whether an AE is believed 
to be “medically important”. Medically important events may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above 
 
9.1.5 Events that Do Not Meet the Definition of Serious Adverse Events 
PD will not be captured as an SAE unless the nature of the PD is different than expected (i.e., 
other diagnosis and/or signs/symptoms that are not typical of PD).  
Note:  PD may be reported as an SAE in the case of patient death, with death being the outcome of the event. 
Elective surgery or other scheduled hospitalization periods that were planned before the patient 
was included in this trial are not to be recorded as SAEs, unless an outcome is considered 
serious.  
Hospitalization for observation or convenience following the Sym015 infusions without an SAE 
occurring should not be recorded as an SAE, e.g., if a patient is hospitalized merely for 


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observation, or if a patient finalizes the infusion at a time of day requiring a convenience 
overnight stay in the hospital.  
If procedures to support the treatment regimens require hospitalization, they should not be 
recorded as SAEs. However, in cases where a procedure results in complications 
requiring/prolonging hospitalization, this must be recorded and reported as an SAE. 
9.2 
Adverse Event Recording and Reporting Instructions 
9.2.1 Adverse Event Recording Period 
All AEs will be recorded from signing of informed consent for participation in the trial. The 
recording period ends at the time of the 1M FUP Visit.  
Note: Patients who sign informed consent and are subsequently deemed to be screening failures will be 
followed for the occurrence of SAEs/AEs until it is determined that they will not be participating in the 
trial. 
The Investigator must record all directly observed AEs and all AEs spontaneously reported by 
the patient. A general, open-ended type of question should be used to elicit a response from the 
patient, such as, “How have you been feeling?” or “Have you had any health problems since 
your last visit?”. 
All AEs that occur in patients during the AE recording period must be recorded/entered on the 
AE section of the Case Report Form (CRF), whether or not the event is assessed as related to 
Sym015. If the AE is serious, the SAE report forms must also be completed and submitted. Refer 
to Section 9.3. 
9.2.2 Diagnosis 
A diagnosis should be recorded if possible. If no diagnosis is available, signs and symptoms 
should be recorded instead. 
9.2.3 Severity 
The Investigator will use the CTCAE v4.03 to describe the severity of an AE. If the severity of 
an AE is not specifically graded by the CTCAE guidance document, the Investigator should use 
the general definitions of Grades 1 to 5 as per the following, and use his/her best medical 
judgment to describe the severity of the AE: 
 Grade 1: Mild 
 Grade 2: Moderate 


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 Grade 3: Severe 
 Grade 4: Life-threatening or disabling 
 Grade 5: Death caused by the event 
Changes in severity of AEs will be recorded. 
Generally, an AE of CTCAE Grade 4 or 5 qualifies for SAE reporting to the Sponsor or 
designee. However, a laboratory abnormality of CTCAE Grade 4 does not need to be reported as 
an SAE, unless it meets one of the seriousness criteria in Section 9.1.4. 
9.2.4 Relationship to Investigational Medicinal Product/Sym015 
The Investigator must assess causal relationship to the IMP, Sym015. Relatedness has to be 
assessed and recorded within the initial report (CRF and SAE report form). 
The causal relationship is an assessment of whether or not the event is related to the use of the 
IMP. It is not an evaluation of whether or not the event could hypothetically occur in the 
investigational patient population. 
The causal relationship of an AE to the IMP, Sym015, will be rated as follows: 
Not Related: The AE is not related to the IMP, which means the event: 
 Does not follow a reasonable temporal sequence from drug administration  
 Is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient 
 The AE is clearly NOT related to the IMP 
Unlikely Related: The AE is considered not related to the IMP based on the following: 
 Does not follow a reasonable temporal sequence from administration of drug 
 Could readily be a result of the patient’s clinical state, environmental, or toxic factors, 
or other modes of therapy 
 Does not follow a known response pattern to the suspected drug 
 Does not reappear or worsen when the drug is re-administered 
Possibly Related: The AE might not be related, but possibility cannot be ruled out with 
certainty and therefore would be considered related based on: 
 Follows a reasonable temporal sequence from administration of drug 


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 Could readily have been a result of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy 
 Follows a known response pattern to the suspected drug 
Probably Related: It has been determined with a high degree of certainty that the AE is 
associated with administration of IMP based on: 
 Follows a reasonable, temporal sequence 
 Cannot be reasonably explained by known characteristics of the patient’s clinical 
state, environmental, or toxic factors, or other modes of administered therapy 
 The AE disappears or decreases in severity upon cessation of drug, or reduction in 
dose. 
 Follows a known response pattern to the suspected drug 
Related: The AE is related to the IMP, which means the event: 
 Follows a reasonable temporal sequence from drug administration  
 Abates upon discontinuation of the IMP (de-challenge)  
 Is confirmed by reappearance of the reaction on repeat exposure (re-challenge)  
 Cannot be reasonably explained by the known characteristics of the patient’s clinical 
state  
 Is not likely to have been produced by the patient’s clinical state or by other modes of 
therapy administered to the patient 
9.2.5 Outcome 
Outcome of the AE must be assessed by the Investigator utilizing one of the following terms: 
 Recovered 
 Recovered with sequelae (if recovered with sequelae, specify sequelae) 
 Not recovered 
 Fatal 
 Unknown 
Instructions for reporting changes in an ongoing AE during a patient's participation in the trial 
are provided in the instructions that accompany the AE CRF pages. 
9.2.6 Follow-up of Adverse Events 
All AEs should be followed until they are resolved or until the 1M FUP Visit, whichever comes 
first. 


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Note: Patients who sign informed consent and are subsequently deemed to be screening failures will be 
followed for the occurrence of SAEs/AEs until it is determined that they will not be participating in the 
trial. 
9.3 
Serious Adverse Event Recording and Reporting 
All SAEs occurring at any time from signing of informed consent for participation in the trial 
and until the 1M FUP Visit must be recorded on the SAE Report Form and recorded as an SAE 
in the CRF. 
Note: Patients who sign informed consent and are subsequently deemed to be screening failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
In case of an SAE, the Investigator must, within 24 hours of first awareness of the event, report 
the SAE to the Sponsor (or designee) by fax or e-mail. Fax number(s) and e-mail address(es) will 
be stated on the SAE Report Form and the SAE Report Form Completion Instructions. SAE 
follow-up information must also be reported to the Sponsor (or designee) within 24 hours of 
awareness. 
SAEs still ongoing after the 1M FUP Visit should be followed on a regular basis according to the 
Investigator’s clinical judgment, until the event resolves or until the Investigator assesses it as 
chronic or stable. The Sponsor (or designee) will pursue sufficient information and will return to 
the trial sites for such information as deemed required. 
If the Investigator becomes aware of an SAE that occurred after the 1M FUP Visit and finds it to 
be related to the IMP (possibly-, probably-, or related to the IMP) or trial conduct, it must be 
recorded and reported to the Sponsor (or designee) as an SAE. These SAEs considered related to 
the IMP and occurring after the 1M FUP Visit will not be reported in the CRF but only on an 
SAE Report Form for recording in the Safety Database. 
The Investigator should be aware of local reporting regulations to the Institutional Review Board 
(IRB)/Ethics Committee (EC). The Sponsor (or designee) will either supply the Investigator with 
the reports, which should be forwarded to the IRB/EC, or report directly to the IRB/EC 
depending on local regulations. 
9.4 
Safety Reporting to Health Authorities, Institutional Review Boards/Ethics 
Committees, and Investigators 
Reportability of an SAE as a “suspected unexpected serious adverse reaction” (SUSAR) will be 
determined solely by the Sponsor, based on seriousness, causality and expectedness.  In addition 
to SUSARs, the Sponsor or designee is responsible for reporting all relevant safety information 
regarding SUSARs, or other safety developments, to appropriate Health Authorities and central 


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IRBs/ECs, as well as participating Investigators. Requirements for reporting SUSARs to local 
IRBs/ECs will be handled via the Investigator. The timeline for notification of SUSARs is within 
7 calendar days for fatal/life-threatening events and within 15 calendar days for all other 
SUSARs.  
Additionally, the annual Development Safety Update Report (DSUR) will be submitted by the 
Sponsor or designee to all appropriate Health Authorities and central IRBs/ECs as per ICH 
Guidelines. Submission of the DSUR to local IRBs/ECs will handled as per local regulations 
and/or requests.  
9.5 
Dose-Limiting Toxicities (Part 1 Only) 
9.5.1 Definition of Dose-Limiting Toxicities 
A DLT is defined as any of the following toxicities that occur during the DLT observation 
period, if considered related (causality rating of possibly, probably, or related) to Sym015:   
1. Grade 3 non-hematologic toxicity regardless of duration, with the exceptions of:  
a. Grade 3 nausea, vomiting, diarrhea, or fatigue lasting ≤ 2 days with best supportive 
care  
b. Grade 3 asymptomatic electrolyte abnormalities lasting ≤ 3 days that are not 
considered clinically relevant by the Investigator and that resolve with medical 
therapy  
2. Any Grade 4 non-hematologic toxicity, with the exception of: 
a. Grade 4 asymptomatic electrolyte abnormalities lasting < 3 days that are not 
considered clinically relevant by the Investigator and that resolve with medical 
therapy.  
3. Neutropenia that is: 
a. Grade 3-4 febrile neutropenia 
b. Grade 4 and sustained (i.e., ANC <500 per mm3, duration >5 days) 
4. Thrombocytopenia that is: 
a. Grade 3 with clinically significant hemorrhage 
b. Grade 4 (platelets < 25,000 per mm3) 
5. AST/ALT elevation > 3xULN with bilirubin elevation > 2xULN that cannot be explained 
by factors not related to study drug 
6. Inability to complete Cycle 1 at the assigned dose due to ≥ Grade 3 toxicity 


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7. Treatment delays >2 weeks from the scheduled “next dose” due to ≥ Grade 3 toxicity 
9.5.2 Observation Period for Dose-Limiting Toxicities 
The observation period for DLTs is defined as Cycle 1 with a final assessment 14 (±2) days after 
the last dose of Cycle 1 or prior to dosing on C2/D1. 
Cycle 1 must have been completed at the assigned dose of Sym015 for a patient to complete the 
DLT observation period. 
9.5.3 Reporting of Dose-Limiting Toxicities 
All presumed DLTs must be reported to the Sponsor or designee within 24 hours after the 
Investigator or designee have become aware of the event. In addition, DLTs fulfilling the SAE 
criteria must be reported in an expedited manner according to the procedure for SAEs, as 
outlined in Section 9.3. 
9.6 
Reporting of Infusion-Related Reactions 
The definition of an IRR is included in Section 7.1.3.6. 
All IRRs must be reported in the CRF as an AE with the term “Infusion-related Reaction” 
followed by a specification of symptoms (e.g., “Infusion-related Reaction with dyspnea and 
flushing”).  
To facilitate ongoing safety review throughout the course of this trial, the occurrence of ≥ Grade 
2 IRRs must be reported to the Sponsor or designee within 24 hours of occurrence. 
IRRs fulfilling the SAE criteria must be reported in an expedited manner according to the 
procedure for SAEs, as outlined in Section 9.3. 
9.7 
Pregnancy 
If any trial patient becomes pregnant during the course of the trial, the patient must be 
discontinued from Sym015 immediately and the pregnancy must be reported to the Sponsor or 
designee according to the same timelines as an SAE. While pregnancy is not considered an AE, 
all pregnancies are tracked as SAEs within the safety database in order to follow-up on exposure 
to the fetus/infant.  
Pregnancies reported in female partners of male trial patients must also be included in the 
database; therefore, a pregnant partner must provide informed consent before information can be 
collected. 


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All pregnancies must be followed up every third month to determine outcome (including 
premature termination) and status of mother and child. Pregnancy complications and elective 
terminations for medical reasons must be reported as AEs or SAEs as appropriate (trial patients 
only). Elective terminations for non-medical reasons should not be reported as AEs. Spontaneous 
abortion must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s attention after 
the patient has completed the trial and considered by the Investigator as possibly related to the 
IMP (possibly, probably, or related to Sym015), must be promptly reported to the Sponsor or 
designee. 
All pregnancy information including follow-up information must be reported in a designated 
pregnancy form provided by the Sponsor or designee. 
 


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10. STATISTICS 
10.1 Statistical Considerations and Analysis Plan 
No formal hypothesis testing is planned.  Descriptive statistics will be used to summarize the 
safety, tolerability, pharmacokinetics, and clinical activity of Sym015 in all patient cohorts. 
Data will be described and summarized as warranted by sample sizes.  Listings will be used in 
place of tables in the event of small sample sizes.  Dose-escalation assessment will be based on 
the DLT-evaluable population, defined as patients who complete the DLT assessment window.  
All other analyses will be based on the safety-evaluable population, defined as all patients who 
receive any amount of the study drug. 
Continuous variables will be summarized with the use of means, standard deviations, medians, 
and ranges; categorical variables will be summarized using counts and percentages.  All 
summaries will be presented separately by cohort, in both Part 1 and Part 2 of the study. 
All details of the data analyses will be described in the Statistical Analysis Plan. 
10.2 Sample Size Determination 
The primary endpoint of Part 1 of the trial is the occurrence of DLTs measured during Cycle 1 of 
Sym015 administration. The number of enrolled patients will depend on the extent of observed 
DLTs independently in each cohort. Refer to Section 7.1.3.1 for a description of planned dose 
levels and decision points for dose-escalation. Based on a 3+3 design, it is planned to enroll 
between 12 and 15 patients during dose-escalation, however the actual number of patients will 
depend on observed DLTs.  
In Part 2 of the trial, the primary endpoint is documented, confirmed OR assessed by RECIST 
v1.1, at any time during trial participation by Investigator assessment. It is planned to include 25 
patients with various advanced solid tumor malignancies, documented and confirmed as MET-
amplified in the Basket Cohort, 20 patients in the NSCLC MET-Amplified Cohort, and 6-12 
patients in the NSCLC METEx14Del Cohort, for the total of approximately 51-57 patients in Part 2.  
No power and type I error considerations were used to determine the sample size in each cohort. 
Proposed sample sizes in Basket and NSCLC Cohorts should allow to obtain preliminary safety, 
PK, response, and pharmacodynamic information of Sym015 in the respective patient 
populations (Table 10). 


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The expected (target) range of OR in any of these three cohorts is in the range of 20%-50%, 
depending on histology, previous therapies, and other prognostic factors defining the enrolled 
patient population.  
Table 10 
90% Confidence Intervals for Observed Response Rates for N=20 and N=25 
 
Method Responses 
N 
Mean 
Lower 
Upper 
1 
exact 
1 
20 
0.05 
0.002561379 
0.2161062 
2 
exact 
2 
20 
0.10 
0.018065203 
0.2826185 
3 
exact 
3 
20 
0.15 
0.042169408 
0.3436638 
4 
exact 
4 
20 
0.20 
0.071353884 
0.4010281 
5 
exact 
5 
20 
0.25 
0.104080836 
0.4555824 
6 
exact 
6 
20 
0.30 
0.139553749 
0.5078184 
7 
exact 
7 
20 
0.35 
0.177310918 
0.5580345 
8 
exact 
8 
20 
0.40 
0.217068589 
0.6064151 
9 
exact 
9 
20 
0.45 
0.258650610 
0.6530686 
10 
exact 
10 
20 
0.50 
0.301953911 
0.6980461 
11 
exact 
11 
20 
0.55 
0.346931398 
0.7413494 
12 
exact 
12 
20 
0.60 
0.393584887 
0.7829314 
 
1 
exact 
1 
25 
0.04 
0.002049628 
0.1761207 
2 
exact 
2 
25 
0.08 
0.014403198 
0.2310399 
3 
exact 
3 
25 
0.12 
0.033519595 
0.2817225 
4 
exact 
4 
25 
0.16 
0.056562559 
0.3296083 
5 
exact 
5 
25 
0.20 
0.082290900 
0.3754051 
6 
exact 
6 
25 
0.24 
0.110056200 
0.4195200 
7 
exact 
7 
25 
0.28 
0.139475307 
0.4622089 
8 
exact 
8 
25 
0.32 
0.170303654 
0.5036416 
9 
exact 
9 
25 
0.36 
0.202377780 
0.5439332 
10 
exact 
10 
25 
0.40 
0.235586130 
0.5831620 
11 
exact 
11 
25 
0.44 
0.269853059 
0.6213784 
12 
exact 
12 
25 
0.48 
0.305129680 
0.6586113 
13 
exact 
13 
25 
0.52 
0.341388663 
0.6948703 
14 
exact 
14 
25 
0.56 
0.378621563 
0.7301469 
15 
exact 
15 
25 
0.60 
0.416838037 
0.7644139 
16 
exact 
16 
25 
0.64 
0.456066786 
0.7976222 
17 
exact 
17 
25 
0.68 
0.496358438 
0.8296963 
18 
exact 
18 
25 
0.72 
0.537791078 
0.8605247 
19 
exact 
19 
25 
0.76 
0.580479993 
0.8899438 
20 
exact 
20 
25 
0.80 
0.624594865 
0.9177091 
  


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10.3 Analysis Population 
Analysis sets will be defined in accordance with the consolidated ICH E9 GCP guidelines.  
The Full Analysis Set (FAS) will comprise all enrolled patients who have received at least one 
dose of Sym015. The FAS will be used for evaluation of all endpoints except evaluation of 
DLTs. The patients in the FAS will contribute to the analyses as allocated to treatment. For the 
evaluation of PK endpoints; patients, full profiles, or single measurements can be excluded from 
the analyses. The decision of excluding patients, full profiles, or part of profiles will be described 
in the clinical trial report (CTR). 
The DLT Analysis Set will comprise all patients in the FAS enrolled in Part 1, except patients 
who did not complete Cycle 1 (i.e., the initial 28-day period of Q2W dosing) for reasons other 
than drug toxicity. The DLT Analysis Set will be used for evaluation of DLTs. 
10.4 Primary Endpoint and Analysis 
10.4.1 Part 1, Dose-Escalation  
The primary objective of the dose-escalation part is to assess the safety and tolerability of 
Sym015. This will be assessed by the primary endpoint for Part 1, occurrence of DLTs during 
Cycle 1 of Sym015 administration. 
All DLT events will be listed by dose cohort and patient. A summary table of DLTs by System 
Organ Class (SOC) and Preferred Term will be presented for each dose cohort, if applicable. The 
summaries will include number of DLTs, and number and percentages of patients experiencing a 
DLT. The definition of a DLT is included in Section 9.5.1.  
The MTD is defined as the highest dose with a maximum of 1 out of 6 patients experiencing a 
DLT. The MTD may or may not be found within the dose levels tested. Based on an overall 
evaluation of the dose-escalation part, the Q2W RP2D and highest safe dose tested will be 
selected. The Q2W RP2D might not necessarily be the MTD or the highest administered dose.  
10.4.2 Part 2 
The primary objective of Part 2 is to evaluate the antitumor activity of Sym015 when 
administered at the Q2W RP2D. The primary endpoint is documented, confirmed OR, defined as 
documented PR or CR and assessed by RECIST v1.1 at any time during trial participation by 
Investigator assessment. The assessment will be performed after completion of Part 2 of the trial. 


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Number and percentages of patients with documented OR will be presented including 
corresponding 90% exact Confidence Intervals (CI), separately for each cohort. 
10.5 Secondary Endpoint and Analysis 
All statistical analyses of the secondary endpoints for both phases will be performed after 
completion of Part 2 of the trial. 
10.5.1 Efficacy Endpoints and Analyses 
All statistical analyses of the secondary endpoints will be presented using the FAS.  
The following anti-tumor response endpoints will be measured in Part 1: 
 Documented OR, defined as documented PR or CR and assessed by RECIST v1.1 at any 
time during trial participation by Investigator assessment. 
 Additionally, the following anti-tumor response endpoints will be measured in both Part 
1 and 2: 
o Duration of response (DR) 
o Best overall response (BOR) 
o SD for >4 months  
o Time to disease progression (TTP) as determined based on radiological evidence  
o Progression-free survival (PFS) 
o Overall survival (OS)  
Best overall response (BOR) by RECIST v1.1 will be summarized by trial part and dose cohort 
by means of counts and percentages for the categories CR, PR, SD, PD and NE.  In addition, the 
number and percentages of patients with SD for more than 4 months will be presented. 
Number and percentages of patients with documented OR in the dose-escalation part will be 
presented including corresponding 90% exact CI. All documented ORs (Part 1 and Part 2) will 
be listed including duration (in days) of OR, measured from time of first PR or CR to PD. 
Time to disease progression (TTP), PFS, and OS will be summarized using the product-limit 
method and Kaplan-Meier plots. The median TTP, PFS, and OS, including 90% CI, will be 
calculated. 
10.5.2 Other Efficacy Assessments 
Tumor markers will be listed and summarized descriptively, as appropriate. 


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10.5.3 Safety Endpoints and Analyses 
The safety endpoints are presented below. These endpoints will all be presented for the FAS by 
trial part. Safety data will be summarized using descriptive statistics and frequency distributions 
as appropriate. 
In Part 1 and Part 2 of the trial, the following safety endpoints will be assessed: 
 Nature, incidence and severity of AEs measured from baseline to end of trial participation  
 AEs leading to dose-reductions, dose delays and permanent treatment cessation 
 Changes in safety laboratory values from baseline to end of trial participation 
 Changes in vital signs and physical examinations from baseline to end of trial 
participation 
 Occurrence of ADAs to Sym015 measured in serum at selected timepoints from baseline 
to end of trial participation 
10.5.3.1 Adverse Events 
The AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) current 
version. AEs will be regarded as treatment emergent AEs (TEAEs) if they occur after first 
treatment. Non-treatment emergent AEs (non-TEAEs) are defined as AEs collected before 
dosing. TEAEs will be presented by SOC and Preferred Term unless stated otherwise. The 
frequencies of TEAEs will be presented including number and percentages of patients having 
experienced an event and the total number of events.  
AEs including SAEs are reported from signing of the informed consent for participation in the 
trial and until the end of trial participation. SAEs reported outside the required reporting window 
are only entered into the safety database and will be described separately in the report.  
Note: Patients who sign informed consent and are subsequently deemed to be screening failures will be 
followed for the occurrence of SAEs/AEs until it is determined that they will not be participating in the 
trial. 
All AEs will be listed. The TEAEs will be presented using summary tables by trial phase 
including: 
 AEs, in total and sorted by frequency  
 AEs by relationship 
 AEs by CTCAE Grade and maximum CTCAE Grade 


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 SAEs, in total, and by relationship 
 AEs leading to withdrawal from treatment 
 AEs leading to trial drug-interruption or dose-reduction 
 Fatal AEs 
10.5.3.2 Clinical Laboratory Values 
Biochemistry, hematology, and coagulation parameters will be presented using box plots by 
visits and by cohort and trial part. In addition, individual patient biochemistry, hematology, and 
coagulation parameters during the trial will be presented graphically using longitudinal plots. 
Urinalysis parameters will be summarized using descriptive statistics. 
Laboratory values outside normal range will be flagged, and all laboratory values will be listed 
including CTCAE grading of abnormal values. 
10.5.3.3 Other Safety Assessments 
Change in vital signs from baseline to end of trial participation will be summarized by visit, 
cohort, and trial part. Normal and abnormal findings in physical examination and ECG 
measurements will be presented in shift tables by visit, cohort, and trial part. 
ECOG PS, body weight, and ADA results will be listed. 
10.5.4 Pharmacokinetic Endpoints and Analyses 
The PK endpoints will be derived based on the concentration time curves of Sym015, and the 
first infusion of Sym015 in both parts of the trial.  Refer to Table 11. 


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Table 11 
PK Endpoints Definitions and Derivations 
Symbol 
Definition and derivation 
Ctrough 
Trough concentration (i.e., concentration of Sym015 
measured pre-infusion) 
AUCτ 
 
Area under the concentration-time curve in a dosing 
interval (i.e., from time zero (end of infusion) up to 336 
hours or 504 hours depending on regimes). AUCτ will 
be calculated using the linear trapezoidal method and 
interpolated in case of measurements after 336/504 
hours, or extrapolated using terminal rate constant and 
the last quantifiable concentration, Cz 
Cz 
Last quantifiable concentration. Cz is not an endpoint, 
but is used for derivation of endpoints 
AUCnorm, τ 
 
Dose normalized area under the concentration-time 
curve in a dosing interval, calculated as AUC τ divided 
by the dose infused 
Cmax 
Maximum concentration 
Tmax 
Time to reach maximum concentration 
λz 
Terminal rate constant (negative of the slope of an ln-
linear regression of the un-weighted data considering 
the terminal phase of the concentration-time curve ≥ 
limit of quantification. λz is not an endpoint, but is used 
for derivation of endpoints 
T½ 
Terminal elimination half-life, calculated as ln(2)/ λz 
CL 
Clearance (Dose/AUCτ)  
Vz 
Volume of distribution during the terminal phase 
(CL/ λz) 
 
Cmax, Ctrough and Tmax will be derived from observed data while AUC τ, AUCnorm, τ, CL, Vz, and 
T½ will be estimated using non-compartmental methods and actual time points. 
Individual curves of serum concentration versus time after the first dosing of Sym015 will be 
presented on log- and linear scale for all patients in the FAS. Furthermore, trough serum 
concentrations for the period from first dose to end of treatment will be presented on linear scale 
individual plots. In addition, mean concentration time curves will be presented on linear scale 
using nominal time point by cohort and trial part. All PK endpoints will be listed and 
summarized by cohort and trial part. 
10.5.5 Additional Endpoints and Analyses 
The following additional endpoints will be assessed in Part 1 and Part 2 of the trial: 


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 Part 1 only: MET-receptor down-regulation measured by percentage and nominal change 
in target expression from baseline to EOC2 or PD (whichever comes first) in skin biopsy 
samples 
 Biomarkers relevant to Sym015 activity 
 Tumor genetics, drug target genes, and other biomarker genes that are known to be 
involved in the development and progression of MET-amplified solid tumor malignancies 
The additional endpoints, outlined above may include genes that are unknown or have not been 
included in the scientific hypotheses of this trial, but that, during the collection of data from this 
trial, may evolve as new candidate genes and markers related to Sym015 safety, efficacy, or 
mechanism of action. 
Percentage and nominal change in target expression from baseline to EOC2 or PD (whichever 
comes first) in skin biopsy samples will be presented. Descriptive statistics will be used, 
including scatter plots of values at EOC2 versus baseline. 
Potential biomarkers include genes, gene transcripts, and proteins of RTKs and molecules of the 
MET signaling pathway. All biomarkers will be listed and descriptively summarized. 
Exploratory analyses using the biomarkers might be performed. 
10.6 Interim Analysis 
No interim analysis is planned. 
10.7 Deviations from the Statistical Plan 
Any deviation(s) from the original analysis plan will be described in a protocol amendment 
and/or in a statistical analysis plan and/or in the final CTR, as appropriate. 


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11. ETHICS 
11.1 Institutional Review Board/Ethics Committee 
An IRB/EC will review the protocol and any amendments and advertisements used for 
recruitment, as well as the informed consent documents, their updates (if any), and any other 
written materials given to the patients. The CTR will include a list of all IRBs/ECs to which the 
protocol has been submitted and the name of the committee chair. 
11.2 Patient Information and Informed Consent 
The Investigator or his/her designee must obtain written informed consent from each patient 
before any trial related procedures are performed. Each patient must receive full patient 
information before giving consent. The patient information must contain full and adequate verbal 
and written information regarding the objective and procedures of the trial and the possible risks 
involved. 
Before signing the informed consent form the patient must be given sufficient time to consider 
his/her possible participation. Each patient must also be informed about his/her right to withdraw 
from the trial at any time. 
Each patient must sign the informed consent form; the patient receives a copy of the signed form 
and the original is retained in the Investigator Site File (ISF). The informed consent form must 
be signed and dated both by the patient and by the Investigator or designee providing the 
information to the patient. 


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12. SAFETY SURVEILLANCE SET-UP 
12.1 Safety Review 
An SMC will be established. This committee will include Investigator(s), Medical Monitor(s), 
Drug Safety Physician, and Sponsor’s medical representatives. The SMC will review clinical and 
laboratory safety data regularly throughout the trial and make decisions regarding the 
advisability of continuing accrual to a particular dose cohort, and/or escalating the dose and 
allowing accrual to a higher dose cohort.  In order to do so, the Investigator must ensure to report 
safety data to the Sponsor or designee in a timely manner. This includes, but is not limited to: 
 SAEs must be reported within 24 hours of awareness (SAE report form) 
 DLTs must be reported within 24 hours of occurrence 
 IRRs of ≥ Grade 2 must be reported within 24 hours of occurrence 
 All AEs will be reported in the CRF in a timely manner 
 Dose-modifications (i.e., dose-reduction, temporary interruptions regardless of cause) 
will be reported in the CRF in a timely manner 
 Local laboratory data will be reported in the CRF in a timely manner  
Availability of these data will enable the Sponsor to act promptly in response to safety signals 
and to ensure Health Authorities, as well as Investigators, who may be participating in other 
Sym015 clinical trials, are informed of events occurring during this trial.  
Safety teleconferences will be held between the Investigational Site(s) and the Sponsor and/or 
designee. Patients will be carefully evaluated for evidence of all AEs, including potential 
cumulative and/or delayed toxicities throughout the duration of their time in the trial. 
 Part 1: It is intended that safety teleconferences will be held biweekly; however, 
frequency may fluctuate based on accrual and trial activity, as indicated 
 Part 2: It is intended that safety teleconferences will be conducted after enrollment of 
approximately 15 and 30 patients. If safety concerns emerge, more frequent meetings will 
be held on an ad hoc basis. 
 


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12.2 Other Safety Surveillance Activities 
A Medical Monitor is assigned to review and evaluate relevant clinical/safety information 
concerning the clinical trial. The responsibilities of the Medical Monitor include, but are not 
limited to: 
 Evaluation of coding and trending of AEs in conjunction with the Drug Safety physician 
 Performing surveillance on potential safety signals in conjunction with the Drug Safety 
physician 
 Evaluating abnormal laboratory values 
 Providing medical support to the Sponsor in answering questions related to the trial 
protocol 
 Updating the SMC on trial status at scheduled meetings 
A Drug Safety physician is assigned to review, assess, and approve all SAE cases and associated 
reports. This physician will also perform the following: 
 Assess for safety signals and trends in conjunction with the Medical Monitor 
 Assist with questions regarding medical coding of SAEs 
 Discussing with the Sponsor Chief Medical Officer, any cases which may present a 
concern with regard to a signal or safety issue. 
 


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13. MONITORING AND QUALITY ASSURANCE 
13.1 Compliance with Good Clinical Practice 
The responsibilities of the Sponsor, the Monitor, and the Investigator are defined in ICH GCP 
E6(R2), and applicable regulatory requirements in the country where the trial takes place. The 
Investigator is responsible for adhering to the ICH GCP responsibilities of the Investigators, and 
for dispensing IMP only in accordance with this protocol or a signed amendment, and for its 
storage and safe handling throughout the trial. 
13.2 Source Documents 
Each trial site will permit authorized representatives of the Sponsor and relevant authorities 
direct access to (and when required by applicable law, to copy) clinical records for the purposes 
of quality assurance reviews, audits, and evaluation of the trial safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to: Hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ written diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
The Investigator must maintain source documentations for each patient in the trial and all 
information in the CRF must be traceable to these source documents in the patient’s file. Data 
not requiring a separate written record, i.e., data, which may be recorded directly in the CRF, 
will be defined before trial start. 
13.3 Monitoring 
Monitoring visits to the trial sites will be made periodically during the trial to ensure that all 
aspects of the protocol are followed. The Investigator must give the Sponsor and/or their 
representatives direct access to all relevant source documents to confirm consistency with the 
CRF entries. Source Data Verification will be conducted according to Sponsor or designee 
Standard Operating Procedures (SOPs) and requirements will be specified in a trial specific 
monitoring plan.  


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It is important that the Investigator and their relevant personnel are available during monitoring 
visits and possible audits and that sufficient time is devoted to the process. 


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14. DATA HANDLING AND RECORD KEEPING 
Study data collection, processing, transfer, and reporting, as well as handling of study personnel 
information, will be done in compliance with ICH E6(R2) GCP and all applicable data protection 
regulations, including Regulation (EU) 2016/679 of the European Parliament and of the Council 
of 27 April 2016 on the protection of natural persons with regard to the processing of personal 
data and on the free movement of such data (General Data Protection Regulation; GDPR). 
14.1 Data Protection 
The Investigator, Sponsor, and Sponsor designee(s) will ensure that the confidentiality of the 
patients’ data is preserved. Each participating site will maintain appropriate medical and research 
records for this trial, in compliance with ICH GCP E6(R2) and regulatory and institutional 
requirements for the protection of confidentiality of patients. 
14.2 Data Transactions and Access 
The trial data and any other documents transferred to the Sponsor or designee will not contain 
patient names or other confidential personal data, but patients will be identified using the 
assigned trial specific patient numbers. 
When data are transferred to the Sponsor or designee, access will be limited to relevant persons. 
Documents that are not for collection by the Sponsor, e.g., patient identification list and the 
signed informed consent forms, will be maintained by the Investigator in confidence. 
14.3 Data Processing 
A Data Management Plan (DMP) will be prepared for this trial. The Sponsor (or designee) will 
be responsible for data processing in accordance with applicable Data Management SOPs and 
the trial DMP. 
Once recorded within the electronic CRF, study data will pass through a set of preprogrammed 
data validation checks designed to identify inconsistencies and other data errors, and will 
undergo an additional study-specific data review process.  Data issues will be queried via the 
electronic data capture (EDC) system and query resolutions will be documented.  
Entry and processing of data other than those directly recorded on electronic CRFs by trial sites 
(e.g., imports of laboratory results) will follow vendors’ SOPs. Transfer of such data from 
vendors to Sponsor (or designee) will be handled according to vendors’ data transfer SOPs and 
the Sponsor data transfer requirements with full compliance to applicable regulations. 


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Database Lock will occur upon reaching the predefined data cut-off for primary analysis and 
completion of Sponsor’s (or designee’s) quality control and quality assurance procedures. 
Portable Document Format (PDF) files of the electronic CRFs will be provided to the 
Investigator upon removal of access to the electronic CRFs. 
14.4 Clinical Trial Report 
Following study completion, a final integrated clinical/statistical CTR will be prepared.  
14.5 Compliance with the General Data Protection Regulation 
The applicable EU data protection legislation requires that parties enter into a written contract if 
one party (data processor) processes personal data on behalf of the other party (data controller). 
This written contract must regulate the subject-matter and duration of the processing, the nature 
and purpose of the processing, the types of personal data and categories of data subjects, as well 
as the obligations and rights of the data controller. Accordingly, the parties must enter into a data 
processing agreement. To the extent the processing of personal data involves transfers of 
personal data to third countries (e.g., jurisdictions outside of the European Economic Area 
[EEA]), the parties will enter into the European Commission's standard contractual clauses 
between the data controller, the data processor, and all sub-processors, if any. The European 
Commission's standard contractual clauses ensure an adequate level of protection in relation to 
transfers of personal data to third countries. 
14.6 Retention of Trial Documents at Site 
The Investigator at each trial site must make arrangements to store the essential trial documents 
(including the ISF) after the end of the trial according to ICH GCP E6(R2) and local 
requirements. In addition, the Investigator is responsible for archiving all relevant source 
documents so that the trial data can be compared against source data after completion of the trial 
(e.g., in case of inspection from relevant authorities). The Investigator is required to ensure the 
continued storage of the documents, even if the Investigator should leave the clinic/practice or 
retire before the end of the required storage period. 


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15. REGISTRATION AND COMMUNICATION OF RESULTS 
15.1 Use of Information 
All unpublished information relating to this trial and the IMP is considered confidential by the 
Sponsor and shall remain the sole property of the Sponsor. The Investigator must accept that the 
Sponsor may use information from this trial in connection with the development of the IMP, and 
therefore, may disclose it as required to Investigators, government licensing authorities, Health 
Authorities of other governments, stock exchange market, and commercial partners. 
15.2 Registration and Publication 
The trial will be registered in one or more public trial registries (e.g., ClinicalTrials.gov). The 
trial results will be posted in the same clinical trial registries as the initial registration in 
accordance with the latest International Committee of Medical Journal Editors (ICMJE) 
recommendations (URL: www.icmje.org). 
The Sponsor acknowledges the Investigators’ rights to publish the full results of the trial, 
regardless of the outcome, in accordance with the latest ICMJE recommendations. 
The Coordinating Investigator and the Sponsor will decide on the publication strategy. The 
Coordinating Investigator has the right to publish and present the results and methods as first or 
last author of multicenter publications. Co-authorship will be decided by the Sponsor and the 
Coordinating Investigator and will be limited to a number of persons who have contributed 
substantially to the trial. The Sponsor will have representation in the list of authors. 
Publication is subject to the following conditions: 
 No publication before the completion of the trial at all participating trial sites without 
preceding written approval from the Sponsor 
 Publications shall not disclose any Sponsor confidential information and property (not 
including the trial results) 
 The Sponsor reserves the right to review results communications prior to public release 
and can embargo communications regarding trial results for a period that is less than or 
equal to 60 days. The Sponsor cannot require changes to the communication and cannot 
extend the embargo. 


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16. INSURANCE AND LIABILITY 
The Sponsor will obtain Human Clinical Trials Insurance for its legal liability in accordance with 
laws and regulations, and with limits customary or required by law in the territory in question. 


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17. CHANGES TO THE FINAL CLINICAL TRIAL PROTOCOL 
Changes to the protocol will not be implemented without agreement from the Sponsor and prior 
review and written approval from the appropriate Health Authority (as indicated) and the 
IRB/EC, except where necessary to eliminate an immediate hazard to the patients. No protocol 
waivers will be allowed.  
Protocol changes to eliminate an apparent hazard to trial patients may be implemented by the 
Investigator immediately. The Investigator must then, without delay, inform the local IRB/EC, 
and the Sponsor (or designee) will immediately notify local governing Health Authorities. 
 


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18. PREMATURE TERMINATION OF THE TRIAL OR A TRIAL SITE 
18.1 Premature Termination of the Trial 
If the Sponsor, the Coordinating Investigator, or the SMC discovers conditions arising during the 
trial, which indicates that the trial should be halted, the trial can be terminated after appropriate 
consultation between the Sponsor, the SMC, and the Coordinating Investigator. The Health 
Authority and IRB/EC will be notified in writing. The reason will be stated. 
Conditions that may warrant termination of the trial include, but are not limited to the following: 
 The discovery of an unexpected and significant or unacceptable risk to the patients 
enrolled in the trial 
 The discovery of lack of efficacy 
 Failure of the Investigators to enter patients at an acceptable rate in the trial as a whole 
 A decision on the part of the Sponsor to suspend or discontinue development of the IMP 
18.2 Premature Termination of a Trial Site 
The Sponsor can also decide to terminate single trial sites prematurely. Conditions that may 
warrant termination include, but are not limited to the following: 
 Insufficient adherence to protocol requirements 
 Failure to enter patients at an acceptable rate 
 


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19. REFERENCES 
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7. Cappuzzo F, Marchetti A, Skokan M, et al: Increased MET Gene Copy Number 
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12. Catenacci DVT, Tang R, Oliner KS, et al: MET as a prognostic biomarker of survival in 
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16. Paik PK, Drilon A, Fan PD, et al. Response to MET inhibitors in patients with stage IV 
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17. Seo JS, Ju YS, Lee WC, et al. The transcriptional landscape and mutational profile of 
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MET targeting in preclinical models of MET-expressing tumor cells. Mol Oncol. 2015 
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20. Kwak EL, Ahronian LG, Sirabegna G, et al: Molecular Heterogeneity and Receptor 
Coamplification Drive Resistance to Targeted Therapy in MET-Amplified 
Esophagogastric Cancer. Cancer Discov. 2015 Oct 2. 
21. Camidge DR, Ou SH, Shapiro G, et al: Efficacy and safety of crizotinib in patients with 
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2014 (suppl; abstr 8001). 
22. Kwak EL, LoRusso P, Hamid O, et al: Clinical activity of AMG 337, an oral MET kinase 
inhibitor, in adult patients (pts) with MET-amplified gastroesophageal junction (GEJ), 
gastric (G), or esophageal (E) cancer. J Clin Oncol 33, 2015 (suppl 3; abstr 1). 
23. Goldman JW, Rosen LS, Algazi AP, et al: First-in-human dose escalation study of 
LY2875358 (LY), a bivalent MET antibody, as monotherapy and in combination with 
erlotinib (E) in patients with advanced cancer. J Clin Oncol 31, 2013 (suppl; abstr 8093). 


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24. Strickler JH, LoRusso P, Yen C, et al: Phase 1, open-label, dose-escalation, and 
expansion study of ABT-700, an anti-C-met antibody, in patients (pts) with advanced 
solid tumors. J Clin Oncol 32:5s, 2014 (suppl; abstr 2507). 
25. Mol Cancer Ther. 2017 Aug 11. pii: molcanther.0374.2017. doi: 10.1158/1535-
7163.MCT-17-0374. [Epub ahead of print] 
<https://www.ncbi.nlm.nih.gov/pubmed/28802255> 
26. Poulsen TT, Grandal MM, Skartved NJØ, et al: Sym015: A highly efficacious antibody 
mixture against MET-amplified tumors. Clin Cancer Res. 2017 Oct 1;23(19):5923-5935. 
27. Aftimos PG, Barthelemy P, Rolfo CD, et al: A phase I, first-in-human study of argx-111, 
a monoclonal antibody targeting c-met in patients with solid tumors. J Clin Oncol 33, 
2015 (suppl; abstr 2580). 
28. Camidge DR, Moran T, Demedts I, et al: A randomized, open-label, phase 2 study of 
emibetuzumab plus erlotinib (LY+E) and emibetuzumab monotherapy (LY) in patients 
with acquired resistance to erlotinib and MET diagnostic positive (MET Dx+) metastatic 
NSCLC. J Clin Oncol 34, 2016 (suppl; abstr 9070). 
29. Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228–247.  
30. American Heart Association. Classification of Functional Capacity and Objective 
Assessment. Available at: 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/Previ
ousYears/Classification-of-Functional-Capacity-and-Objective-
Assessment_UCM_423811_Article.jsp 
31. Dela Cruz CS, Tanoue LT, and Matthay RA. Lung cancer: Epidemiology, etiology, and 
prevention. Clin Chest Med 2011; 32(4):doi:10.1016/j.ccm.2011.09.001. 
32. Tong JH, Yeung SF, Chan AWH, et al. MET amplification and exon 14 splice site 
mutation define unique molecular subgroups of non-small cell lung carcinoma with poor 
prognosis. Clinical Cancer Research 2016; 22(12):3048-3056. 
33. Ye S, Li, J, Hao K, et al. The efficacy and risk profile of c-Met inhibitors in non-small 
cell lung cancer: a meta-analysis. Scientific Reports 2016; 6:35770: 
doi:10.1038/srep35770. 
34. Felip E, Horn L, Patel JD, et al. Tepotinib in patients with advanced non-small cell lung 
cancer (NSCLC) harboring MET exon 14-skipping mutations: Phase II trial. J Clin Oncol 
2018; 36 (suppl; abstr 9016). 


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35. Wolf J, Seto T, Han J-Y, et al. Results of the GEOMETRYmono-1 phase II study for 
evaluation of the MET inhibitor capmatinib (INC280) in patients (pts) with METex14 
mutated advanced non-small cell lung cancer (NSCLC). Annals of Oncology 2018, 29(8), 
https://doi.org/10.1093/annonc/mdy424.090. 
 


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20. APPENDICES 
Appendix 1: Summary of Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
For details, see Eisenhauer EA, Therasse P, Bogaerts J, et al (2009). New response evaluation 
criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247 (29) 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
Measurable: 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. See also notes below on “Baseline documentation of target and non-
target lesions” for information on lymph node measurement. 
Non-measurable: 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
Special considerations regarding lesion measurability: 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 


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Bone lesions 
 Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above 
 Blastic bone lesions are non-measurable 
Cystic lesions 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts 
 “Cystic lesions” thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions 
Lesions with prior local treatment 
 Tumor lesions situated in a previously irradiated area, or other loco-regional therapy area, 
are usually not considered measurable unless there has been demonstrated progression in 
the lesion. Study protocols should detail the conditions under which such lesions would 
be considered measurable 
Methods of measurement 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 


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 Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. As noted above, when lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective and may also be reviewed at the end of the study 
 Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung 
 CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 
scans) 
 Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement 
 Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following CR or surgical resection is an endpoint 
 Tumor markers: Tumor markers alone cannot be used to assess objective tumor response 
 Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain). When effusions are 
known to be a potential adverse effect of treatment (e.g., with certain taxane compounds 
or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment can be considered if the measurable 
tumor has met criteria for response or SD in order to differentiate between response (or 
SD) and progressive disease 
Tumor response evaluation 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 


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measurable disease at baseline should be included in protocols where objective tumor response is 
the primary endpoint. Measurable disease is defined by the presence of at least one measurable 
lesion. Response criteria are listed in Table 12 and Table 13. 
 
Table 12 
Response Criteria for Evaluation of Target Lesions 
 
Evaluation of 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 
Progressive Disease 
(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.   
(Note: 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 13 
Response Criteria for Evaluation of Non-Target Lesions 
 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis) 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions.  
(Note: the appearance of one or more new lesions is also considered 
progression) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
 
 
Evaluation of Best Overall Response 
It is assumed that at each protocol specified time point, a response assessment occurs.  Table 14 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 


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Table 14 
Overall Response Status for Patients with Baseline Measurable 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 
Abbreviation: CR, complete response; NE, non-evaluable; PD, progressive disease; PR, partial response; SD, stable disease 
 
The best overall response is determined once all the data for the patient is known. 
 
Best response determination in trials where confirmation of CR or PR is NOT required:  
Best response in these trials is defined as the best response across all time points (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment has 
a best overall response of PR). When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best time point response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same patient lost to follow-
up after the first SD assessment would be considered NE. 
 
Best response determination in trials where confirmation of CR or PR is required:  
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). In this circumstance, 
the best overall response can be interpreted as shown in Table 15. 


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Table 15 
Best Overall Response when Confirmation of CR and PR Required  
Overall Response  
First Time Point 
Overall Response  
Subsequent Time Point 
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 
Abbreviation: CR, complete response; NE, non-evaluable; PD, progressive disease; PR, partial response; SD, stable disease 
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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21. SUMMARY OF CHANGES 
21.1 Protocol Amendment 1 dated 17-Feb-2016 
1. Modified Part 1 of the trial to make premedication mandatory prior to each dose of 
Sym015. Modified Part 2 of the trial to make premedication mandatory prior to each dose 
of Sym015 during Cycle 1   
2. Modified the definition of dose-limiting toxicities 
3. Modified protocol to discontinue therapy for all patients who meet Hy’s Law criteria that 
cannot be explained by factors not related to Sym015 
4. Included additional criteria for dose reduction due to toxicity 
5. Allowed GnRH analogs in patients with prostate cancer 
 
Refer to Table 16 for the changes in Protocol Amendment 1.  
 
Table 16 
Protocol Amendment 1 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
1. Synopsis: 
Investigational 
Medicinal 
Product, 
Dose(s) and 
Treatment 
Schedule 
Sym015 will be administered over a 1-hour (+10 
minutes) period following delivery of premedication 
prior to the first infusion. If the patient is without 
evidence of infusion related reactions (IRRs) after 
the first dose of Sym015, the Investigator may opt to 
withdraw premedications with subsequent dosing. 
 
For Part 1 of the trial, Sym015 will be administered over a 
1-hour (+10 minutes) period, following delivery of 
premedication prior to each infusion. For Part 2 of the trial, 
Sym015 will be administered over a 1-hour (+10 minutes) 
period, following delivery of premedication prior to each 
infusion during Cycle 1. In Part 2, if the patient is without 
evidence of infusion related reactions (IRRs) after Cycle 1, 
the Investigator may opt to withdraw premedication on a 
patient-by-patient basis with subsequent dosing. 
6.2 Exclusion 
Criteria 
Not applicable 
f. GnRH analogs in patients with prostate cancer 
6.3.1 Withdrawal 
from Treatment 
with Sym015 
Not applicable 
Patients who meet Hy’s Law criteria that cannot be 
explained by factors not related to Sym015… 
7.1.4.3 Dose-
Reduction for 
Sym015-Related 
Toxicities 
1. Grade 3 non-hematologic toxicity regardless of 
duration, with the exceptions of:  
b.     Grade 3 asymptomatic electrolyte 
abnormalities… 
 
3. Neutropenia that is: 
a. 
Grade 3 or 4, associated with fever (ANC 
<1000 per mm3; temperature >38.5ºC), 
and requiring antibiotic therapy  
b. 
Grade 4 and sustained (i.e. ANC <500 per 
mm3, duration >5 days) 
 
4. Thrombocytopenia that is Grade 4 (platelets 
<25,000 per mm3) 
1. Grade 3 non-hematologic toxicity regardless of duration, 
with the exceptions of:  
b.     Grade 3 asymptomatic electrolyte 
abnormalities… without requiring 
hospitalization 
 
3. Neutropenia that is: 
a. 
Grade 3-4 febrile neutropenia 
b. 
Grade 4 and sustained (i.e. ANC <500 per mm3, 
duration >5 days) 
 
4. Thrombocytopenia that is: 
a. 
Grade 3 with clinically significant hemorrhage 
b. 
Grade 4 (platelets <25,000 per mm3) 
7.2.1 Pre-
Medication for 
Sym015 
Infusions 
Prior to the first infusion of Sym015, all patients will 
receive…  
 
If a patient is without evidence of IRRs after the first 
dose of Sym015, the Investigator may opt to 
withdraw premedications with subsequent dosing in 
order to determine whether such continued therapy 
is necessary in that patient. Where practical, it is 
recommended that withdrawal of premedication be 
For Part 1 of the trial, premedication is mandatory prior to 
each dose of Sym015. 
 
For Part 2 of the trial, premedication is mandatory prior to 
each dose of Sym015 during Cycle 1. 
 
All patients will receive the following premedication… 
 
In Part 2, if a patient is without evidence of IRRs after 


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Table 16 
Protocol Amendment 1 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
done in a gradual fashion. 
For those patients who have previously experienced 
an IRR, consideration should be given to continuing 
premedications for at minimum 1 to 2 additional 
doses. 
 
Cycle 1, the Investigator may opt to withdraw 
premedication on a patient-by-patient basis with 
subsequent dosing in order to determine whether such 
continued therapy is necessary in that patient. Where 
practical, it is recommended that withdrawal of 
premedication be done in a gradual fashion. 
 
For those patients who experienced symptoms suggestive 
of an IRR after Cycle 1, consideration should be given to 
continuing premedication for at minimum 1 to 2 additional 
doses before any future attempt to withdraw. 
7.5.2 Prohibited 
Medication/ 
Therapy and 
Procedures 
During the Trial 
Not applicable 
o 
GnRH analogs in patients with prostate cancer 
9.5.1 Definition 
of Dose-Limiting 
Toxicities 
A DLT is defined as any of the following… 
 
3. Neutropenia that is: 
a. 
Grade 3 or 4, associated with fever (ANC 
<1000 per mm3; temperature >38.5ºC), 
and requiring antibiotic therapy  
b. 
Grade 4 and sustained (i.e. ANC <500 per 
mm3, duration >5 days) 
4. Thrombocytopenia that is Grade 4 (platelets 
<25,000 per mm3) 
A DLT is defined as any of the following... 
 
3. Neutropenia that is: 
a. 
Grade 3-4 febrile neutropenia 
b. 
Grade 4 and sustained (i.e. ANC <500 per mm3, 
duration >5 days) 
 
4. Thrombocytopenia that is: 
a. 
Grade 3 with clinically significant hemorrhage 
b. 
Grade 4 (platelets <25,000 per mm3) 
 
5. AST/ALT elevation > 3xULN with bilirubin elevation > 
2xULN that cannot be explained by factors not related 
to study drug 
 
21.2 Protocol Amendment 2 dated 22-Feb-2016 
1. Modified Part 1 of the trial to make KRAS mutation testing mandatory to include only 
patients with KRAS WT solid tumor malignancies 
 
Refer to Table 17 for the changes in Protocol Amendment 2.  
 
Table 17 
Protocol Amendment 2 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
1. Synopsis: 
Phase and 
Overall Trial 
Design 
Part 1 is a Phase 1a dose-escalation in patients with 
advanced solid tumor malignancies… 
Part 1 is a Phase 1a dose-escalation in patients with Kirsten 
Rat Sarcoma (KRAS) wild-type (WT) advanced solid 
tumor malignancies… 
1. Synopsis: 
Objectives 
Primary objective of Part 1, Dose-Escalation: To 
assess… with advanced solid tumor malignancies… 
Primary objective of Part 1, Dose-Escalation: To assess… 
with KRAS WT advanced solid tumor malignancies… 
1. Synopsis: 
Overall Trial 
Design 
During Part 1 of the trial, patients with advanced 
solid tumor malignancies…  
During Part 1 of the trial, patients with KRAS WT 
advanced solid tumor malignancies… 
1. Synopsis: Main 
Inclusion and 
Exclusion 
Criteria 
Not applicable 
 
 
 
Main inclusion criteria all patients, Part 1 and Part 
2:… 
 
Tumor documented to be KRAS WT by local 
assessment (i.e. the tumor must express the 


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Table 17 
Protocol Amendment 2 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
 
 
Additional main inclusion criteria applicable to 
Part 2, Basket Cohort patients ONLY:… 
 
Tumor documented to be without KRAS 
gene mutation by local assessment (i.e. the 
tumor must express the KRAS WT, exon 2, 
3 and 4) 
 
Additional main exclusion criteria applicable to 
Part 1, Dose-escalation cohort patients ONLY: 
 
Patients with known KRAS gene mutation 
KRAS WT, exon 2, 3 and 4) 
 
Additional main inclusion criteria applicable to Part 2, 
Basket Cohort patients ONLY:… 
Removed indicated text under this heading 
 
 
 
 
Removed heading and text 
 
1. Synopsis: Trial 
Assessments 
Disease Assessments 
 
Archival tumor tissue for MET and KRAS 
assessment: Not required for patients in 
Part 1, but tissue should be assessed if 
available... 
 
Disease Assessments 
 
Archival tumor tissue for MET and KRAS 
assessment: For patients in Part 1, local 
eligibility assessment for KRAS mutational status 
will be done. Assessment of MET-amplification 
status is not required for patients in Part 1, but 
tissue should be assessed if available... 
4.1.1 Primary 
Objective 
To assess… with advanced solid tumor 
malignancies…  
To assess… with KRAS wild-type (WT) advanced solid 
tumor malignancies…  
5.1 Overall 
Design and Plan 
Part 1 is a Phase 1a dose-escalation in patients with 
advanced solid tumor malignancies… 
 
During Part 1, dose-escalation, cohorts of patients 
with advanced solid tumor malignancies…  
Part 1 is a Phase 1a dose-escalation in patients with KRAS 
WT advanced solid tumor malignancies… 
 
During Part 1, dose-escalation, cohorts of patients with 
KRAS WT advanced solid tumor malignancies… 
5.2.2 Rationale 
for Trial 
Population 
In Part 1, patients with advanced solid tumor 
malignancies… 
In Part 1, patients with KRAS WT advanced solid tumor 
malignancies… 
6.1 Inclusion 
Criteria 
6.     Part 2, Basket Cohort ONLY:… 
c. 
Tumor documented to be without KRAS 
gene mutation by local assessment (i.e. the 
tumor must express the KRAS WT, exon 2, 
3 and 4) 
6.     Tumor documented to be KRAS WT by local 
assessment (i.e. the tumor must express the KRAS WT, 
exon 2, 3 and 4) 
7.     Part 2, Basket Cohort ONLY:… 
Removed indicated text under this heading 
6.2 Exclusion 
Criteria 
2.     Part 1, dose-escalation cohorts ONLY: Patients 
with known KRAS gene mutation  
Removed 
 
8.3.3 Archival 
Tumor Tissue for 
MET and KRAS 
Assessment 
 
Screening 
o Part 1: Not required; to be assessed if 
available 
 
Screening 
o Part 1: Local eligibility assessment for KRAS 
mutational status will be done. Assessment of 
MET-amplification status is not required for 
patients in Part 1, but tissue should be assessed if 
available. 
 
21.3 Protocol Amendment 3 dated 02-May-2016 
1. Modified inclusion criteria No. 6 to require KRAS mutation testing according to 
institutional standards in order to utilize the various testing platforms that are available at 
the participating trial sites 
2. Modified Part 1 of the trial to include a tumor biopsy during screening for assessment of 
KRAS mutational status, if necessary for eligibility assessment 
3. Modified Part 2 of the trial to include an ADA sample timepoint at C2/D1 
4. Clarified that AEs/SAEs are reported from signing of informed consent for participation 
in the trial. Furthermore, clarified that patients who sign informed consent and are 


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subsequently deemed to be screening failures will be followed for AEs/SAEs until it is 
determined that they will not be participating in the trial 
5. Clarified reporting requirements for safety data to Sponsor or designee 
6. Clarified that the sample size considerations are based on a 2-stage design, not a 2-stage 
Minmax design 
 
Refer to Table 18 for the changes in Protocol Amendment 3.     
 
Table 18 
Protocol Amendment 3 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
1. Synopsis: Main 
Inclusion and  
Exclusion 
Criteria 
 
6.1 Inclusion 
Criteria No. 6 
Tumor documented to be KRAS WT by local 
assessment (i.e. the tumor must express the KRAS 
WT, exon 2, 3 and 4) 
Tumor documented to be KRAS WT by local assessment 
according to institutional standards. If KRAS WT is not 
previously documented and if archival tissue is not 
available for pretrial assessment, patient must be willing to 
undergo a tumor biopsy to confirm eligibility  
1. Synopsis: Trial 
Assessments 
 
Safety Assessments 
DLT evaluation (Part 1, dose-escalation only) during 
Cycle 1 with a final assessment on scheduled first 
day of Cycle 2, prior to dosing 
 
 
Disease Assessments 
For patients in Part 1, local eligibility assessment for 
KRAS mutational status will be done. 
 
 
 
Tumor biopsy (optional for patients in Part 1 with 
known MET-amplification; required for patients in 
Part 2): 
 
 
 
Additional Assessments 
Skin biopsy 
Safety Assessments 
DLT evaluation (Part 1, dose-escalation only) during Cycle 
1 with a final assessment 14 (±2) days (Q2W dosing) or 21 
(±2) days (Q3W dosing) after the last dose of Cycle 1 or 
prior to dosing on Cycle 2/Day 1 (C2/D1)  
 
Disease Assessments 
For patients in Part 1, local eligibility assessment for KRAS 
mutational status will be done using archival tissue 
whenever possible. If archival tissue is not available, a 
tumor biopsy will be performed for eligibility assessment.    
 
Tumor biopsy to be assessed locally as part of eligibility 
assessment for Part 1 and Part 2 patients, if applicable. In 
addition, to be assessed centrally for biomarker analysis 
(optional for patients in Part 1 with known MET-
amplification; required for patients in Part 2):  
 
Additional Assessments 
Skin biopsy for biomarker analysis 
1. Synopsis: 
Statistical 
Methods and 
Sample Size 
Calculation 
 
10.1 Sample Size 
Determination 
Sample size considerations are based on a 2-stage 
MinMax design, testing a null hypothesis… 
Sample size considerations are based on a 2-stage design, 
testing a null hypothesis… 
5.3.1 Screening 
Furthermore, once eligibility is confirmed: 
 
All patients in Part 1 and 2 will have a 
blood sample taken for exploratory 
biomarker analysis 
 
All patients in Part 1 and 2 will have a skin 
biopsy performed 
 
Patients in Part 1 with known MET-
amplification who consent to optional 
biopsies will have a biopsy performed, 
unless it is confirmed that suitable archival 
tissue is available for central analysis  
Furthermore, once eligibility is confirmed: 
 
Patients in Part 1 with known MET-amplification 
who consent to optional biopsies will have a 
biopsy performed for biomarker analysis 
(archival tissue or tissue from a biopsy 
performed during screening as part of eligibility 
assessment may be submitted) 
 
All patients in Part 2 will have a tumor biopsy 
performed for biomarker analysis  (archival 
tissue or tissue from a biopsy performed during 
screening as part of eligibility assessment may 


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Table 18 
Protocol Amendment 3 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
 
All patients in Part 2 will have a tumor 
biopsy performed, unless it is confirmed 
that suitable archival tissue is available for 
central analysis 
Note: The tumor biopsy at screening may 
be assessed locally as part of eligibility 
assessment in Part 2 patients for whom 
MET-amplification and KRAS mutational 
status have not previously been assessed 
and no archival tissue is available 
be submitted) 
 
All patients in Part 1 and 2 will have a skin 
biopsy performed for biomarker analysis 
 
All patients in Part 1 and 2 will have a blood 
sample taken for biomarker analysis 
8.1.1 Signing of 
Informed Consent 
Not applicable 
Note: Informed consent may be obtained outside the 14-
day screening period prior to C1/D1 
8.2.2 Adverse 
Events Survey 
Starting from signing of informed consent 
Starting from signing of informed consent for participation 
in the trial 
8.2.2 Adverse 
Events Survey 
 
9.2.1 Adverse 
Event Recording 
Period 
 
9.2.6 Follow-up 
of Adverse 
Events 
 
9.3 Serious 
Adverse Event 
Recording and 
Reporting 
 
10.4.3.1 Adverse 
Events 
Not applicable 
Note: Patients who sign informed consent and are 
subsequently deemed to be screening failures will be 
followed for the occurrence of SAEs/AEs until it is 
determined that they will not be participating in the trial. 
8.2.3 Dose-
Limiting 
Toxicities 
Evaluation (Part 1 
Only) 
Reported during Cycle 1 with final assessment on 
scheduled Day 1 of Cycle 2 (C2/D1) 
Reported during Cycle 1 with a final assessment 14 (±2) 
days (Q2W dosing) or 21 (±2) days (Q3W dosing) after the 
last dose of Cycle 1 or prior to dosing on C2/D1 
8.3.3 Archival 
Tumor Tissue for 
MET and KRAS 
Assessment 
To be assessed locally, if tissue is available… 
 
Screening 
o     Part 1: Local eligibility assessment for 
KRAS mutational status will be done.  
Assessment of MET-amplification status 
is not required for patients in Part 1… 
o     Part 2: Local eligibility assessment… 
To be assessed locally… 
 
Screening 
o 
Part 1: Eligibility assessment for KRAS 
mutational status will be done using archival 
tumor tissue, whenever possible. If archival 
tissue is not available, tissue from a tumor 
biopsy performed during screening will be 
used.  
Assessment of MET-amplification status is 
not required… 
o 
Part 2: Eligibility assessment… 
8.3.4 Tumor 
Biopsy for 
Eligibility 
Assessment and 
Biomarker 
Analysis 
To be assessed centrally. In addition; to be assessed 
locally as part of eligibility assessment for Part 2 
patients, if applicable as per Section 8.3.3. Archival 
tissue may be accepted for central analysis if suitable 
as specified in the laboratory manual. It must be 
ensured that the archival tissue can be made 
available to the central laboratory prior to deciding 
to omit the tumor biopsy procedure at time of 
screening.  
To be assessed locally for eligibility:  
 
Screening; Part 1 and Part 2, if applicable as per 
Section 8.3.3 
Note: It will be permissible to perform this 
procedure outside the 14-day screening period, 
provided informed consent has been obtained 
To be assessed centrally for biomarker analysis:  
 
Screening 


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 
Screening 
o 
Part 1:… 
o 
Part 2:…  
 
o 
Part 1:… 
o 
Part 2:…  
 
Note: Archival tissue may be accepted for 
central analysis if suitable as specified in the 
laboratory manual… 
8.5 Anti-Drug 
Antibody Testing 
Not applicable 
Added additional timepoint: 
 
C2/D1 (Part 2 only) 
9.2.1 Adverse 
Event Recording 
Period 
All AEs will be recorded from signing of informed 
consent.  
All AEs will be recorded from signing of informed consent 
for participation in the trial. 
9.3 Serious 
Adverse Event 
Recording and 
Reporting 
All SAEs occurring at any time from signing of 
informed consent and until the 1M FUP Visit, must 
be recorded… 
All SAEs occurring at any time from signing of informed 
consent for participation in the trial and until the 1M FUP 
Visit must be recorded… 
9.5.2 Observation 
Period for Dose-
Limiting 
Toxicities 
The observation period for DLTs is defined as Cycle 
1, i.e. the initial 28-day (± 2 days) period of Q2W 
dosing or 42-day (± 2 days) period of Q3W dosing, 
starting from C1/D1. 
The observation period for DLTs is defined as Cycle 1 
with a final assessment 14 (±2) days (Q2W dosing) or 21 
(±2) days (Q3W dosing) after the last dose of Cycle 1 or 
prior to dosing on C2/D1. 
9.5.3 Reporting 
of Dose-Limiting 
Toxicities 
All presumed DLTs must be reported in the eCRF 
within 24 hours… 
All presumed DLTs must be reported to the Sponsor or 
designee within 24 hours… 
9.6 Reporting of 
Infusion-Related 
Reactions 
To facilitate ongoing safety review… in the eCRF 
within 24 hours of occurrence. 
To facilitate ongoing safety review… to the Sponsor or 
designee within 24 hours of occurrence. 
10.4.3.1 Adverse 
Events 
AEs including SAEs are reported from signing of the 
informed consent and until the end of trial 
participation 
AEs including SAEs are reported from signing of the 
informed consent for participation in the trial and until the 
end of trial participation. 
12.1 Safety 
Review 
In order to do so, the Investigator must ensure the 
data in the eCRF is up to date at all times. This 
includes, but is not limited to: 
 
SAEs must be reported within 24 hours of 
awareness (SAE report form and eCRF) 
 
DLTs must be reported in the eCRF within 
24 hours of occurrence 
 
Grade 2 IRRs must be reported in the 
eCRF within 24 hours of occurrence… 
…Such Safety Team teleconferences may fluctuate 
in frequency based on accrual and trial activity, as 
indicated… 
In order to do so, the Investigator must ensure to report 
safety data to the Sponsor or designee in a timely manner. 
This includes, but is not limited to: 
 
SAEs must be reported within 24 hours of 
awareness (SAE report form) 
 
DLTs must be reported within 24 hours of 
occurrence 
 
IRRs of ≥ Grade 2 must be reported within 24 
hours of occurrence… 
…Such safety teleconferences may fluctuate in frequency 
based on accrual and trial activity, as indicated… 
 
21.4 Protocol Amendment 4 dated 04-Nov-2016 
1. Modified the overall trial design by moving the Q3W cohort from Part 1 to Part 2 to 
ensure patients with MET-amplification are treated in this cohort and thereby introducing 
a Q2W Basket Cohort as well as a Q3W Basket Cohort in Part 2 
2. Updated trial objectives, trial endpoints and patient numbers according to the change in 
overall trial design 
3. Allowed 6-12 patients to be included in the Q3W Basket Cohort 
4. Confirmed the selection of the Q2W RP2D as 18 mg/kg loading dose infused over 1.5 
hours on C1/D1 followed by Q2W maintenance doses of 12 mg/kg infused over 1 hour 
beginning on C1/D15 
5. Modified select inclusion criteria  


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6. Modified and/or deleted select exclusion criteria 
7. Clarified that a trial site may choose to prescreen patients utilizing archival tumor tissue 
to confirm MET-amplification status and/or KRAS mutational status before entering 
patients into screening for the treatment portion of the trial 
8. Modified the Sym015 infusion time to 1.5 hour (+10 minutes) for doses ≥18 mg/kg 
9. Clarified preference for the eligibility assessment for MET-amplification be done using 
tissue from a tumor biopsy performed during screening and that this biopsy be submitted 
to the central laboratory 
10. Removed skin biopsies from Part 2 of the trial 
11. Updated dose-delay criteria #4 
12. Clarified one of the dose-limiting toxicities (#2) 
13. Updated dose-reduction criteria #2 and #5 to be in accordance with dose-limiting toxicity 
criteria 
14. Included overall survival status in the continued follow-up after the 1M FUP Visit and 
adjusted the follow-up schedule to be every 2 months 
15. Updated events not to be considered as AEs to include PD, unless the nature of the PD is 
different than expected 
16. Updated timelines for reporting of SAE Follow-up information 
17. Updated sample size determination to be based on a Simon’s Optimal 2-stage design. 
Futility will be performed when 20 patients evaluable for OR have been included in the 
Q2W Basket Cohort 
18. Made updates and clarifications to the secondary endpoints and PK endpoints 
 
Refer to Table 19 for the changes in Protocol Amendment 4.     
 
Table 19 
Protocol Amendment 4 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
1. Synopsis: 
Phase and 
Overall Trial 
Design 
Part 2 is a Phase 2a dose-expansion, in which the 
recommended phase 2 dose (RP2D) and regimen will 
be explored in a Basket Cohort of patients with MET-
amplified, KRAS WT solid tumor malignancies 
without available therapeutic options… 
Part 2 is a Phase 2a dose-expansion in patients with MET-
amplified, KRAS WT solid tumor malignancies without 
therapeutic options. Two cohorts will be included: 
o 
Q2W Basket Cohort: A cohort of approximately 
45 patients…  
o 
Q3W Basket Cohort: A cohort of 6-12 patients… 
1. Synopsis: 
Trial Site and 
Countries 
Part 2, Basket Cohort: 15 to 20 investigational trial 
sites… 
Part 2: 15 to 20 investigational trial sites… Enrollment to 
the Q3W Basket Cohort is expected to take place at select 
sites only. 
1. Synopsis: 
Planned Trial 
Period 
Patients will be enrolled in dose-escalation cohorts 
until establishment of a RP2D and regimen, expected 
by Q2 2017. 
 
Enrollment to the Basket Cohort in Part 2 of the trial 
will commence once the RP2D and regimen has been 
established. Enrollment is expected completed by Q3 
2018.  
 
The end of trial will be reached... Patients with stable 
disease (SD) or an ongoing objective response…at 
that time will continue to be followed to assess 
duration of disease stabilization or response. 
Patients will be enrolled in dose-escalation cohorts until 
establishment of a maximum tolerated dose (MTD) or until 
24 mg/kg has been evaluated, whichever comes first, 
expected by Q1 2017. 
 
Enrollment to Part 2 of the trial will commence upon 
establishment of the Q2W RP2D. Enrollment is expected 
to complete by Q3 2018.  
 
The end of trial will be reached… Patients will continue to 
be followed to assess duration of disease stabilization, 
response, and overall survival (OS). 
1. Synopsis: 
Objectives 
Primary objective of Part 1, Dose-Escalation: To 
assess the safety and tolerability… to patients… 
Primary objective of Part 1, Dose-Escalation: To assess the 
safety and tolerability… on a Q2W schedule to patients… 


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Table 19 
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NEW TEXT 
 
4.1.1 Primary 
Objective 
 
4.2.1 Primary 
Objective 
 
Primary objective of Part 2, Basket Cohort: To 
evaluate the antitumor activity of Sym015 when 
administered at the RP2D and regimen…. 
 
Primary objective of Part 2: To evaluate the antitumor 
activity of Sym015 when administered at the Q2W 
RP2D… 
1. Synopsis: 
Endpoints 
Primary Endpoint of Part 1, Dose-Escalation: The 
occurrence of dose-limiting toxicities (DLT) 
measured during Cycle 1 of Sym015 administration 
on an every second week (Q2W, 28 days equals 1 
cycle) or every third week (Q3W, 42 days equals 1 
cycle) dosing schedule. 
 
Primary Endpoint of Part 2, Basket Cohort: 
Documented OR (defined as PR or CR)… 
Primary Endpoint of Part 1, Dose-Escalation: The 
occurrence of dose-limiting toxicities (DLT) measured 
during Cycle 1 of Sym015 administration on a Q2W (28 
days equals 1 cycle) dosing schedule. 
 
Primary Endpoint of Part 2: Documented objective 
response (OR) (defined as partial response [PR] or 
complete response [CR]) in the Q2W Basket Cohort… 
1. Synopsis: 
Overall Trial 
Design 
 
During Part 1 of the trial, patients… will receive 
increasing doses of Sym015 until establishment of a 
RP2D and regimen to be used in Part 2… Patients 
will be assigned to the next available open treatment 
cohort until establishment of the RP2D and 
regimen…The highest dose level tested and evaluated 
to be safe will be explored… The second-highest dose 
level tested will be expanded… 
During Part 1 of the trial, patients… will receive increasing 
doses of Sym015 on a Q2W schedule until establishment 
of the MTD or until 24 mg/kg has been evaluated… 
 
 
The SMC will review clinical and laboratory safety 
data regularly throughout the trial and will select the 
RP2D and regimen to be used in Part 2… 
The SMC will review clinical and laboratory safety data 
regularly throughout the trial. The SMC will select the 
Q2W RP2D and the highest safe dose for the Q3W 
regimen to be used in Part 2… 
During Part 2, the RP2D and regimen will be 
evaluated in a Basket Cohort of patients with MET-
amplified, KRAS WT advanced solid tumor 
malignancies. 
During Part 2, basket cohorts of patients with MET-
amplified, KRAS WT advanced solid tumor malignancies 
will be evaluated: Q2W Basket Cohort administering the 
Q2W RP2D on a Q2W dosing schedule and Q3W Basket 
Cohort administering the highest safe dose tested in Part 1 
on a Q3W dosing schedule. 
1. Synopsis: 
Trial Periods 
 
6.3.2 
Withdrawal 
from Trial 
 
8.9 Follow-up 
Assessments 
In the event of an ongoing SD or OR as per RECIST 
v1.1 at the 1M FUP Visit, the Investigator will make 
every effort to obtain follow-up information on 
response assessments every 3 months during the first 
year and every 6 months thereafter, until disease 
progression or another therapeutic intervention is 
initiated.  
After the 1M FUP Visit, the Investigator will make every 
effort to obtain follow-up information on response 
assessment and/or OS, every 2 months. Response 
assessment follow-up is required in the event of an 
ongoing stable disease (SD), PR, or CR at the 1M FUP 
Visit, until PD or another therapeutic intervention is 
initiated. Survival follow-up is required until death, 
withdrawal of consent, or termination of the trial. 
1. Synopsis: 
Number of 
Patients 
It is planned to enroll approximately 70 patients… 
Approximately 21-25 patients… during Part 1. 
Approximately 45 patients… during Part 2. 
It is planned to enroll approximately 63-72 patients… 
Approximately 12-15 patients… during Part 1. 
Approximately 51-57 patients… during Part 2. 
1. Synopsis: 
Main Inclusion 
and Exclusion 
Criteria 
 
6.1 Inclusion 
Criteria 
Additional main inclusion criteria applicable to 
Part 2, Basket Cohort patients ONLY: 
 
Confirmed MET-amplification by local 
assessment; i.e…  
 
Willingness to undergo… (total of 2 
biopsies)… 
Additional main inclusion criteria applicable to Part 2 
patients ONLY: 
 
Confirmed MET-amplification by local 
assessment; i.e… silver in situ hybridization 
(SISH)… 
 
Willingness to undergo… (maximum of 2 
biopsies)… 
1. Synopsis: 
Main Inclusion 
and Exclusion 
Criteria 
 
Main exclusion criteria all patients, Part 1 and 
Part 2: 
 
Known central nervous system (CNS) or 
leptomeningeal metastases not controlled by 
prior surgery or radiotherapy, or symptoms 
Main exclusion criteria all patients, Part 1 and Part 2: 
 
Central nervous system (CNS) malignancy 
including primary malignancies of the CNS 
and/or known CNS or leptomeningeal… 
 
Abnormal hematologic, renal or hepatic function 


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6.2 Exclusion 
Criteria  
suggesting CNS involvement for which 
treatment is required 
 
Abnormal hematologic, renal or hepatic 
function as defined by the following 
criteria: 
o 
Prothrombin time… institution 
o 
Partial thromboplastin time (PTT)… 
institution 
 
Known history of human immunodeficiency 
virus (HIV) infection  
 
Known active hepatitis B or C virus 
infection 
as defined by the following criteria: 
o 
Prothrombin time… institution* 
o 
Partial thromboplastin time (PTT)… 
institution* 
*Unless on a stable dose of anticoagulant 
therapy for a prior thrombotic event 
 
 
Removed known history of HIV infection 
 
Removed known active hepatitis B or C virus infection 
Additional main exclusion criteria applicable to 
Part 2, Basket Cohort patients ONLY: 
Radiotherapy against target lesions within 4 weeks 
prior to C1/D1 
Additional main exclusion criteria applicable to Part 2 
patients ONLY: 
 
Prior therapy with antibody to hepatocyte growth 
factor (HGF) 
 
Radiotherapy against…unless there is 
documented progression of the lesion following 
the radiotherapy 
1. Synopsis: 
Investigational 
Medicinal 
Product, Dose(s) 
and Treatment 
Schedule 
Note: Q3W dosing is implemented after highest… 
 
For Part 1 of the trial, Sym015 will be administered 
over a 1-hour (+10 minutes) period, following 
delivery of premedication prior to each infusion. For 
Part 2 of the trial, Sym015 will be administered over a 
1-hour (+10 minutes) period, following delivery of 
premedication prior to each infusion during Cycle 1.  
 
Note: Q3W dosing is implemented in Part 2 after 
highest… 
 
Sym015 will be administered over a 1.5-hour (+10 
minutes) period for doses ≥18 mg/kg and over a 1 hour 
(+10 minutes) period for doses <18 mg/kg, following 
delivery of premedication prior to each infusion.  
Part 1/Dose-Escalation 
During the dose-escalation part of the trial, the 
following dose levels… 
 
Dosing will be on a Q2W schedule for all cohorts 
until completion of Dose Level 4 or establishment of 
an MTD, whichever comes first. At this point, a Q3W 
schedule will be evaluated…  
 
Part 1/Dose-Escalation 
During the dose-escalation part of the trial, the following 
dose levels of Sym015 administered Q2W… 
 
 
Part 2/Basket Cohort 
Once the RP2D and regimen has been established 
during dose-escalation, the enrollment into the Basket 
Cohort will commence.  
 
All patients enrolled to the Basket Cohort will be 
treated with the established RP2D on the selected 
dosing schedule of Sym015 (Q2W or Q3W). 
Part 2 
Once the Q2W RP2D has been established during dose-
escalation, the enrollment into the Q2W Basket Cohort 
will commence.  
Note:  Effective with clinical trial protocol (CTP) version 
5.0 (November 2016), following review… 
 
Once the highest safe dose tested in Part 1 has been 
determined, all patients in the Q3W Basket Cohort will be 
treated at that dose level on a Q3W dosing schedule. 
1. Synopsis: 
Trial 
Assessments 
Safety Assessments 
 
Medication survey 
 
DLT evaluation (Part 1, dose-escalation 
only) during Cycle 1 with a final 
assessment 14 (±2) days (Q2W dosing) or 
21 (±2) days (Q3W dosing)… 
Safety Assessments 
 
Medication/Procedure survey 
 
DLT evaluation (Part 1, dose-escalation only) 
during Cycle 1 with a final assessment 14 (±2) 
days… 
1. Synopsis: 
Trial 
Assessments 
Disease Assessments 
Archival tumor tissue for MET and KRAS assessment:  
Disease Assessments 
Archival tumor tissue for MET and KRAS assessment:  


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8.3.4 Tumor 
Biopsy for 
Eligibility 
Assessment and 
Biomarker 
Analysis 
o 
For patients in Part 2, local eligibility 
assessment for MET-amplification and KRAS 
mutational status will be done using archival 
tumor tissue whenever possible… 
Tumor biopsy to be assessed locally as part of 
eligibility assessment for Part 1 and Part 2 patients… 
o 
Q2W dosing… Archival tissue may be 
acceptable at screening, if suitable for central 
analysis 
o 
Q3W dosing… Archival tissue may be 
acceptable at screening, if suitable for central 
analysis 
 
 
o 
For patients in Part 2, local eligibility assessment 
for KRAS mutational status may be done using 
archival tumor tissue… 
It is preferred that the eligibility assessment for 
MET-amplification will be done using tissue from 
a tumor biopsy performed during screening… 
Tumor biopsy to be assessed locally as part of eligibility 
assessment for Part 1 and Part 2 patients… 
o 
Q2W dosing: At screening and at the end… 
o 
Q3W Basket Cohort: At screening and at the 
end… 
Tissue from a tumor biopsy performed during screening is 
preferred, however archival tissue may be submitted for 
central analysis… 
1. Synopsis: 
Trial 
Assessments 
 
 
Additional Assessments 
Skin biopsy for biomarker analysis: 
o 
Q2W dosing: At screening, at the end… 
o 
Q3W dosing: At screening and at the end… 
Additional Assessments 
Part 1 only: Skin biopsy for biomarker analysis at 
screening, at the end of Cycle 2 or upon PD, whichever 
comes first 
1. Synopsis: 
Statistical 
Methods and 
Sample Size 
Calculation 
 
10.1 Sample 
Size 
Determination 
 
10.3.1 Part 1, 
Dose-Escalation 
 
10.3.2 Part 2 
 
10.5 Interim 
Analysis 
Based on a 3 + 3 design and inclusion of a Q3W 
cohort, it is planned to enroll between 21 and 25 
patients during dose-escalation. 
 
Based on an overall evaluation of the dose-escalation 
part, the RP2D and regimen to be used in Part 2 will 
be selected.  
 
In Part 2 of the trial, the primary endpoint is 
documented OR, assessed by RECIST v1.1 at any 
time during trial participation by Investigator 
assessment. It is planned to include… 
 
Sample size considerations are based on a 2-stage 
design, testing a null hypothesis (poor response) of 
10% OR versus an alternative hypothesis (promising 
response) of 25% OR at an approximate 5% 1-sided 
significance level and 80% power…  
Based on a 3+3 design, it is planned to enroll between 12 
and 15 patients during dose-escalation. 
Based on an overall evaluation of the dose-escalation part, 
the Q2W RP2D and highest safe dose tested will be 
selected.  
In Part 2 of the trial, the primary endpoint is documented 
OR in the Q2W Basket Cohort, assessed by RECIST v1.1 
at any time during trial participation by Investigator 
assessment. It is planned to include… in this cohort.  
Sample size considerations are based on Simon’s Optimal 
2-stage design, testing a null hypothesis (poor response) of 
11% OR versus an alternative hypothesis (promising 
response) of 25% OR at an approximate 10% 1-sided 
significance level and 85% power… 
For the Q3W Basket Cohort, assuming the response rate is 
at least 20%, there is a 74-93% probability of observing 1 
or more responses in 6-12 patients. 
3.2.4.1 Protocol 
Sym015-01 
This is the first clinical trial to study Sym015. 
Addition of new section heading 
This is the first clinical trial to study Sym015.  As of 19 
October 2016, a total of 9 patients have been enrolled in 
this trial… 
3.2.4.2 Other 
Monoclonal 
Antibodies 
Targeting MET 
Section heading did not previously exist 
Based on available literature/reports… 
Addition of new section heading only 
Based on available literature/reports… 
3.4.1 Rationale 
for Starting 
Dose 
Section heading did not previously exist 
The starting dose of Sym015… 
Addition of new section heading 
The starting dose of 6 mg/kg Sym015… 
3.4.2 Rationale 
for 
Recommended 
Phase 2 Dose 
Section did not previously exist 
 
As of 19 October 2016, following review of available 
safety… 
Addition of new Table 1: Preliminary Sym015 Geometric 
Mean PK Parameters 
3.5 Overall 
Benefits/Risk 
If the dose administered in a cohort is safe… to 
establish a recommended phase 2 dose (RP2D) and 
regimen. 
If the dose administered in a cohort is safe… to establish a 
Q2W RP2D and to define an MTD or highest safe dose. 


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4.1.2 Secondary 
Objectives 
 
1. To determine a RP2D and regimen of Sym015 
1. To determine a Q2W RP2D of Sym015 
4.2.2 Secondary 
Objectives 
1. 
To further evaluate the safety…  
2. 
To further evaluate the PK… 
3. 
To further evaluate target-engagement in skin 
biopsy tissue 
4. 
To further evaluate the immunogenicity… 
5. 
To further evaluate potential 
pharmacodynamic… 
 
1. 
To further evaluate the safety… when administered at 
the Q2W RP2D  
2. 
To further evaluate the PK… when administered at 
the Q2W RP2D 
3. 
To further evaluate the immunogenicity… when 
administered at the Q2W RP2D 
4. 
To further evaluate potential pharmacodynamic… 
when administered at the Q2W RP2D 
5. 
To make a preliminary evaluation of the antitumor 
activity of Sym015, and to evaluate… 
5.1 Overall 
Design and Plan 
Part 2 is a Phase 2a dose-expansion, in which the 
RP2D and regimen will be explored in a Basket 
Cohort of patients with MET-amplified, KRAS WT 
solid tumor malignancies without available 
therapeutic options.  
 
 
During Part 1… doses of Sym015 until establishment 
of a RP2D and regimen to be used in Part 2.  
Part 2 is a Phase 2a dose-expansion in patients with MET-
amplified, KRAS WT solid tumor malignancies without 
therapeutic options. Two cohorts will be included: 
o A Basket Cohort of approximately 45 patients… 
o A Basket Cohort of 6-12 patients… 
 
During Part 1… doses of Sym015 on a Q2W schedule until 
establishment of the MTD or until 24 mg/kg has been 
evaluated.  
Dosing will be on a Q2W schedule for all cohorts 
until completion of Dose Level 4 or establishment of 
an MTD, whichever comes first. At this point, a Q3W 
schedule will be evaluated in 6 patients at the highest 
safe dose tested. Furthermore, the dose level below 
the highest safe dose will be expanded to 6 patients on 
a Q2W schedule, if this has not already been done. 
Removed 
The SMC will… select the RP2D and regimen to be 
used in Part 2 based on safety data, as well as 
available PK and target engagement results in skin 
tissue biopsies. 
 
 
The SMC will… select the Q2W RP2D and the highest 
safe dose for the Q3W regimen to be used in Part 2 based 
on safety data and available PK results.  
 
Note:  Effective with CTP version 5.0 (November 2016), 
following review of available safety and PK data, the 
decision has been made to choose the following as the 
Q2W RP2D of Sym015… 
During Part 2, the RP2D and regimen will be 
evaluated in a Basket Cohort of patients with MET-
amplified, KRAS WT, advanced solid tumor 
malignancies.  
 
During Part 2, basket cohorts of patients with MET-
amplified, KRAS WT, advanced solid tumor malignancies 
will be evaluated: Q2W Basket Cohort administering the 
Q2W RP2D on a Q2W schedule and Q3W Basket Cohort 
administering the highest safe dose tested in Part 1 on a 
Q3W schedule. 
 
Enrollment to the Q3W Basket Cohort is expected to take 
place at select trial sites only. 
5.2.1 Rationale 
for Trial Design 
The trial is designed to select a safe and well-tolerated 
dose of Sym015 on a Q2W basis (3 to 6 patients to be 
treated at the highest safe dose and 6 patients to be 
treated at the next lower dose) and also to explore the 
safety of a Q3W dosing schedule at the highest safe 
dose (6 patients). Part 2 of this trial is designed…  
This part of the trial is designed to select a safe and well-
tolerated dose of Sym015 on a Q2W schedule. Part 2 of 
this trial is designed…  
5.3.1 
Prescreening for 
MET-
Section did not previously exist 
The trial site may choose to prescreen patients utilizing 
archival tumor tissue to confirm MET-amplification status 
and/or KRAS mutational status before entering patients into 


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amplification 
and KRAS 
Mutational 
Status 
 
screening for the treatment portion of the trial. In this case, 
the site will use a separate pre-screening informed consent 
form… 
5.3.2 Screening 
This number is composed… 
 
 
Furthermore, once eligibility is confirmed: 
 
All patients in Part 2 will have a tumor 
biopsy performed for biomarker analysis  
(archival tissue or tissue from a biopsy 
performed during screening as part of 
eligibility assessment may be submitted) 
 
All patients in Part 1 and 2 will have a skin 
biopsy performed for biomarker analysis 
This number will identify the patient throughout the trial 
and will be composed… 
 
Furthermore, once eligibility is confirmed: 
 
All patients in Part 2 will have a tumor biopsy 
performed for biomarker analysis (tissue from a 
biopsy performed during screening as part of 
eligibility assessment is preferred…, however 
archival tissue may be submitted at the 
Investigator’s discretion) 
 
All patients in Part 1 will have a skin biopsy… 
5.3.4 Treatment 
Heading previously 5.3.3 
Patients in Part 1 will receive infusions of Sym015 
Q2W at the specified dose level until… 
 
During Part 2, all patients will receive the RP2D of 
Sym015… 
 
Removed 
 
 
Removed 
 
5.3.5 End of 
Treatment and 
Follow-up Visits 
Heading previously 5.3.4 
In the event of an ongoing stable disease (SD) or 
objective response (OR, defined as partial response 
[PR] or complete response [CR])… 
After the 1M FUP Visit, the Investigator will make every 
effort to obtain follow-up information on response 
assessment and/or overall survival (OS) every 2 months. 
Response assessment follow-up is required… Survival 
follow-up is required until… 
5.4 Recruitment 
Period 
Patients will be sequentially enrolled to dose-
escalation cohorts until establishment of a RP2D and 
regimen, expected by Q2 2017. 
 
Enrollment to the Basket Cohort in Part 2 of the trial 
will commence once the RP2D and regimen have 
been established. Enrollment is expected completed 
by Q3 2018. 
Patients will be sequentially enrolled to dose-escalation 
cohorts until completion of Dose Level 4 or establishment 
of an MTD, whichever comes first, expected by Q1 2017. 
Enrollment to Part 2 of the trial will commence upon 
establishment of the Q2W RP2D. Enrollment is expected 
to complete by Q3 2018. 
5.5 Number of 
Patients 
In total, approximately 70 patients will be included in 
this trial. 
 
It is estimated that approximately 21-25 patients… 
Sym015 and occurrence of discontinuation of patients 
during the DLT observation period for reasons other 
than toxicity. 
 
It is planned to enroll and treat approximately 45 
patients with documented and confirmed MET-
amplified and KRAS WT advanced solid tumor 
malignancies during Part 2. 
In total, approximately 63-72 patients will be included in 
this trial. 
It is estimated that approximately 12-15 patients… 
Sym015 and the potential for adding additional patients to 
a cohort to assure a sufficient number of evaluable patients 
per cohort… 
During Part 2, it is planned to enroll and treat 
approximately 45 patients in the Q2W Basket Cohort and 
6-12 patients in the Q3W Basket Cohort… 
5.6 End of Trial 
Patients with SD or an ongoing OR at that time will 
continue to be followed to assess duration of disease 
stabilization or response. 
Patients will continue to be followed to assess duration of 
disease stabilization, response and/or overall survival. 
7.1.3.2 Part 1, 
Dose-Escalation 
Dosing will be on a Q2W schedule for all cohorts 
until completion of Dose Level 4 or establishment of 
an MTD, whichever comes first. At this point, a Q3W 
schedule… 
Removed 
Not applicable 
There is potential for entry of additional patients in the 
dose-escalation portion of the trial to assure a sufficient 
number of evaluable patients per cohort…  
 


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Note: Should this action be taken, cohort tolerability 
assessment and subsequent dose-escalation… 
If the MTD is declared, 6 patients will be included on 
a Q3W dosing schedule at the MTD… 
Removed 
If no DLTs are encountered in any of the first 3 
patients at Dose Level 4, 6 patients will be included 
on a Q3W dosing schedule… 
If no DLTs are encountered in any of the first 3 patients at 
Dose Level 4, 24 mg/kg will be considered the highest safe 
dose tested 
The SMC will review safety data and make decisions 
regarding the advisability of; continuing accrual to a 
particular dose cohort; dose-escalation and accrual of 
patients to a higher dose cohort; and the RP2D and 
regimen to be used in Part 2, the Basket Cohort. 
The SMC will review safety data throughout the trial. 
During Part 1, the SMC will make decisions regarding the 
advisability of: continuing accrual to a particular dose 
cohort; dose-escalation and accrual of patients to a higher 
dose cohort; and the doses to be used in Part 2… 
7.1.3.3 Part 2 
During Part 2 of this trial, all patients will receive the 
RP2D of Sym015 on the chosen dosing schedule 
(Q2W or Q3W). 
During Part 2 of this trial, patients included in the Q2W 
Basket Cohort will receive the Q2W RP2D of Sym015 on 
a Q2W dosing schedule. Patients included in the Q3W 
Basket Cohort… 
The SMC will continue to review safety data and assess 
the tolerability of Sym015 during Part 2 of the trial. 
7.1.3.4 Duration 
of Infusion for 
Administration 
of Sym015 
Sym015 will be administered over a 1-hour (+10 
minutes) period following delivery of 
premedication… 
 
 
 
 
In the event of a Grade 2 IRR… entered to the trial 
will be extended to 1.5 hours (+10 minutes) (or 
longer, if indicated) 
 
 
 
 
In the event of a Grade 3 or greater IRR… entered to 
the trial will be extended to 1.5 hours (+10 minutes) 
(or longer, if indicated)… 
  
 
These same criteria will be applied in the event IRRs 
occur on the extended 1.5 hours infusion schedule. In 
such a case, the duration of infusion for subsequent 
patients entered to the trial will be extended to 2 hours 
(or longer, if indicated). 
Sym015 will be administered over a 1.5-hour (+10 
minutes) period for doses > 18 mg/kg, and over a 1 hour 
(+10 minutes) period for doses <18 mg/kg, following…  
Note:  Effective with CTP version 5.0 (November 2016), 
the duration of infusion has been extended to 1.5 hours… 
In the event of a Grade 2 IRR... entered at that dose and 
higher doses will be extended from 1 hour (+10 minutes) 
to 1.5 hours (+10 minutes) (or longer, if indicated) 
Note: This action was implemented 13Sep2016 and applies 
to doses > 18 mg/kg.  
In the event of a Grade 3 or greater IRR… entered at that 
dose and higher doses will be extended from 1 hour (+10 
minutes) to 1.5 hours (+10 minutes) (or longer, if 
indicated)…. 
These same criteria will be applied in the event IRRs occur 
on the extended 1.5 hours infusion schedule. In such a 
case, the duration of infusion for subsequent patients 
entered at that dose and higher doses will be extended to 2 
hours (or longer, if indicated). 
7.1.4.2 Dose-
Delays for 
Sym015-Related 
or Disease-
Related 
Toxicities 
4. 
Any ongoing AEs, assessed as possibly, 
probably, or related to Sym015, should have 
either ameliorated to ≤ Grade 1 severity, returned 
to baseline status, or resolved with the exception 
of laboratory abnormalities that are considered 
clinically insignificant 
 
4. 
Any ongoing AEs, assessed as possibly, probably, or 
related to Sym015… with the exception of  Grade 2 
clinical events that are being adequately controlled 
with best supportive care (e.g. nausea, vomiting, 
diarrhea, fatigue) and asymptomatic laboratory 
abnormalities that are considered clinically 
insignificant or that are resolving with medical 
therapy 
7.1.4.3 Dose-
Reduction for 
Sym015-Related 
Toxicities 
 
2. 
Any Grade 4 non-hematologic toxicity 
2. 
Any Grade 4 non-hematologic toxicity, with the 
exception of: 
b. 
Grade 4 asymptomatic electrolyte abnormalities 
lasting ≤ 3 days that are not considered clinically 


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9.5.1 Definition 
of Dose-
Limiting 
Toxicities 
relevant by the Investigator and that resolve with 
medical therapy 
5. 
AST/ALT elevation > 3×ULN with bilirubin 
elevation >2×ULN that cannot be explained by 
factors not related to study drug 
7.6 Medical 
Care of Patients 
after End of 
Trial 
Participation 
After completing participation… 
After completing treatment… 
Patients will continue to be followed for survival. 
8.2.1 
Medication/ 
Procedure 
Survey 
To include all medications and/or treatments taken… 
 
To include all medications taken other than Sym015 and 
all procedures performed during trial.  For medications… 
For procedures: Include date and reason for procedure. 
8.2.6 Physical 
Examination 
To include evaluation of: General appearance, skin, 
head… 
Removed breasts, lungs, pulses 
 
 
8.3.3 Archival 
Tumor Tissue 
for MET and 
KRAS 
Assessment 
Not applicable 
May be performed as part of prescreening outside the 14-
day screening period, provided separate informed consent 
has been obtained. 
Part 2: Eligibility assessment for MET-amplification 
and KRAS mutational status will be done using 
archival tumor tissue, whenever possible. If archival 
tissue is not available, tissue from the tumor biopsy 
performed during screening will be used. 
Part 2: Eligibility assessment for KRAS mutational status 
may be done using archival tumor tissue. If archival tissue 
is not available… 
 
It is preferred that the eligibility assessment for MET-
amplification will be done using… 
Note: If a new biopsy is performed for MET-amplification 
testing, tissue from this biopsy… 
8.6 Skin Biopsy 
(Part 1 only) 
 
Skin biopsies are requested from a rash-free area. 
• Screening, after confirmation of eligibility 
• For Q2W dosing schedule only: End of Cycle 2 (i.e. 
coinciding with time of first response assessment) or 
upon PD, whichever occurs first  
• For Q3W dosing schedule only: At the end of the 
follow-up… 
 
Skin biopsies are requested from a rash-free area. 
• Screening, after confirmation of eligibility 
• End of Cycle 2 (i.e. coinciding with time of first response 
assessment) or upon PD, whichever occurs first  
9.1.1 Adverse 
Event 
PD will be captured as an AE. Events associated with 
the actual PD will also be captured, as determined by 
the Investigator. Additionally, AEs occurring 
simultaneously with PD, but which may not be related 
to the actual PD, will also be captured. 
 
Removed 
9.1.2 Events Not 
to be Considered 
as Adverse 
Events 
 
9.1.5 Events that 
Do Not Meet the 
Definition of 
Serious Adverse 
Events 
Not applicable 
PD will not be captured as an AE/SAE unless the nature of 
the PD is different than expected (i.e. other diagnosis 
and/or signs/symptoms that are not typical of PD). PD may 
be reported as an AE/SAE in the case of patient death, with 
death being the outcome of the event. 
An abnormal laboratory value or an abnormality in 
physiological testing (such as ECGs) need not be reported 
as an AE unless one of the following applies: 
 
The Investigator considers the abnormality 
clinically significant  
 
The event meets the definition of an SAE 
 
The event requires an intervention 
 
The event results in an action taken with Sym015 
(dose-reduction and/or withdrawal) 


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9.5.1 Definition 
of Dose-
Limiting 
Toxicities 
2. Any Grade 4 non-hematologic toxicity 
 
2. Any Grade 4 non-hematologic toxicity, with the 
exception of: 
a. Grade 4 asymptomatic electrolyte abnormalities lasting 
< 3 days that are not considered clinically relevant by the 
Investigator and that resolve with medical therapy 
10.4.1 Efficacy 
Endpoints and 
Analyses 
The following anti-tumor response endpoints will be 
measured in Part 1, Dose-Escalation… 
 
The following anti-tumor response 
endpoints will be measured in Part 2, 
Basket Cohort: 
o 
Changes in sum of diameters of target 
lesions from baseline to end of trial 
participation 
o 
SD for >4 months from baseline 
o 
Time to documented PD, death, patient 
withdrawal or end of trial participation, 
whichever comes first 
 
Number and percentages of patients with documented 
OR in the dose-escalation part will be presented 
including corresponding 95% exact CI.  
 
All documented ORs (Part 1 and 2) will be listed 
including duration (in days) of OR, measured from 
time of first PR or CR to PD. 
 
Duration of SD is calculated from baseline until first 
measurement of PD… 
 
Time to documented PD, death, patient withdrawal or 
end of trial participation, whichever comes first, will 
be presented in a Kaplan-Meier plot. The median 
progression free survival time, including 95% CI, will 
be derived. 
The following anti-tumor response endpoints will be 
measured in Part 1 and in the Q3W Basket Cohort… 
 
Additionally, the following anti-tumor response 
endpoints will be measured in both Part 1 and 2: 
o 
Duration of response (DR) 
o 
Best overall response (BOR) 
o 
SD for >4 months  
o 
Time to disease progression (TTP) as 
determined based on radiological evidence  
o 
Progression-free survival (PFS) 
o 
Overall survival (OS)  
 
In addition, the number and percentages of patients with 
SD for more than 4 months will be presented… 
 
TTP, PFS, and OS will be summarized using the product-
limit method and Kaplan-Meier plots. The median TTP, 
PFS, and OS, including 95% CI, will be calculated. 
12.1 Safety 
Review 
Biweekly safety teleconferences will be held between 
the Investigational Site(s) and the Sponsor and/or 
designee. Such safety teleconferences may fluctuate 
in frequency based on accrual and trial activity, as 
indicated. Patients will be carefully evaluated… 
 
Safety teleconferences will be held between the 
Investigational Site(s) and the Sponsor and/or designee. 
Patients will be carefully evaluated… 
 
Part 1: It is intended that safety teleconferences 
will be held biweekly; however frequency may 
fluctuate based on accrual and trial activity, as 
indicated 
 
Part 2: It is intended that safety teleconferences 
will be conducted after enrollment of 
approximately 15 and 30 patients. If safety 
concerns emerge, more frequent meetings will be 
held on an ad hoc basis. 
 
21.5 Protocol Amendment 5 dated 11-May-2017 
1. Modified inclusion criterion 5 to clarify that patients must have recurrent and/or 
progressive disease and be without other therapeutic options 
2. Revised inclusion criterion 7 to allow local assessment of KRAS-mutation and MET-
amplification based on a peripheral blood sample (liquid biopsy) 


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3. Modified inclusion and exclusion criteria to allow a subset of patients pretreated with a 
MET-targeting TKI 
4. Specified that patients included based on MET-amplification from a liquid biopsy will be 
withdrawn if subsequent analysis of a tumor biopsy does not meet eligibility criteria, and 
the patients do not have clinical benefit from therapy. Such patients will be replaced 
5. Added the option for investigators to include an H2 antagonist and/or acetaminophen 
premedication, where indicated 
6. Modified prohibited medication section to allow steroid therapy as prophylaxis for 
contrast reactions 
7. Included other minor updates and clarifications 
 
Refer to Table 20 for the changes in Protocol Amendment 5.     
 
Table 20 
Protocol Amendment 5 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
1. Synopsis: Phase 
and Overall Trial 
Design 
 
5.1 Overall Design 
and Plan 
Part 2 is a Phase 2a dose-expansion in patients with 
MET-amplified, KRAS WT solid tumor malignancies 
without therapeutic options. Two cohorts will be 
included: 
 
Q2W Basket Cohort: A cohort of 
approximately 45 patients, in which dosing will 
be… 
 
Part 2 is a Phase 2a dose-expansion in patients with MET-
amplified, KRAS WT solid tumor malignancies without 
therapeutic options. With the exception of a subset of 
patients entered to the Q2W Basket Cohort, patients must 
not have received prior therapy with MET-inhibiting 
agents.  Two cohorts will be included: 
 
Q2W Basket Cohort: A cohort of approximately 45 
patients, in which dosing will be… Included in this 
group will be a subset of approximately 6 patients 
who have received prior therapy with a MET-
targeting tyrosine kinase inhibitor (TKI).  
1. Synopsis: Main 
Inclusion and 
Exclusion Criteria 
 
6.1 Inclusion 
Criteria 
Documented (histologically- or cytologically-
proven) solid tumor malignancy…  
Documented (histologically- or cytologically-proven) 
solid tumor malignancy… (i.e. patients must have 
recurrent and/or progressive disease and be without other 
therapeutic options) 
Not applicable 
Additional main inclusion criteria applicable to Part 2 
patients ONLY: 
 
Tumor documented to be KRAS WT by local 
assessment according to institutional standards. 
Note:  Peripheral blood collection for KRAS-mutation 
assessment in circulating tumor deoxyribonucleic acid 
(ctDNA)… 
Additional main inclusion criteria applicable to 
Part 2 patients ONLY: 
 
Confirmed MET-amplification by local 
assessment; i.e. gene [G]-to-copy number 
[CN] control probe ratio…  
Additional main inclusion criteria applicable to Part 2 
patients ONLY: 
 
Confirmed MET-amplification by local 
assessment; i.e. gene [G]-to-copy number [CN] 
control probe ratio… 
Note:  Peripheral blood collection for MET-amplification 
assessment in ctDNA will be allowed… 
Not applicable 
Additional main inclusion criteria applicable to Part 2 
patients ONLY: 
 
No prior therapy with MET-targeting agents 
Note:  An exception will be a subset of approximately 6 
patients entered to the Q2W Basket Cohort after having 
received prior therapy with a MET-targeting TKI.  
1. Synopsis: Main 
Inclusion and 
Exclusion Criteria 
 
Additional main exclusion criteria applicable to 
Part 2 patients ONLY: 
 
Prior therapy with MET-inhibiting agents 
Additional main exclusion criteria applicable to Part 2 
patients ONLY: 
 
Prior therapy with MET-inhibiting agents 
Note:  An exception will be a subset of approximately 6 


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Table 20 
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6.2 Exclusion 
Criteria 
patients entered to the Q2W Basket Cohort after having 
received prior therapy with a MET-targeting TKI. 
 
6. Central nervous system (CNS) malignancy 
including: 
Note: Patients with treated CNS metastases… 
performed at least 4 weeks prior to first trial drug 
administration 
6. Central nervous system (CNS) malignancy including: 
Note: Patients with treated CNS metastases… performed 
> 4 weeks apart with the most recent performed within 4 
weeks prior to first trial drug administration 
7. Inadequate recovery from an acute toxicity… 
Note: With the exception of alopecia, patients must 
have recovered… 
7. Inadequate recovery from an acute toxicity… 
Note: With the exception of persistent Grade 2 alopecia 
and/or peripheral neuropathy, patients must have 
recovered… 
 
1. Synopsis: Trial 
Assessments 
Disease Assessments 
 
Archival tumor tissue for MET and KRAS 
assessment:  
o 
For patients in Part 2… It is preferred 
that the eligibility assessment for 
MET-amplification will be done using 
tissue… 
   
 
Disease Assessments 
 
Archival tumor tissue for MET and KRAS 
assessment:  
o 
For patients in Part 2… It is preferred that 
the eligibility assessment for MET-
amplification will be done using tissue… 
Note:  During Part 2 ONLY, peripheral blood collection 
for KRAS-mutation assessment and for MET-
amplification assessment in ctDNA is allowed…   
 
3.2.4.1 Protocol 
Sym015-01 
As of 19 October 2016, a total of 9 patients have 
been enrolled in this trial: 3 patients at each of 3 
dose levels (6, 12, and 18 mg/kg, dosed every 
second week [Q2W]). All 3 dose levels have been 
considered well tolerated, no DLTs or trial drug-
associated serious adverse events (SAEs) have been 
reported to date… 
 
As of Amendment 5, a total of 12 patients were enrolled 
in the completed Part 1 of this trial: 3 patients at each of 4 
dose levels (6, 12, 18, and 24 mg/kg, dosed every second 
week [Q2W]). All 4 dose levels were considered well 
tolerated, no DLTs or trial drug-associated serious 
adverse events (SAEs) were reported….  
3.4.2 Rationale for 
Recommended 
Phase 2 Dose 
As of 19 October 2016… 
As of Amendment 4… 
4.2.2 Secondary 
Objectives 
Not applicable 
5. To make a preliminary evaluation of the antitumor 
activity of Sym015, and to evaluate all of the above 
secondary objectives, in a subset of approximately 6 
patients administered Sym015 at the Q2W RP2D after 
having received prior therapy with a MET-targeting 
tyrosine kinase inhibitor (TKI) 
5.3.1 Prescreening 
for MET-
amplification and 
KRAS Mutational 
Status 
Not applicable 
*Part 2 ONLY:  Peripheral blood collection for MET-
amplification assessment and for KRAS-mutation 
assessment in circulating tumor deoxyribonucleic acid 
(ctDNA) (also referred to as “liquid biopsy”) will be 
allowed…   
 
5.3.2 Screening 
The trial site staff must complete a Screening and 
Allocation Form, stating the allocated patient 
number… 
The trial site staff must complete a Screening and 
Allocation Form, stating the allocated patient number… 
and whether the patient has received prior therapy with 
MET-inhibiting agents. 
6.3.1 Withdrawal 
from Treatment 
with Sym015 
Not applicable 
Results from archival tumor tissue or a tumor biopsy 
submitted to confirm MET-amplification status that do 
not meet study eligibility criteria.   
Note:  Such patients may remain on study if there is 
evidence of an OR, SD, or other clinical benefit, but will 
not be included in the Evaluable for Response Population. 
6.4.2 Part 2 
It is not planned to replace any patients in Part 2 of 
the trial. 
Patients enrolled to the study based on local MET-
amplification assessments conducted in ctDNA, but with 
subsequent confirmatory tumor tissue evaluation… 


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Table 20 
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NEW TEXT 
7.2.1 
Premedication for 
Sym015 Infusions 
All patients will receive the following premedication 
All patients must be premedicated as described with 
standard therapies that include a glucocorticoid and an H1 
antagonist.  Where indicated, consideration may be given 
to including an H2 antagonist and/or acetaminophen...   
 
Antihistamine (H2) antagonist (optional) such 
as 50 mg IV ranitidine or 30 mg famotidine, 
approx. 0.5 hours prior to the start of Sym015 
infusion 
 
Acetaminophen (optional) such as 1000 mg IV 
or PO (orally), approx. 0.5 hours prior to the 
start of Sym015 infusion 
7.5.2 Prohibited 
Medication/ 
Therapy and 
Procedures During 
the Trial 
Not applicable 
Steroid therapy as prophylaxis for contrast reactions 
 
8.3.3 Archival 
Tumor Tissue for 
MET and KRAS 
Assessment 
Not applicable 
During Part 2 ONLY, peripheral blood collection for 
KRAS-mutation assessment and for MET-amplification 
assessment in ctDNA is allowed as a local pre-screening 
methodology by Guardant360 analysis…   
 
8.4 
Pharmacokinetic 
Assessments 
Not applicable 
Note:  Comprehensive collection of clinical samples is 
critical to the conduct of this study.  In situations where 
collection of EOI + 8h samples is logistically difficult… 
 
8.7 Biomarker 
Blood Sample 
Aliquots of plasma samples will be stored… 
Biomarker samples will be stored… 
 
 
21.6 Protocol Amendment 6 dated 20-Nov-2017 
1. Modified the overall trial design by removing Q3W dosing with Sym015, which will not 
be evaluated, and added a separate cohort of KRAS WT, advanced NSCLC patients with 
METex14 mutation.  
2. Updated secondary trial objectives according to the change in overall trial design. 
3. Updated the summary of clinical findings based on the 7 MET-amplified patients that 
have been enrolled in the ongoing Part 2 Basket Cohort at the time of the amendment. 
4. Modified inclusion and exclusion criteria to allow enrollment of patients with NSCLC 
and other malignancies with METex14 mutation, and who have been pre-treated with 
MET-targeting TKI. 
5. Modified exclusion criteria to specify time required between prior antineoplastic agent 
and C1/D1, and prior immunosuppressive or systemic hormonal therapy.   
6. Modified prohibited medication to specify when the use of steroid therapy is considered 
not allowed. 
7. Specified the order of collection of tumor biopsy and biomarker blood sample if collected 
at the same timepoint. 
8. Included other minor updates and clarifications. 
 
Refer to Table 21 for the changes in Protocol Amendment 6.     
 


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Table 21 
Protocol Amendment 6 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
1. Synopsis: Trial 
Phases 
 Part 1 is a Phase 1a dose-escalation in patients with 
Kirsten Rat Sarcoma (KRAS)… 
 Part 2 is a Phase 2a dose-expansion in patients with 
MET-amplified, KRAS WT solid tumor malignancies 
without therapeutic options. With the exception of a 
subset of patients entered to the Q2W Basket Cohort, 
patients must not have received prior therapy with 
MET-inhibiting agents.  Two cohorts will be 
included: 
o Q2W Basket Cohort: A cohort of approximately 
45 patients, in which dosing will be at the 
recommended phase 2 dose (RP2D) on an every 
second week (Q2W) schedule, in the following 
referred to as the Q2W RP2D…  
o Q3W Basket Cohort: A cohort of 6-12 patients, 
in which the highest safe dose tested in Part 1 
will be evaluated on an every third week (Q3W) 
schedule 
A basket trial is designed… 
 Part 1 is a Phase 1a dose-escalation in patients with 
KRAS proto-oncogene (KRAS)… 
 Part 2 is a Phase 2a dose-expansion in which dosing 
will be at the recommended phase 2 dose (RP2D) on 
an every second week (Q2W) schedule. Two cohorts 
will be included: 
o Basket* Cohort: A cohort of approximately 45 
patients with KRAS WT advanced solid tumor 
malignancies with MET-amplification, and 
without therapeutic options… 
o NSCLC Cohort: A cohort of 6-12 patients with 
KRAS WT non-small cell lung carcinoma 
(NSCLC) with MET exon 14 skipping mutation 
(METex14), and without therapeutic options.  
Patients need not be MET-amplified and may have 
received prior therapy with a MET-targeting TKI. 
Note:  Patients with malignancies other than 
NSCLC may be considered for entry to this cohort 
following discussion with the Sponsor’s Medical 
Monitor(s). 
 
*A basket cohort is designed… 
 
1. Synopsis: Trial 
Sites and Countries 
Part 2: 15 to 20 investigational trial sites, located 
within the USA, Asia Pacific, and Europe. Enrollment 
to the Q3W Basket Cohort is expected to take place at 
select sites only. 
 
Part 2: 15 to 25 investigational trial sites, located 
within the USA, Asia Pacific, and Europe. 
1. Synopsis: 
Planned Trial 
Period  
Enrollment to Part 2… Enrollment is expected to 
complete by Q3 2018. 
Enrollment to Part 2… Enrollment is expected to 
complete by Q2 2019. 
 
1. Synopsis: 
Overall Trial 
Design 
The SMC will select the Q2W RP2D and the highest 
safe dose for the Q3W regimen to be used in Part 2… 
 
During Part 2, basket cohorts of patients with MET-
amplified, KRAS WT advanced solid tumor 
malignancies will be evaluated: Q2W Basket Cohort 
administering the Q2W RP2D on a Q2W dosing 
schedule and Q3W Basket Cohort administering the 
highest safe dose tested in Part 1 on a Q3W dosing 
schedule. 
The SMC will select the Q2W RP2D to be used in Part 
2… 
 
During Part 2, two cohorts will receive Sym015 at the 
RP2D on a Q2W dosing schedule: 
• Basket Cohort: A basket cohort of KRAS WT, 
advanced solid tumor malignancy patients with 
MET-amplification will be evaluated. Patients must 
be MET-targeting TKI-naïve; an exception will be 
a subset of approximately 6 patients entered who 
have received prior therapy with a MET-targeting 
TKI. 
• NSCLC Cohort:  A cohort of KRAS WT, advanced 
NSCLC patients with METex14 mutation will be 
evaluated. Patients need not be MET-amplified and 
may have received prior therapy with a MET-
targeting TKI. 
1. Synopsis: Trial 
Periods 
Treatment Period: Patients in the trial will receive IV 
infusions of Sym015 on a Q2W or Q3W schedule… 
  
Treatment Period: Patients in the trial will receive IV 
infusions of Sym015 on a Q2W schedule… 
  


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End of Treatment/Follow-up: …This One-Month 
Follow-up (1M FUP) visit will constitute the end of 
trial participation for the patient. 
 
After the 1M FUP Visit, the Investigator will make 
every effort to obtain follow-up information on 
response assessment and/or OS, every 2 months… 
Survival follow-up is required until death, withdrawal 
of consent, or termination of the trial. 
End of Treatment/Follow-up: …Removed  
 
 
After the 1-Month Follow-up (1M FUP) Visit, the 
Investigator will make every effort to obtain follow-up 
information on response assessment and/or OS, about 
once every 2 months… Survival follow-up is required 
until death, withdrawal of consent, trial site closure, or 
termination/end of the trial. Occurrence of one of these 
events constitutes the end of trial for the patient. 
1. Synopsis: 
Number of Patients 
Approximately 51-57 patients with documented and 
confirmed MET-amplified and KRAS WT advanced 
solid tumor malignancies will be enrolled and treated 
during Part 2. 
Approximately 51-57 patients will receive Sym015 at 
the RP2D on a Q2W schedule during Part 2.  Two 
cohorts will be included:  
• Approximately 45 patients with KRAS WT, 
advanced solid tumor malignancies with 
documented and confirmed MET-amplification will 
be enrolled and treated.  A subset of approximately 
6 patients will have received prior therapy with a 
MET-targeting TKI. 
• 6-12 patients with KRAS WT, advanced NSCLC 
with documented METex14 mutation will be 
enrolled and treated. Patients need not be MET-
amplified and may have received prior therapy with 
a MET-targeting TKI. 
1. Synopsis: Main 
Inclusion and 
Exclusion Criteria 
Additional main inclusion criteria applicable to 
Part 2 patients ONLY: 
 Tumor documented to be KRAS WT… 
Note:  …Other liquid biopsy methodologies will only be 
allowed if previously approved by the Sponsor.    
 
 
 
 Confirmed MET-amplification by local 
assessment… 
 No prior therapy with MET-targeting agents 
Note:  An exception will be a subset of approximately 6 
patients entered to the Q2W Basket Cohort… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main exclusion criteria all patients, Part 1 and Part 
2: 
 Any antineoplastic agent (standard or 
Additional main inclusion criteria applicable to 
Part 2 patients ONLY: 
 Tumor documented to be KRAS WT… 
Note:  …Other liquid biopsy methodologies, except if 
used to detect METex14 mutation, will only be allowed if 
previously approved by the Sponsor.   
  
 Basket Cohort ONLY: 
o Confirmed MET-amplification by local 
assessment… 
o No prior therapy with MET-targeting agents 
Note:  An exception will be a subset of approximately 
6 patients entered to the Basket Cohort…  
 
 NSCLC Cohort ONLY:  
o Documented METex14 mutations* (patients 
need not be MET-amplified and may have 
received prior therapy with a MET-targeting 
TKI) 
Note:  Patients with malignancies other than NSCLC 
may be considered for entry to this cohort following 
discussion with the Sponsor’s Medical Monitor(s).  
METex14 mutation status to be documented according 
to local institutional standards.  Assessment in ctDNA 
by Guardant360 technology or equivalent is allowed.  
Subsequent confirmation in tumor tissue is preferred 
but not required. 
 
Main exclusion criteria all patients, Part 1 and Part 
2: 
 Any antineoplastic agent for the primary 
malignancy (standard or investigational) without 


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investigational) within 4 weeks prior to C1/D1 
 
 
 
 
 
 Central nervous system (CNS) malignancy 
including primary malignancies of the CNS and/or 
known CNS or leptomeningeal metastases not 
controlled by prior surgery… 
Additional main exclusion criteria applicable to Part 2 
patients ONLY: 
 Prior therapy with MET-inhibiting agents 
Note:  An exception will be a subset of approximately 6 
patients entered to the Q2W Basket Cohort… 
 
 
 
 Tumor status demonstrating MET-polysomy  
 
delayed toxicity within 4 weeks or 5 plasma half-
lives, whichever is shortest, prior to C1/D1, except:  
o Nitrosoureas and mitomycin C within 6 weeks 
prior to C1/D1 
 
 Central nervous system (CNS) malignancy 
including primary malignancies of the CNS and/or 
known, untreated CNS or leptomeningeal 
metastases, or spinal cord compression; patients 
with any of these not controlled by prior surgery… 
Additional main exclusion criteria applicable to Part 2 
patients ONLY: 
 Prior therapy with MET-inhibiting agents 
Note:  Exceptions will be a subset of approximately 6 
patients entered to the Basket Cohort…, and patients 
entered to the NSCLC Cohort who may have received 
prior therapy with a MET-targeting TKI. 
 
 Basket Cohort ONLY: Tumor status demonstrating 
MET-polysomy in the absence of MET-
amplification, as specified 
Note: Patients in the NSCLC Cohort with polysomy are 
eligible 
 
1. Synopsis: 
Investigational 
Medicinal Product, 
Dose(s) and 
Treatment 
Schedule 
Sym015 will be administered on a Q2W or Q3W 
schedule by IV infusion.  
 Q2W dosing: Day 1 and Day 15 of each 28-day 
cycle (± 2 days) 
 Q3W dosing: Day 1 and Day 22 of each 42-day 
cycle (± 2 days)  
Note: Q3W dosing is implemented in Part 2 after 
highest safe dose is identified on Q2W schedule 
 
Part 2 
Once the Q2W RP2D has been established during 
dose-escalation, the enrollment into the Q2W Basket 
Cohort will commence… 
 
Once the highest safe dose tested in Part 1 has been 
determined, all patients in the Q3W Basket Cohort will 
be treated at that dose level on a Q3W dosing schedule. 
 
Sym015 will be administered on a Q2W schedule by 
IV infusion.  
 Q2W dosing: Day 1 and Day 15 of each 28-day 
cycle (± 2 days) 
 
 
 
 
Part 2 
Once the Q2W RP2D has been established during 
dose-escalation, the enrollment into the Basket Cohort 
and NSCLC Cohort will commence. 
 
 
Removed 
1. Synopsis: Trial 
Assessments 
Disease Assessments 
 Q2W dosing schedule: Disease status evaluation… 
 Q3W Basket Cohort only: Disease status evaluation 
by CT or MRI at screening and at the end of the 
follow-up period following every third dose. 
Further potential timepoints are in the event of 
suspected PD, in the event of CR/PR and at 
EOT/1M FU 
 Archival tumor tissue for MET and KRAS 
assessment:  
o For patients in Part 2… 
It is preferred… 
Disease Assessments 
 Disease status evaluation… 
Removed 
 
 
 
 
 
 Archival tumor tissue for MET and KRAS 
assessment:  
o For patients in Part 2… 
 Basket Cohort: It is preferred… 
Note:  …Other liquid biopsy methodologies, 


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Note:  …Other liquid biopsy methodologies will only 
be allowed if previously approved by the Sponsor.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 Tumor biopsy to be assessed locally as part of 
eligibility assessment for Part 1 and Part 2 patients, 
if applicable. In addition, to be assessed centrally 
for biomarker analysis (optional for patients in Part 
1 with known MET-amplification; required for 
patients in Part 2): 
o Q2W dosing: At screening and at the end of 
Cycle 2 or upon PD, whichever comes first.  
o Q3W Basket Cohort: At screening and at the 
end of the follow-up period following the third 
dose or upon PD, whichever comes first.  
Tissue from a tumor biopsy performed during 
screening is preferred, however archival tissue 
may be submitted for central analysis at the 
Investigator’s discretion, provided the archival 
tissue is suitable as specified in the laboratory 
manual. 
 
 
 
 
 
 
Additional Assessments 
 Biomarker blood sample: 
o Q2W dosing: At screening, at the end of Cycle 
2 or upon PD, whichever comes first, and at 
EOT 
o Q3W Basket Cohort: At screening, at the end of 
the follow-up period following the third dose or 
upon PD, whichever comes first, and at EOT 
 
except if used to detect METex14 mutation, will 
only be allowed if previously approved by the 
Sponsor.  
 
 NSCLC Cohort: Eligibility assessment for 
METex14 mutation status will be done 
according to local institutional standards.  
Assessment in ctDNA by Guardant360 
technology or equivalent is allowed.  
Subsequent confirmation in tumor tissue is 
preferred but not required, however, 
archival tissue to be submitted for central 
testing, if available. 
 Tumor biopsy for eligibility assessment and 
biomarker analysis:  
o To be assessed locally for eligibility assessment 
for Part 1 and Part 2 patients if not already 
assessed in archival tumor tissue and if 
applicable (i.e. Basket Cohort only) 
o To be assessed centrally for biomarker analysis 
 Part 1, optional for patients with known 
MET-amplification 
 Part 2: 
 Basket Cohort: Required at screening if 
archival tissue is unavailable or 
insufficient, and at the end of Cycle 2 
or upon PD, whichever comes first.  At 
screening, tissue from a tumor biopsy 
is preferred, however archival tissue 
may be submitted for central analysis 
at the Investigator’s discretion, 
provided the archival tissue is suitable 
as specified in the laboratory manual. 
 NSCLC Cohort: Optional, at the 
timepoints specified 
 
 
Additional Assessments 
 Biomarker blood sample: At screening, at the end 
of Cycle 2 or upon PD, whichever comes first, and 
at EOT 
 
 
Removed 
 
1. Synopsis: 
Statistical Methods 
and Sample Size 
Calculation 
In Part 2 of the trial, the primary endpoint is 
documented OR in the Q2W Basket Cohort… 
 
For the Q3W Basket Cohort, assuming the response… 
In Part 2 of the trial, the primary endpoint is 
documented OR in the Basket Cohort… 
 
For the NSCLC Cohort, assuming the response… 
 
3.1.2 MET-
amplified Solid 
Tumor 
Not applicable 
Mutations leading to skipping of MET exon 14 
(METex14) result in the deletion of the juxtamembrane 
domain of MET, which stabilizes and accumulates 


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Malignancies 
receptor on the cell surface and leads to enhanced 
signaling through the MET receptor pathway. MET 
alterations that result in exon 14 skipping are found in 
3-4% of lung adenocarcinomas, both in the presence 
and absence of MET-amplification and studies have 
demonstrated clinical benefit of targeting patients with 
tumors harboring METex14 mutations. Over 100 
mutations in MET-mutated cancers resulting in exon 
14 skipping have been described. 
3.2.3 Summary of 
Non-Clinical 
Findings 
Responsive models include MET-amplified, MET-exon 
14 deleted, and autocrine HGF-expressing tumors. 
Response to Sym015 was observed in models with 
MET-amplification, METex14 mutations, and autocrine 
HGF-expression. 
 
3.2.4.1 Protocol 
Sym015-01 
While data in this ongoing clinical trial have not been 
fully monitored… 
While data in this ongoing clinical trial have not been 
fully monitored… all AEs were Grade 1 or Grade 2 in 
severity.   
As of Amendment 6, a total of 7 MET-amplified 
patients have been enrolled in the ongoing Part 2 
Basket Cohort of this trial… 
 
3.3 Trial Rationale 
As outlined in the sections above, recent results 
suggest that MET-amplification identifies a small but 
clinically important subgroup of patients who are 
likely to respond to MET targeted therapies. The 
potent tumor inhibitory activity, observed in preclinical 
studies in MET-amplified models, suggests that 
Sym015 may provide a clinically relevant effect in this 
patient population. Based on the nonclinical 
pharmacology and toxicity testing, Sym015 is expected 
to be well tolerated and the benefit-risk ratio for 
patients enrolled is considered to be favorable. 
As outlined in the sections above, recent results 
suggest that MET-amplification and METex14 
mutations identify small but clinically important 
subgroups of patients who are likely to respond to 
MET targeted therapies. The potent tumor inhibitory 
activity, observed in preclinical studies in models with 
MET-amplification and/or METex14 mutations, 
suggests that Sym015 may provide a clinically relevant 
effect in these patient populations. Based on the 
nonclinical pharmacology and toxicity testing, Sym015 
is expected to continue to be well tolerated and the 
benefit-risk ratio for patients enrolled is considered to 
be favorable. 
 
3.4.1 Rationale for 
Starting Dose 
The dosing schedules to be explored in this clinical 
trial are based on... PK data (long terminal T½ and 
accumulation with weekly dosing) support the 
selection of the dosing schedules, dosing every second 
week (Q2W) and dosing every third week (Q3W), to 
be evaluated in this trial. 
 
The dosing schedule to be explored in this clinical trial 
is based on... PK data (long terminal T½ and 
accumulation with weekly dosing) support the 
selection of the dosing schedule, dosing every second 
week (Q2W), to be evaluated in this trial. 
4.2.2 Secondary 
Objectives 
6. To make a preliminary evaluation of the antitumor 
activity of Sym015, and to evaluate all of the above 
secondary objectives, in a cohort of patients 
administered Sym015 on a Q3W dosing schedule at the 
highest safe dose tested in Part 1 
6. To make a preliminary evaluation of the antitumor 
activity of Sym015, and to evaluate all the above 
secondary objectives, in a subset of approximately 6-
12 KRAS WT NSCLC patients with METex14 
mutations administered Sym015 at the Q2W RP2D.  
Patients need not be MET-amplified and may have 
received prior therapy with a MET-targeting TKI. 
Note:  Patients with malignancies other than NSCLC may be 
considered for entry to this cohort following discussion with 
the Sponsor’s Medical Monitor(s). 
 
5.1 Overall Design 
Plan 
 Part 2 is a Phase 2a dose-expansion in patients with 
MET-amplified, KRAS WT solid tumor malignancies 
without therapeutic options. With the exception of a 
subset of patients entered to the Q2W Basket Cohort, 
patients must not have received prior therapy with 
MET-inhibiting agents.  Two cohorts will be 
 Part 2 is a Phase 2a dose-expansion in which dosing 
will be at the recommended phase 2 dose (RP2D) on 
an every second week (Q2W) schedule, in the 
following referred to as the Q2W RP2D.  Two 
cohorts will be included: 


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included: 
o A Basket Cohort of approximately 45 patients, 
in which dosing will be at the Q2W RP2D 
(Q2W Basket Cohort).  Included in this group 
will be a subset of approximately 6 patients who 
have received prior therapy with a MET-
targeting TKI.   
o A Basket Cohort of 6-12 patients, in which the 
highest safe dose tested in Part 1 will be 
evaluated on a Q3W schedule (Q3W Basket 
Cohort) 
A basket trial is designed… 
 
The SMC will select the Q2W RP2D and the highest 
safe dose for the Q3W regimen to be used in Part 2… 
 
During Part 2, basket cohorts of patients with MET-
amplified, KRAS WT, advanced solid tumor 
malignancies will be evaluated: Q2W Basket Cohort 
administering the Q2W RP2D on a Q2W schedule and 
Q3W Basket Cohort administering the highest safe 
dose tested in Part 1 on a Q3W schedule. 
 
 
 
 
 
 
 
 
 
 
 
The number of investigational trial sites…15 to 20 in 
Part 2. Enrollment to the Q3W Basket Cohort is 
expected to take place at select trial sites only. 
 
o Basket* Cohort: A cohort of approximately 45 
patients with KRAS WT advanced solid tumor 
malignancies with MET-amplification, and 
without therapeutic options. Included in this 
group will be a subset of approximately 6 
patients who have received prior therapy with a 
MET-targeting TKI.   
o NSCLC Cohort: A cohort of 6-12 patients with 
KRAS WT NSCLC with METex14 mutation, 
and without therapeutic options.  Patients need 
not be MET-amplified and may have received 
prior therapy with a MET-targeting TKI. 
*A basket cohort is designed… 
 
The SMC will select the Q2W RP2D to be used in Part 
2… 
 
During Part 2, two cohorts will receive Sym015 at the 
RP2D on a Q2W dosing schedule: 
 Basket Cohort: A basket cohort of KRAS WT, 
advanced solid tumor malignancy patients with 
MET-amplification will be evaluated. Patients must 
be MET-targeting TKI-naïve; an exception will be 
a subset of approximately 6 patients entered who 
have received prior therapy with a MET-targeting 
TKI. 
 NSCLC Cohort: A cohort of KRAS WT advanced 
NSCLC patients with METex14 mutation will be 
evaluated. Patients need not be MET-amplified and 
may have received prior therapy with a MET-
targeting TKI. 
The number of investigational trial sites…15 to 25 in 
Part 2. 
5.2.1 Rationale for 
Trial Design 
Part 2 of this trial is designed: to evaluate the antitumor 
activity of Sym015 administered at the selected Q2W 
RP2D on a Q2W schedule and to further explore 
safety, tolerability and preliminary antitumor effect of 
the highest safe dose tested in Part 1 on a Q3W 
schedule.  
 
The choice of basket cohorts… 
Part 2 of this trial is designed to evaluate the antitumor 
activity of Sym015 administered at the selected Q2W 
RP2D on a Q2W schedule.  
 
 
 
 
The choice of a basket cohort… 
 
5.2.2 Rationale for 
Trial Population 
Nonclinical studies have documented that the activity 
of Sym015 is greater in MET-amplified tumors, and 
similar findings have been observed in preliminary 
studies of other anti-MET mAbs in early clinical trials. 
In addition, a cohort of KRAS WT NSCLC patients 
with METex14 mutation will be entered to evaluate the 
antitumor activity of Sym015. Nonclinical studies have 
documented that the activity of Sym015 is greater in 
tumors with MET-amplification and/or METex14 
mutation, suggesting that Sym015 may provide a 
clinically relevant effect in these patient populations.  
Similar findings have been observed in preliminary 
studies in patients with MET-amplified tumors of other 
anti-MET mAbs in early clinical trials. 


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5.3.1 Prescreening 
for MET-
amplification, 
METex14, and 
KRAS Mutational 
Status  
The trial site may choose to prescreen patients utilizing 
archival tumor tissue to confirm MET-amplification 
status* and/or KRAS mutational status*...   
*Part 2 ONLY:  Peripheral blood collection for MET-
amplification assessment and for KRAS-mutation 
assessment… Other liquid biopsy methodologies will only 
be allowed if previously approved by the Sponsor… 
The trial site may choose to prescreen patients utilizing 
archival tumor tissue to confirm MET-amplification 
status*, METex14 mutation status*, and/or KRAS 
mutational status*...   
*Part 2 ONLY:  Peripheral blood collection for MET-
amplification assessment, METex14 assessment, and 
KRAS-mutation assessment… Other liquid biopsy 
methodologies, except if used to detect METex14 
mutation, will only be allowed if previously approved by 
the Sponsor… 
5.3.2 Screening 
Furthermore, once eligibility is confirmed: 
 All patients in Part 2 will have a tumor biopsy 
performed… 
Furthermore, once eligibility is confirmed: 
 All patients in the Part 2 Basket Cohort will have a 
tumor biopsy performed… 
 For patients in the Part 2 NSCLC Cohort, biopsy 
for biomarker analysis is optional; archival tissue to 
be submitted, if available   
 
5.3.4 Treatment 
Sym015 will be administered on a Q2W or Q3W 
schedule by IV infusion: 
 Q2W dosing: Day 1 and Day 15 of each 28-day 
cycle (± 2 days) 
 Q3W dosing: Day 1 and Day 22 of each 42-day 
cycle (± 2 days) (Q3W Basket Cohort only) 
 
Sym015 will be administered on a Q2W schedule by 
IV infusion: 
 Q2W dosing: Day 1 and Day 15 of each 28-day 
cycle (± 2 days) 
5.3.5 End of 
Treatment and 
Follow-up Visits 
After the 1M FUP Visit, the Investigator will make 
every effort… every 2 months… Survival follow-up is 
required until death, withdrawal of consent, or 
termination of the trial… 
After the 1M FUP Visit, the Investigator will make 
every effort… about once every 2 months… Survival 
follow-up is required until death, withdrawal of 
consent, trial site closure, or termination/end of the 
trial.  Occurrence of one of these events constitutes the 
EOS for the patient…  
 
5.3.6 Flow Chart – 
Schedule of 
Assessments 
Schedules of assessments are provided in the trial flow 
charts in Table 3 (Q2W dosing) and Table 4 (Q3W 
dosing, Q3W Basket Cohort only), respectively. 
 
Furthermore, each new cycle must be initiated as soon 
as possible after completion of the previous cycle in 
order to achieve the Q2W/Q3W dosing schedule as 
applicable for the individual patient. 
 
Schedules of assessments are provided in the trial flow 
chart in Table 3 (Q2W dosing). 
 
 
Furthermore, each new cycle must be initiated as soon 
as possible after completion of the previous cycle in 
order to achieve the Q2W dosing schedule. 
5.5 Number of 
Patients 
During Part 2, it is planned to enroll and treat 
approximately 45 patients in the Q2W Basket Cohort 
and 6-12 patients in the Q3W Basket Cohort; i.e. a 
total of 51-57 patients with documented and confirmed 
MET-amplified and KRAS WT advanced solid tumor 
malignancies. 
It is estimated that approximately 51-57 patients will 
be enrolled to receive Sym015 at the RP2D on a Q2W 
schedule during Part 2. Two cohorts will be included: 
 Basket Cohort: Approximately 45 patients with 
KRAS WT, advanced solid tumor malignancies 
with documented and confirmed MET-
amplification will be enrolled and treated. A subset 
of 6 patients will have received prior therapy with a 
MET-targeting TKI.  
 NSCLC Cohort: 6-12 patients with KRAS WT, 
advanced NSCLC with documented METex14 
mutation will be enrolled and treated. Patients need 
not be MET-amplified and may have received prior 
therapy with a MET-targeting TKI.   
5.6 End of Trial 
The end of trial will be reached at the latest 1 month 
The end of trial will be reached at the latest 1 month 


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(30 +7 days) after the last patient has been withdrawn 
from Sym015. Patients will continue to be followed to 
assess duration of disease stabilization, response and/or 
overall survival. 
 
(30 +7 days) after the last patient has been withdrawn 
from Sym015. 
6.1 Inclusion 
Criteria 
Part 2 ONLY: 
b. Tumor documented to be KRAS WT… 
Note:  …Other liquid biopsy methodologies will only 
be allowed if previously approved by the Sponsor. 
 
 
c. Confirmed MET-amplification by local… 
 
d. No prior therapy with MET-targeting agents 
Note:  An exception will be a subset of approximately 6 
patients entered to the Q2W Basket Cohort… 
Part 2 ONLY: 
b. Tumor documented to be KRAS WT…  
Note:  …Other liquid biopsy methodologies, except if 
used to detect METex14 mutation, will only be allowed 
if previously approved by the Sponsor. 
 
c. Basket Cohort ONLY: 
 Confirmed MET-amplification by local… 
 No prior therapy with MET-targeting agents 
Note:  An exception will be a subset of approximately 
6 patients entered to the Basket Cohort…  
 
d. NSCLC Cohort ONLY:  
 Documented METex14 mutations (patients need 
not be MET-amplified and may have received 
prior therapy with a MET-targeting TKI) 
Note: Patients with malignancies other than NSCLC and with 
documented METex14 mutation may be considered for entry 
to this cohort following discussion with the Sponsor’s 
Medical Monitor(s). 
Note: METex14 mutation status to be documented according 
to local institutional standards.  Assessment in ctDNA by 
Guardant360 technology or equivalent is allowed.  
Subsequent confirmation in tumor tissue is preferred but not 
required. 
 
6.2 Exclusion 
Criteria 
1. Any antineoplastic agent (standard or 
investigational) within 4 weeks prior to C1/D1 
 
 
 
 
 
2. Part 2 ONLY:  
a. Prior therapy with MET-inhibiting agents  
Note:  An exception will be a subset of approximately 
6 patients entered to the Q2W Basket Cohort after 
having received prior therapy with a MET-targeting 
TKI. 
 
 
c. Tumor status demonstrating MET-polysomy  
 
 
 
 
 
3. Immunosuppressive or systemic hormonal therapy 
within 2 weeks prior to C1/D1 with the exception of 
the following allowed therapies: 
e. Hormonal contraceptive therapy  
f. GnRH analogs in patients with prostate cancer 
 
 
1. Any antineoplastic agent for the primary malignancy 
(standard or investigational) without delayed toxicity 
within 4 weeks or 5 plasma half-lives, whichever is 
shortest, prior to C1/D1 except:  
 Nitrosoureas and mitomycin C within 6 weeks 
prior to C1/D1 
2. Part 2 ONLY:  
a. Prior therapy with MET-inhibiting agents  
Note:  Exceptions will be a subset of approximately 6 
patients entered to the Basket Cohort after having 
received prior therapy with a MET-targeting TKI, and 
patients entered to the NSCLC Cohort who may have 
received prior therapy with a MET-targeting TKI. 
 
c. Basket Cohort ONLY: Tumor status 
demonstrating MET-polysomy in the absence of 
MET-amplification, as specified 
Note: Patients in the NSCLC Cohort with polysomy are 
eligible  
 
3. Immunosuppressive or systemic hormonal therapy 
(> 10 mg daily prednisone equivalent) within 2 
weeks prior to C1/D1 with the exception of the 
following allowed therapies: 
e. Steroid therapy for contrast reaction 
prophylaxis 
f. Stable hormonal therapy for ovarian suppression 


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6. Central nervous system (CNS) malignancy 
including: 
b. Known CNS or leptomeningeal metastases not 
controlled by prior surgery… 
Note: Patients with treated CNS metastases… 
for non-malignant conditions, hormonal 
contraceptive therapy, or post-menopausal 
hormone replacement therapy (HRT)*  
g. GnRH analogs in patients with prostate cancer 
h. Intra-articular steroid injections 
i. Higher dose steroid therapy for treatment of an 
acute intercurrent illness in patients with stable 
disease or an ongoing response. In such 
situations, protocol therapy treatment should be 
interrupted. 
*Prior or concomitant therapies are permitted; 
however, patients must have been on a stable 
dose for at least 6 months prior to study start, and 
if continuing must remain on the stable dose 
while receiving study treatment (i.e. such 
treatment will not be considered as systemic 
hormonal therapy for the purpose of study 
eligibility). 
 
6. Central nervous system (CNS) malignancy 
including: 
b. Known, untreated CNS or leptomeningeal 
metastases, or spinal cord compression; patients 
with any of these not controlled by prior 
surgery… 
Note: Patients with treated CNS metastases… 
Patients with newly identified CNS metastases during 
study treatment will be considered to have PD and 
will be discontinued from treatment 
 
6.3.1 Withdrawal 
from Treatment 
with Sym015 
 Results from archival tumor tissue or a tumor biopsy 
submitted to confirm MET-amplification status that 
do not meet study eligibility criteria.   
 Basket Cohort ONLY: Results from archival tumor 
tissue or a tumor biopsy submitted to confirm MET-
amplification status that do not meet study eligibility 
criteria.   
6.4.2 Part 2 
Patients enrolled to the study… 
Basket Cohort ONLY: Patients enrolled to the study… 
 
7.1.3.1 Treatment 
Schedule 
Sym015 will be administered Q2W (Day 1 and Day 15 
of each 28-day cycle [±2 days]) or Q3W (Day 1 and 
Day 22 of each 42-day cycle [±2 days]).   
 
Sym015 will be administered Q2W (Day 1 and Day 15 
of each 28-day cycle [±2 days]).   
7.1.3.2 Part 1, 
Dose-Escalation 
The SMC will review safety data… and the doses to be 
used in Part 2 (i.e. Q2W RP2D to be evaluated in the 
Q2W Basket Cohort and the highest safe dose in Part 1 
to be evaluated in the Q3W Basket Cohort). 
 
The SMC will review safety data… and the dose(s) to 
be used in Part 2 (i.e. Q2W RP2D to be evaluated). 
7.1.3.3 Part 2 
During Part 2 of this trial, patients included in the 
Q2W Basket Cohort will receive the Q2W RP2D of 
Sym015 on a Q2W dosing schedule. Patients included 
in the Q3W Basket Cohort will receive the highest safe 
dose tested in Part 1 on a Q3W dosing schedule. 
 
During Part 2 of this trial, patients will receive the 
RP2D of Sym015 on a Q2W dosing schedule. 
7.1.4 Dose-
Adjustment and 
Delays of Sym015 
The dose of Sym015 in mg/kg and the dosing schedule, 
Q2W or Q3W, assigned to the individual patient, will 
be confirmed by the Sponsor…  
 
The dose of Sym015 in mg/kg assigned to the 
individual patient will be confirmed by the Sponsor… 
7.5.2 Prohibited 
Medication/ 
Therapy and 
 Systemic immunosuppressive or systemic hormonal 
therapy with the exception of the following allowed 
 Systemic immunosuppressive or systemic hormonal 
therapy with the exception of the following allowed 


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Procedures During 
the Trial 
therapies: 
o Hormonal contraceptive therapy 
therapies: 
o Stable hormonal therapy for ovarian 
suppression for non-malignant conditions, 
hormonal contraceptive therapy, or post-
menopausal HRT*  
o Intra-articular steroid injections 
o Higher dose steroid therapy for treatment of an 
acute intercurrent illness in patients with stable 
disease or an ongoing response. In such 
situations, protocol therapy treatment should be 
interrupted. 
*Prior or concomitant therapies are permitted; 
however, patients must have been on a stable dose 
for at least 6 months prior to study start, and if 
continuing must remain on the stable dose while 
receiving study treatment (i.e. such treatment will 
not be considered as systemic hormonal therapy for 
the purpose of study eligibility). 
 
8.3.1 Disease 
Status Evaluation 
by CT or MRI 
 For Q2W dosing schedule only: 
o End of Cycle 2 and end of every second cycle 
thereafter, i.e. end of Cycle 4, 6, 8, etc. 
Note: May be performed at any time during the week 
prior to Day 1 of the next cycle 
 
 For Q3W Basket Cohort only: 
o At the end of the follow-up period following 
every third dose, i.e. end of the follow-up 
period following C2/D1, C3/D22, C5/D1 etc. 
Note: May be performed at any time during the week 
prior to the next scheduled dose 
 
 End of Cycle 2 and end of every second cycle 
thereafter, i.e. end of Cycle 4, 6, 8, etc. 
Note: May be performed at any time during the week prior 
to Day 1 of the next cycle 
 
 
 
Removed 
8.3.3 Archival 
Tumor Tissue for 
MET and KRAS 
Assessment 
 Screening 
o Part 2… 
It is preferred that the eligibility assessment for 
MET-amplification will be done using… 
During Part 2 ONLY… Other liquid biopsy 
methodologies will only be allowed if previously 
approved by the Sponsor… 
 Screening 
o Part 2… 
Basket Cohort: It is preferred that the eligibility 
assessment for MET-amplification be done 
using… 
During Part 2 ONLY… Other liquid biopsy 
methodologies, except if used to detect METex14 
mutation, will only be allowed if previously approved 
by the Sponsor…   
 
NSCLC Cohort: Eligibility assessment for 
METex14 mutation status will be done 
according to local institutional standards.  
Assessment in ctDNA by Guardant360 
technology or equivalent is allowed.  
Subsequent confirmation in tumor tissue is 
preferred but not required, however, archival 
tissue to be submitted, if available. 
 
8.3.4 Tumor 
Biopsy for 
Eligibility 
 Screening 
o Part 2: Required, if archival tissue… 
 
 Screening 
o Part 2:  
Basket Cohort: Required, if archival tissue… 


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Assessment and 
Biomarker 
Analysis 
 
 
 
 Post-dosing 
o Part 2: Required 
 For Q2W dosing schedule only: End of Cycle 
2… 
 For Q3W Basket Cohort only: At the end of the 
follow-up period following the third dose (i.e. 
coinciding with time of first response 
assessment) or upon PD, whichever occurs first 
Note: May be performed at any time during the week 
prior to the next scheduled dose 
 
NSCLC Cohort: Optional 
 
 Post-dosing 
o 
Part 2:  
Basket Cohort: Required; End of Cycle 2… 
 
NSCLC Cohort: Optional, at the timepoint 
specified above 
8.7 Biomarker 
Blood Sample 
 Screening, after confirmation of eligibility 
 For Q2W dosing schedule only: End of Cycle 2… 
 For Q3W Basket Cohort only: At the end of the 
follow-up period following the third dose 
(coinciding with time of first response assessment) 
or upon PD, whichever occurs first 
Note: May be performed at any time during the week prior 
to the next scheduled dose 
 EOT 
 Screening, after confirmation of eligibility 
 End of Cycle 2… 
Removed 
 
 
 
 
 EOT 
 
Note:  If a tumor biopsy is collected at the same time point as 
the biomarker blood sample, the biomarker blood sample 
should be collected prior to collecting the tumor biopsy. 
 
10.1 Sample Size 
Determination 
In Part 2 of the trial, the primary endpoint is 
documented OR in the Q2W Basket Cohort… 
 
For the Q3W Basket Cohort, assuming the response… 
 
In Part 2 of the trial, the primary endpoint is 
documented OR in the Basket Cohort… 
 
For the NSCLC Cohort, assuming the response… 
10.3.2 Part 2 
This will be assessed by the primary endpoint for Part 
2, documented OR in the Q2W Basket Cohort… 
 
This will be assessed by the primary endpoint for Part 
2, documented OR in the Basket Cohort… 
10.4.1 Efficacy 
Endpoints and 
Analyses 
The following anti-tumor response endpoints will be 
measured in Part 1 and in the Q3W Basket Cohort… 
The following anti-tumor response endpoints will be 
measured in Part 1… 
10.4.5 Additional 
Endpoints and 
Analyses 
 Part 1 only: MET-receptor down-regulation 
measured by percentage and nominal change in 
target expression from baseline to end of Cycle 
2/end of follow-up period following the third dose 
(Q2W/Q3W) or PD (whichever comes first) in skin 
biopsy samples 
 Part 1 only: MET-receptor down-regulation 
measured by percentage and nominal change in 
target expression from baseline to end of Cycle 2 or 
PD (whichever comes first) in skin biopsy samples 
10.5 Interim 
Analysis 
In Part 2 an assessment of futility will be performed… 
in the Q2W Basket Cohort. 
 
In Part 2 an assessment of futility will be performed… 
in the Basket Cohort. 
 


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21.7 Protocol Amendment 7 dated 07-Dec-2018 
1. Effective with this protocol amendment, accrual to the Basket Cohort is suspended. 
Emerging literature allowed for the identification of specific tumor types that are more 
likely to respond to Sym015 treatment (e.g., NSCLC). With this change, a new cohort of 
NSCLC MET-amplified patients has been added to Part 2 of the trial design, for a total of 
three cohorts. 
2. With the suspension of the Basket Cohort, NSCLC MET-amplified patients entered to the 
Basket Cohort will be counted toward the NSCLC MET-Amplified Cohort; NSCLC 
METEx14Del patients entered to the Basket Cohort will be counted toward the NSCLC 
METEx14Del Cohort; patients with both will be counted as MET-Amplified.   
3. Updated clinical experience information have been added to the scientific background. 
4. According to the ASCO/CAP guidelines for testing of HER2 amplification, MET-
amplification may be defined as positive with a MET/CEP7 ratio of >2.2 (occasionally 
2.0). Symphogen has opted to change the cutoff to > 3.0 based on emerging data that 
suggest higher degrees of MET-amplification are associated with higher degree of 
response. 
5. Specified that concomitant therapy with bisphosphonates and denosumab are allowed 
during the dosing portion of the trial. 
6. Clarified that after the Screening assessments, targeted physical examination may be 
performed as indicated. 
7. The number of pharmacokinetic timepoints have been reduced for patients entered to the 
NSCLC cohorts. 
8. The mandatory post-dosing tumor biopsy scheduled to be performed at the EOC2 or upon 
disease progression is now optional. 
9. Clarified that all analyses will be related to and used only in connection with the data 
collected in the present trial as well as future development of Sym015. 
10. Clarified that EOC assessments may be performed at any time during the week prior to 
Day 1 of the next cycle, including Day 1 of the next cycle, prior to dosing. 
11. Clarified that initial SAE and follow-up SAE information are to be submitted within 24 
hours of awareness. 
12. Due to the new cohort sample sizes, an initially planned interim analysis becomes 
obsolete and will no longer be performed. 
13. Guidelines pertaining to the General Data Protection Regulation have been added. 
14. Formatting adjustments, typographical corrections, outline modifications, and 
wording/abbreviation changes are included. 
15. The synopsis, figure, tables, and references have been updated based on changes 
described, where applicable. 
 
Refer to Table 22 for the changes in Protocol Amendment 7.   
 
 
 
 
 


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3.1.1 Solid Tumor 
Malignancies 
Not applicable 
Non-small cell lung cancer (NSCLC) is the leading 
cause of death due to malignancy globally. 
3.1.2 MET-
Amplified Solid 
Tumor 
Malignancies 
Mutations leading to skipping of MET exon 14 
(METex14) result in the deletion of the juxtamembrane 
domain of MET,…  
 
Although this molecular alteration is rare, testing of 
KRAS status in clinical trials involving anti-MET 
therapy may be warranted to avoid treating patients 
that may not experience clinical benefit from these 
agents (10,19). 
Mutations leading to skipping of MET exon 14 
(METEx14Del) result in the deletion of the 
juxtamembrane domain of MET,…  
Because these two molecular alterations are rare in 
NSCLC patients, testing of KRAS status in clinical 
trials involving anti-MET therapy may not be 
warranted (10,19). 
NSCLC patients with either MET-amplification or 
METEx14Del have been documented to have a poor 
prognosis (32). MET-amplification was observed in 
0.7% of all patients with NSCLC and MET mutations 
were observed in 2.6% of patients in this population. 
3.1.3 Current 
Treatment of MET-
Amplified Solid 
Tumor 
Malignancies 
These include both small-molecule tyrosine-kinase 
inhibitors, such as crizotinib, cabozantinib and 
tivantinib, as well as monoclonal antibodies (mAbs). 
The small-molecule inhibitors are generally 
promiscuous in their target specificity and thus have 
activity on additional RTKs besides MET. 
These include both small-molecule tyrosine-kinase 
inhibitors, such as crizotinib, cabozantinib, tivantinib, 
tepotinib, and capmatinib as well as single monoclonal 
antibodies (mAbs). The small-molecule inhibitors are 
generally promiscuous in their target specificity and 
may have activity on additional RTKs besides MET. 
The activity of MET inhibitors in patients with 
NSCLC has recently been reviewed (33), and more 
recent data are cited below with respect to additional 
inhibitors. 
Not applicable 
Tepotinib is another MET tyrosine kinase inhibitor 
(TKI) that has been studied in Phase 1 and Phase 2 
clinical studies…. (34). 
Capmatinib (INC280), a MET TKI, is also in Phase 2 
studies enrolling NSCLC patients with METEx14Del as 
well as in combination with gefitinib in patients with 
epidermal growth factor receptor (EGFR)-mutated 
MET dysregulated NSCLC... (35). 
3.2.4.1 Protocol 
Sym015-01 
As of Amendment 6, a total of 7 MET-amplified 
patients have been enrolled in the ongoing Part 2 
Basket Cohort of this trial to receive Sym015 at a 
loading dose of 18 mg/kg delivered over 1.5 hours, 
followed by Q2W maintenance doses of 12 mg/kg 
delivered over 1 hour… Other study drug-related AEs 
have been limited to fatigue (Grade 2) and prolonged 
prothrombin time (Grade 1).  Accrual to this portion of 
the trial continues. 
As of September 2018, a total of 21 MET-amplified 
patients and 2 METEx14Del patients have been enrolled 
in the ongoing Part 2 portion of this trial to receive 
Sym015 at a loading dose of 18 mg/kg delivered over 
1.5 hours, followed by Q2W maintenance doses of 12 
mg/kg delivered over 1 hour…  In another patient, the 
SAEs of Grade 3 anasarca and Grade 3 
hypoalbuminemia (both possibly related) have been 
reported. Other study drug-related AEs have been 
limited to Grade 2 fatigue and mouth sores, and Grade 
1 asthenia, anorexia, gastric pain, abdominal cramping, 
abdominal gas, nausea, diarrhea, constipation, xerosis, 
pruritus, and voice change… Accrual to the Part 2 
portion of the trial continues. 
Note:  Effective with protocol version 8.0 (December 2018), 
accrual to the Part 2 Basket Cohort comprised of patients with 
MET-amplified solid tumor malignancies is suspended; 
accrual will continue to cohorts of patients with MET-
amplified NSCLC or METEx14Del NSCLC. 


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4.2.1 Primary 
Objective 
To evaluate the antitumor activity of Sym015 when 
administered at the Q2W RP2D to patients with MET-
amplified, KRAS WT solid tumor malignancies without 
available therapeutic options.   
To evaluate the antitumor activity of Sym015 when 
administered at the Q2W RP2D to patients in the 
following cohorts:  
1. Basket Cohort: MET-amplified, KRAS WT solid 
tumor malignancies without available therapeutic 
options; patients may not have received prior therapy 
with a MET-targeting TKI  
2. NSCLC MET-Amplified Cohort: MET-amplified 
advanced NSCLC without available therapeutic 
options; patients may have received prior therapy with 
MET-targeting and/or EGFR-targeting agents   
3. NSCLC METEx14Del Cohort: METEx14Del NSCLC 
without available therapeutic options; patients may 
have received prior therapy with MET-targeting and/or 
EGFR-targeting agents 
4.2.2 Secondary 
Objectives 
5. To make a preliminary evaluation of the antitumor 
activity of Sym015, and to evaluate all of the above 
secondary objectives, in a subset of approximately 6 
patients administered Sym015 at the Q2W RP2D after 
having received prior therapy with a MET-targeting 
tyrosine kinase inhibitor (TKI) 
5. Basket Cohort: To make a preliminary assessment of 
the antitumor activity of Sym015, and to evaluate all of 
the above secondary objectives, in a subset of 
approximately 6 patients with solid tumor 
malignancies administered Sym015 at the Q2W RP2D 
after having received prior therapy with a MET-
targeting TKI 
6. To make a preliminary evaluation of the antitumor 
activity of Sym015, and to evaluate all the above 
secondary objectives, in a subset of approximately 6-
12 KRAS WT NSCLC patients with METex14 
mutations administered Sym015 at the Q2W RP2D.  
Patients need not be MET-amplified and may have 
received prior therapy with a MET-targeting TKI. 
Note:  Patients with malignancies other than NSCLC may be 
considered for entry to this cohort following discussion with 
the Sponsor’s Medical Monitor(s). 
Text removed 
5.1 Overall Design 
and Plan 
 Part 2 is a Phase 2a dose-expansion in which dosing 
will be at the recommended phase 2 dose (RP2D) on 
an every second week (Q2W) schedule, in the 
following referred to as the Q2W RP2D.  Two 
cohorts will be included: 
o Basket* Cohort: A cohort of approximately 45 
patients with KRAS WT advanced solid tumor 
malignancies with MET-amplification, and 
without therapeutic options. Included in this 
group will be a subset of approximately 6 
patients who have received prior therapy with a 
MET-targeting TKI.   
 
o NSCLC Cohort: A cohort of 6-12 patients with 
KRAS WT NSCLC with METex14 mutation, 
and without therapeutic options.  Patients need 
not be MET-amplified and may have received 
prior therapy with a MET-targeting TKI. 
 
 Part 2 is a Phase 2a dose-expansion in which dosing 
will be at the RP2D on an every second week (Q2W) 
schedule. Three cohorts will be included: 
o Basket* Cohort: A cohort of approximately 25 
patients with KRAS WT advanced solid tumor 
malignancies with MET-amplification, and 
without available therapeutic options. Included 
in this group will be a subset of approximately 6 
patients who have received prior therapy with a 
MET-targeting TKI.   
Note:  Effective with protocol version 8.0 (December 
2018), accrual to the Basket Cohort is suspended. 
 
o NSCLC MET-Amplified Cohort: A cohort of 
approximately 20 patients with advanced 
NSCLC with MET-amplification, and without 
available therapeutic options.  Patients may 
have received prior therapy with MET-targeting 
and/or EGFR-targeting agents. 
 
o NSCLC METEx14Del Cohort: A cohort of 
approximately 6-12 patients with advanced 
NSCLC with METEx14Del, and without available 
therapeutic options.  Tumors need not be MET-


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amplified, and patients may have received prior 
therapy with MET-targeting and/or EGFR-
targeting agents. 
5.1 Overall Design 
and Plan 
(continued) 
During Part 2, two cohorts will receive Sym015 at the 
RP2D on a Q2W dosing schedule: 
 Basket Cohort: A basket cohort of KRAS WT, 
advanced solid tumor malignancy patients with 
MET-amplification will be evaluated. Patients must 
be MET-targeting TKI-naïve; an exception will be 
a subset of approximately 6 patients entered who 
have received prior therapy with a MET-targeting 
TKI. 
 
 NSCLC Cohort: A cohort of KRAS WT advanced 
NSCLC patients with METex14 mutation will be 
evaluated. Patients need not be MET-amplified and 
may have received prior therapy with a MET-
targeting TKI. 
During Part 2, three cohorts will receive Sym015 at the 
RP2D on a Q2W dosing schedule: 
 Basket Cohort: A basket cohort of KRAS WT, 
advanced solid tumor malignancy patients with 
MET-amplification will be evaluated. Patients must 
be MET-targeting TKI-naïve; an exception will be 
a subset of approximately 6 patients entered who 
have received prior therapy with a MET-targeting 
TKI. 
Note:  Effective with protocol version 8.0 (December 
2018), accrual to the Basket Cohort is suspended. 
 
 NSCLC MET-Amplified Cohort: A cohort of 
advanced NSCLC patients with MET-amplification 
will be evaluated. Patients may have received prior 
therapy with MET-targeting and/or EGFR-targeting 
agents.  
 NSCLC METEx14Del Cohort: A cohort of advanced 
NSCLC patients with METEx14Del will be evaluated.  
Tumors need not be MET-amplified, and patients 
may have received prior therapy with MET-
targeting and/or EGFR-targeting agents. 
The number of investigational trial sites…15 to 25 in 
Part 2. 
The number of investigational trial sites…15 to 27 in 
Part 2. 
5.2.1 Rationale for 
Trial Design 
Additionally, this trial design may also allow for the 
identification of specific tumor types that are more 
likely to respond to Sym015 treatment. 
Emerging literature allowed for the identification of 
specific tumor types that are more likely to respond to 
Sym015 treatment (e.g., NSCLC).  
Note:  Effective with protocol version 8.0 (December 2018), 
accrual to the Basket Cohort is suspended. 
5.2.2 Rationale for 
Trial Population 
In Part 2, patients with MET-amplified, KRAS WT, 
advanced solid tumor malignancies of any tissue origin 
will be entered to evaluate the antitumor activity of 
Sym015. In addition, a cohort of KRAS WT NSCLC 
patients with METex14 mutation will be entered to 
evaluate the antitumor activity of Sym015.  
 
Nonclinical studies have documented that the activity 
of Sym015 is greater in tumors with MET-
amplification and/or METex14 mutation, suggesting 
that Sym015 may provide a clinically relevant effect in 
these patient populations.  Similar findings have been 
observed in preliminary studies in patients with MET-
amplified tumors of other anti-MET mAbs in early 
clinical trials. 
In Part 2, patients with MET-amplified, KRAS WT, 
advanced solid tumor malignancies of any tissue origin 
will be entered to evaluate the antitumor activity of 
Sym015 in the Basket Cohort. In addition, a cohort of 
NSCLC patients with MET-amplification and a cohort 
of NSCLC patients with METEx14Del will be entered to 
evaluate the antitumor activity of Sym015 in these 
populations.  
 
Nonclinical studies have documented that the activity 
of Sym015 is greater in tumors with MET-
amplification and/or METEx14Del, suggesting that 
Sym015 may provide a clinically relevant effect in 
these patient populations.  Similar findings have been 
observed in preliminary studies in patients with MET-
amplified tumors with other anti-MET mAbs in early 
clinical trials. 


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5.3.1 Prescreening 
for MET-
amplification and 
METEx14Del Status 
 
5.3.1 Prescreening for MET-amplification, METex14, 
and KRAS Mutational Status 
The trial site may choose to prescreen patients utilizing 
archival tumor tissue to confirm MET-amplification 
status*, METex14 mutation status*, and/or KRAS 
mutational status*...   
*Part 2 ONLY:  Peripheral blood collection for MET-
amplification assessment, METex14 assessment, and 
KRAS-mutation assessment… Other liquid biopsy 
methodologies, except if used to detect METex14 
mutation, will only be allowed if previously approved by 
the Sponsor… 
5.3.1 Prescreening for MET-amplification and 
METEx14Del Status 
The trial site may choose to prescreen patients utilizing 
genomic analysis (e.g., Guardant360 or other similar 
liquid biopsy methodology) or tumor tissue (archival, 
or recently obtained if acquired outside of the 
screening process as part of the site’s usual practice) to 
assess MET-amplification status and METEx14Del 
status… 
Peripheral blood collection for assessment in 
circulating tumor deoxyribonucleic acid (ctDNA) (also 
referred to as “liquid biopsy”) may be used as a local 
pre-screening methodology by Guardant360 analysis 
(http://guardanthealth.com/guardant360/).  Other liquid 
biopsy methodologies, if used to detect METEx14Del, are 
acceptable alternatives.     
5.3.2 Screening 
When the trial site identifies a patient suitable for 
screening, the Sponsor or designee should be contacted 
to ensure that a cohort is open for inclusion. Once 
confirmed, the patient may be approached for informed 
consent. 
When the trial site identifies a patient suitable for 
screening, the Sponsor or designee should be contacted 
to ensure that a cohort is open for inclusion (applies to 
Part 1 only). With this assurance, the patient may be 
approached for informed consent. 
The trial site staff must complete a Screening and 
Allocation Form, stating the allocated patient number 
along with the planned dates of screening and the day 
of first scheduled Sym015 administration (C1/D1), and 
whether the patient has received prior therapy with 
MET-inhibiting agents. The planned date of C1/D1 
will be agreed upon in collaboration with Sponsor or 
designee for the dose-escalation cohorts in order to 
ensure adequate time between dosing of the first 
patient and dosing of subsequent patients within each 
cohort.  
The trial site staff must complete a Screening and 
Allocation Form, stating the allocated patient number 
along with the planned dates of screening and the day 
of first scheduled Sym015 administration (C1/D1). The 
planned date of C1/D1 will be agreed upon in 
collaboration with Sponsor or designee for the dose-
escalation cohorts in order to ensure adequate time 
between dosing of the first patient and dosing of 
subsequent patients within each cohort (applies to Part 
1 only).  
Furthermore, once eligibility is confirmed: 
• Patients in Part 1… 
• All patients in the Part 2 Basket Cohort…  
• For patients in the Part 2 NSCLC Cohort, biopsy for 
biomarker analysis is optional; archival tissue to be 
submitted, if available   
 
 
 
• Part 1: Patients in Part 1… 
• Basket Cohort: All patients in the Part 2 Basket 
Cohort…   
• NSCLC MET-Amplified Cohort: All patients in the 
Part 2 NSCLC MET-Amplified Cohort will have a 
tumor biopsy performed and submitted for central 
confirmation of MET-amplification status, and for 
biomarker analysis.   
 
Note: Peripheral blood for ctDNA analysis by Guardant 360 
will be obtained for assessment of MET-amplification status. 
If central confirmation of MET-amplification status cannot be 
assessed in tumor due to assay failure/technical error, the 
Sponsor may decide to enroll based on MET-amplification 
detected by Guardant360 on a case per case basis. As data are 
acquired on concordance between findings in tumor tissue 
versus ctDNA, the Sponsor may decide to transition to 
screening for MET-amplification using Guardant360 analysis 
only (e.g., 2+ or 3+ amplification score) without requiring 
confirmation in a recent or newly performed tumor biopsy. 
Not applicable 
• NSCLC METEx14Del Cohort: All patients in the Part 2 
NSCLC METEx14Del Cohort will have a tumor biopsy 
performed and submitted for central assessment of 
METEx14Del status, and for biomarker analysis.   
5.3.6 Flow Chart – 
Schedule of 
Assessments 
Schedules of assessments are provided in the trial flow 
chart in Table 3 (Q2W dosing). 
Schedules of assessments are provided in the trial flow 
charts in Table 3 (Part 1 and Part 2 Basket Cohort) and 
Table 4 (Part 2 NSCLC Cohorts). 


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5.4 Recruitment 
Period 
Enrollment is expected to complete by Q3 2018. 
Enrollment is expected to complete by Q4 2019. 
5.5 Number of 
Patients 
It is estimated that approximately 51-57 patients will 
be enrolled to receive Sym015 at the RP2D on a Q2W 
schedule during Part 2. Two cohorts will be included: 
 Basket Cohort: Approximately 45 patients with 
KRAS WT, advanced solid tumor malignancies 
with documented and confirmed MET-
amplification will be enrolled and treated. A subset 
of 6 patients will have received prior therapy with a 
MET-targeting TKI.  
It is estimated that approximately 51-57 patients will 
be enrolled to receive Sym015 at the RP2D on a Q2W 
schedule during Part 2. Three cohorts will be included: 
 Basket Cohort: Approximately 25 patients with 
KRAS WT, advanced solid tumor malignancies 
with documented MET-amplification will be 
enrolled and treated. A subset of approximately 6 
patients will have received prior therapy with a 
MET-targeting TKI.  
Note:  Effective with protocol version 8.0 (December 
2018), accrual to the Basket Cohort is suspended. 
NSCLC MET-Amplified patients entered to the Basket 
Cohort will be counted toward the NSCLC MET-
Amplified Cohort; NSCLC METEx14Del patients entered to 
the Basket Cohort will be counted toward the NSCLC 
METEx14Del Cohort; patients with both will be counted as 
MET-Amplified. 
 NSCLC Cohort: 6-12 patients with KRAS WT, 
advanced NSCLC with documented METex14 
mutation will be enrolled and treated. Patients need 
not be MET-amplified and may have received prior 
therapy with a MET-targeting TKI.   
 NSCLC MET-Amplified Cohort: approximately 20 
patients with advanced NSCLC with documented 
MET-amplification will be enrolled and treated. 
Patients may have received prior therapy with 
MET-targeting agents and/or EGFR-targeting 
agents. 
Not applicable 
 NSCLC METEx14Del Cohort: approximately 6-12 
patients with advanced NSCLC with documented 
METEx14Del will be enrolled and treated. Tumors 
need not be MET-amplified, and patients may have 
received prior therapy with MET-targeting and/or 
EGFR-targeting agents.   
Note:  NSCLC patients with tumors identified as both 
MET-Amplified and METEx14Del will be enrolled to the 
MET-Amplified cohort. 
6.1 Inclusion 
Criteria 
Part 2 ONLY: 
b. Tumor documented to be KRAS WT by local 
assessment according to institutional standards. 
Note:  Peripheral blood collection for KRAS-mutation 
assessment in ctDNA will be allowed as a local pre-screening 
methodology by Guardant360* analysis.  Other liquid biopsy 
methodologies, except if used to detect METex14 mutation, 
will only be allowed if previously approved by the Sponsor. 
 
c. Basket Cohort ONLY: 
 Confirmed MET-amplification by local… 
 No prior therapy with MET-targeting agents… 
 Willingness to undergo a pre- and post-dosing 
biopsy… 
 
 
Part 2 ONLY: 
b. Basket Cohort ONLY: 
 Tumor documented to be KRAS WT by local 
assessment according to institutional standards. 
If KRAS WT is not previously documented and if 
archival tissue is not available for pretrial 
assessment, patient must be willing to undergo a 
tumor biopsy to confirm eligibility.   
Note:  Peripheral blood collection for KRAS-mutation 
assessment in ctDNA will be allowed as a local pre-
screening methodology by Guardant360* analysis.  
Other liquid biopsy methodologies, if used to detect 
METEx14Del, are acceptable alternatives. 
 
 
Confirmed MET-amplification by local… 
 
No prior therapy with MET-targeting agents… 
 
Willingness to undergo a pre- and post-dosing 
biopsy… 


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6.1 Inclusion 
Criteria 
(continued) 
d. NSCLC Cohort ONLY:  
 Documented METex14 mutations (patients need 
not be MET-amplified and may have received 
prior therapy with a MET-targeting TKI) 
Note: Patients with malignancies other than NSCLC and with 
documented METex14 mutation may be considered for entry 
to this cohort following discussion with the Sponsor’s 
Medical Monitor(s). 
Note: METex14 mutation status to be documented according 
to local institutional standards.  Assessment in ctDNA by 
Guardant360 technology or equivalent is allowed.  
Subsequent confirmation in tumor tissue is preferred but not 
required. 
c. NSCLC MET-Amplified Cohort ONLY:  
 Documented NSCLC meeting disease criteria as 
defined above   
 Documented MET-amplification by either: 
o Local assessment in a recent* tumor biopsy; 
i.e.,  G:CN ≥3.0 scored in 50 tumor nuclei 
by FISH, CISH, SISH or similar assay, or a 
copy number >5 by NGS or qPCR 
(subsequent central confirmation required, 
however patient may be enrolled and treated 
based on local assessment, before central 
confirmation results have been obtained) 
*Tissue for local assessment may be from a 
recent tumor biopsy, defined as one 
performed since last documented disease 
progression as part of the site’s usual 
practice, and where no intervening 
antineoplastic therapy has been 
administered; otherwise tissue from a newly 
performed biopsy must be obtained and 
submitted.       
o Central confirmation** in a newly performed 
pre-dosing tumor biopsy; i.e.,  G:CN ≥3.0 
scored in 50 tumor nuclei by FISH 
o **If central confirmation of MET-
amplification status cannot be assessed in 
tumor due to assay failure/technical error, 
the Sponsor may decide to enroll based on 
MET-amplification detected by 
Guardant360 on a case per case basis (see 
Note below regarding Guardant360 
analysis). 
 May have received prior therapy with MET-
targeting and/or EGFR-targeting agents 
(antibodies or TKIs) 
 Willingness to undergo a pre-dosing biopsy 
(mandatory unless a recent* tumor biopsy as 
defined above is available), and potentially a 
biopsy at the End of Cycle 2 (EOC2) (optional), 
from a primary or metastatic tumor site 
considered safely accessible for biopsy  
Note: Peripheral blood for ctDNA analysis by Guardant 360 
will be obtained for assessment of MET-amplification status. 
As data are acquired on concordance between findings in 
tumor tissue versus ctDNA, the Sponsor may decide to 
transition to screening for MET-amplification using 
Guardant360 analysis only (e.g., 2+ or 3+ amplification score) 
without requiring confirmation in a recent or newly performed 
tumor biopsy. 
6.1 Inclusion 
Criteria 
(continued) 
Not applicable 
d. NSCLC METEx14Del Cohort ONLY:  
 Documented NSCLC meeting disease criteria as 
defined above   
 Documented METEx14Del (tumors need not be 
MET-amplified) 


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 Note: METEx14Del status to be documented 
according to local institutional standards.  
Assessment in ctDNA by Guardant360 
technology or equivalent is allowed. Tissue from 
a recent* or newly performed pre-dosing tumor 
biopsy must be submitted for central assessment. 
*Recent tumor biopsy, defined as one performed 
since last documented disease progression as part 
of the site’s usual practice, and where no 
intervening antineoplastic therapy has been 
administered; otherwise tissue from a newly 
performed biopsy must be obtained and 
submitted. 
 
 May have received prior therapy with MET-
targeting and/or EGFR-targeting agents 
(antibodies or TKIs) 
 Willingness to undergo a pre-dosing biopsy 
(mandatory unless a recent* tumor biopsy as 
defined above is available), and potentially a 
biopsy at the EOC2 (optional), from a primary or 
metastatic tumor site considered safely accessible 
for biopsy 
Note: Peripheral blood for ctDNA analysis by Guardant 
360 will be obtained for assessment of METEX14Del 
status.   
6.2 Exclusion 
Criteria 
2. Part 2 ONLY:  
a. Prior therapy with MET-inhibiting agents 
Note:  Exceptions will be a subset of approximately 6 
patients entered to the Basket Cohort after having 
received prior therapy with a MET-targeting TKI, and 
patients entered to the NSCLC Cohort who may have 
received prior therapy with a MET-targeting TKI. 
b. Prior therapy with antibody to HGF 
c. Basket Cohort ONLY: Tumor status demonstrating 
MET-polysomy in the absence of MET-
amplification, as specified 
Note: Patients in the NSCLC Cohort with polysomy are 
eligible  
d. Radiotherapy against target lesions within 4 weeks 
prior to C1/D1, unless there is documented 
progression of the lesion following the radiotherapy 
Note: Radiotherapy for pain control against non-target 
lesions is allowed, as long as it does not influence bone 
marrow function 
2. Part 2 ONLY:  
a. Basket Cohort:  
 Prior therapy with MET-inhibiting agents Note:  
Exceptions will be a subset of approximately 6 patients 
entered to the Basket Cohort after having received prior 
therapy with a MET-targeting TKI 
 
 Prior therapy with antibody to HGF 
b. Basket Cohort and NSCLC MET-Amplified Cohort: 
Tumor status demonstrating MET-polysomy in the 
absence of MET-amplification, as specified 
Note: Patients in the NSCLC METEx14Del Cohort with 
polysomy are eligible.   
c. Radiotherapy against target lesions within 4 weeks 
prior to C1/D1, unless there is documented 
progression of the lesion following the radiotherapy 
Note: Radiotherapy for pain control against non-target 
lesions is allowed, as long as it does not influence bone 
marrow function 
3. Immunosuppressive or systemic hormonal therapy 
(> 10 mg daily prednisone equivalent) within 2 weeks 
prior to C1/D1 with the exception of the following 
allowed therapies: 
a. Hormonal therapy… 
b. Nasal, ophthalmic, inhaled… 
c. Oral replacement glucocorticoid… 
d. Low-dose maintenance steroid therapy… 
3. Immunosuppressive or systemic hormonal therapy 
(> 10 mg daily prednisone equivalent) within 2 weeks 
prior to C1/D1 (for exceptions, see Section 7.5.2) 


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7.5.1 Allowed 
Medication/ 
Therapy and 
Procedures During 
the Trial 
Not applicable 
Bisphosphonates and denosumab:  Bisphosphonates 
and denosumab for bone metastases and other skeletal 
conditions provided the patient is on a stable dose for 
at least 2 months prior to study start and remains on the 
stable dose while receiving study treatment 
7.5.2 Prohibited 
Medication/ 
Therapy and 
Procedures During 
the Trial 
Not applicable 
Basket Cohort ONLY: MET-targeting therapies, 
except in subset of approximately 6 patients 
8.1.2 
Demographics 
To include date of birth, sex, race and ethnicity. 
To include date of birth, sex, race and ethnicity (as 
allowed by country) 
8.2.6 Physical 
Examination 
To include evaluation of the following: General 
appearance, skin, head, ears, eyes, nose, throat, 
neck/thyroid, chest, cardiovascular system, abdomen, 
musculoskeletal system, lymph nodes, neurologic 
status, and mental status. At Screening, include height 
(without shoes, rounded to nearest centimeter). 
To include evaluation of the following at Screening: 
General appearance, skin, head, ears, eyes, nose, 
throat, neck/thyroid, chest, cardiovascular system, 
abdomen, musculoskeletal system, lymph nodes, 
neurologic status, and mental status; include height 
(without shoes, rounded to nearest centimeter). 
Thereafter, a targeted physical examination may be 
performed as indicated. 
8.3.3 Archival 
Tumor Tissue for 
MET and KRAS 
Assessment (Part 1 
and Part 2 Basket 
Cohort) 
8.3.3 Archival Tumor Tissue for MET and KRAS 
Assessment 
 
o Part 2: Eligibility assessment for KRAS mutational 
status… 
Basket Cohort: It is preferred that the eligibility 
assessment for MET-amplification be done… 
 
NSCLC Cohort: Eligibility assessment for METex14 
mutation status… 
8.3.3 Archival Tumor Tissue for MET and KRAS 
Assessment (Part 1 and Part 2 Basket Cohort) 
 
o Part 2:  
Eligibility assessment for KRAS mutational status… 
It is preferred that the eligibility assessment for MET-
amplification be done… 
 
NSCLC METEx14Del Cohort (pre-protocol v8.0): 
Eligibility assessment for METEx14Del status… (applies 
only to patients with METEx14Del tumors entered prior 
to suspension of the Basket Cohort and establishment 
of NSCLC METEx14Del Cohort). 
8.3.5 Tumor 
Biopsy for MET 
Status and 
Biomarker 
Analysis (Part 2 
NSCLC MET-
Amplified Cohort 
and NSCLC 
METEx14Del Cohort) 
Not applicable 
To be assessed centrally:  
 Screening (Mandatory) 
Note: It will be permissible to perform this procedure 
outside the 14-day screening period, provided informed 
consent for the trial has been obtained 
 
o NSCLC MET-Amplified Cohort: Required; 
tissue from a newly performed pre-dosing 
tumor biopsy must be submitted for central 
confirmation of MET-amplification  
(Patients may be entered and treated based on 
local assessment of a recent tumor biopsy [if 
available and performed outside of the 
screening process as part of the site’s usual 
practice] provided no intervening antineoplastic 
therapy has been administered; otherwise tissue 
from a newly performed biopsy must be 
obtained and submitted) 
 
o NSCLC METEx14Del Cohort:  Required; tissue 
from a recent or newly performed pre-dosing 
tumor biopsy must be submitted for central 
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(Patients may be entered and treated based on 
local institutional standards; alternatively, 
assessment in ctDNA by Guardant360 
technology or equivalent is allowed; a recent [as 
defined above] or newly performed pre-dosing 
biopsy must still be submitted) 
 
 Post-dosing (Optional) 
EOC2 (i.e., coinciding with time of first 
response assessment) or upon PD, whichever 
occurs first 
Note: EOC assessments may be performed at any 
time during the week prior to Day 1 of the next cycle, 
including Day 1 of the next cycle, prior to dosing   
8.7 Blood Sample 
for Genomic and 
Biomarker 
Analyses 
8.7 Biomarker Blood Sample 
 
To be performed only after eligibility has been 
confirmed. 
Analysis of all samples taken for pharmacodynamic 
assessments will be performed at a central laboratory. 
A detailed laboratory manual specifying sample 
collection, handling, storage, and shipment will be 
provided to the trial sites.  
 Screening, after confirmation of eligibility 
 End of Cycle 2 (coinciding with time of first 
response assessment) or upon PD, whichever 
occurs first  
Note: End of cycle assessments may be performed at 
any time during the week prior to Day 1 of the next 
cycle 
 EOT 
8.7 Blood Sample for Genomic and Biomarker 
Analyses 
 
To include assessment of MET-amplification and 
METEx14Del status; analysis of all samples taken will be 
performed at a central laboratory. A detailed laboratory 
manual specifying sample collection, handling, 
storage, and shipment will be provided to the trial sites.  
 Screening (it will be permissible to perform this 
procedure outside the 14-day screening period, 
provided informed consent for the trial has been 
obtained) 
 EOC2 (coinciding with time of first response 
assessment or upon PD, whichever occurs first)  
 Note: EOC assessments may be performed at any 
time during the week prior to Day 1 of the next 
cycle, including Day 1 of the next cycle, prior to 
dosing  
 
EOT (if after EOC2; need not repeat if patient is 
discontinuing at the EOC2 or if a sample was 
obtained upon PD) 
9.3 Serious 
Adverse Event 
Recording and 
Reporting 
 
In case of an SAE, the Investigator must, within 24 
hours of first awareness of the event, report the SAE to 
the Sponsor or designee by fax or e-mail. Fax 
number(s) and e-mail address will be stated in the SAE 
report form and the SAE report form instructions. 
In case of an SAE, the Investigator must, within 24 
hours of first awareness of the event, report the SAE to 
the Sponsor (or designee) by fax or e-mail. Fax 
number(s) and e-mail address(es) will be stated on the 
SAE Report Form and the SAE Report Form 
Completion Instructions. SAE follow-up information 
must also be reported to the Sponsor (or designee) 
within 24 hours of awareness. 
10.1 Statistical 
Considerations and 
Analysis Plan 
 
Not applicable 
No formal hypothesis testing is planned.  Descriptive 
statistics will be used to summarize the safety, 
tolerability, pharmacokinetics, and clinical activity of 
Sym015 in all patient cohorts. 
Data will be described and summarized as warranted 
by sample sizes.  Listings will be used in place of 
tables in the event of small sample sizes.  Dose-
escalation assessment will be based on the DLT-
evaluable population, defined as patients who complete 
the DLT assessment window.  All other analyses will 
be based on the safety-evaluable population, defined as 
all patients who receive any amount of the study drug. 
Continuous variables will be summarized with the use 


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of means, standard deviations, medians, and ranges; 
categorical variables will be summarized using counts 
and percentages.  All summaries will be presented 
separately by cohort, in both Part 1 and Part 2 of the 
study. 
All details of the data analyses will be described in the 
Statistical Analysis Plan. 
10.2 Sample Size 
Determination 
In Part 2 of the trial, the primary endpoint is 
documented OR in the Basket Cohort, assessed by 
RECIST v1.1, at any time during trial participation by 
Investigator assessment. It is planned to include 45 
patients with various advanced solid tumor 
malignancies, documented and confirmed as MET-
amplified and KRAS WT in this cohort. It is expected 
to see a meaningful number of patients with OR, based 
on preclinical data as well as data from other MET-
targeting mAbs presently in clinical development. The 
expected range of OR is in the range of 25-50%, 
depending on histology, previous therapies and other 
prognostic factors defining the enrolled patient 
population. Sample size considerations are based on a 
Simon’s Optimal 2-stage design (31), testing a null 
hypothesis (poor response) of 11% OR versus an 
alternative hypothesis (promising response) of 25% 
OR at an approximate 10% 1-sided significance level 
and 85% power. In Stage 1 (futility assessment) 
enrollment will include 20 evaluable patients for OR 
assessment and accrual will continue to Stage 2, if at 
least 3 of 20 (15%) patients respond (PR or CR). The 
probability of early stopping assuming poor response is 
about 62%.  In stage 2, if the futility boundary is 
exceeded, an additional 25 patients evaluable for OR 
assessment will be enrolled for a total of 45 patients. 
Further development will be considered warranted if at 
least 8 of 45 (18%) patients respond.    
For the NSCLC Cohort, assuming the response rate is 
at least 20%, there is a 74 93% probability of 
observing 1 or more responses in 6-12 patients. 
In Part 2 of the trial, the primary endpoint is 
documented, confirmed OR assessed by RECIST v1.1, 
at any time during trial participation by Investigator 
assessment. It is planned to include 25 patients with 
various advanced solid tumor malignancies, 
documented and confirmed as MET-amplified in the 
Basket Cohort, 20 patients in the NSCLC MET-
Amplified Cohort, and 6-12 patients in the NSCLC 
METEx14Del Cohort, for the total of approximately 51-
57 patients in Part 2.  
 
No power and type I error considerations were used to 
determine the sample size in each cohort. Proposed 
sample sizes in Basket and NSCLC Cohorts should 
allow to obtain preliminary safety, PK, response, and 
pharmacodynamic information of Sym015 in the 
respective patient populations (Table 10). 
The expected (target) range of OR in any of these three 
cohorts is in the range of 20%-50%, depending on 
histology, previous therapies, and other prognostic 
factors defining the enrolled patient population. 
10.4.2 Part 2 
The primary objective of Part 2 is to evaluate the 
antitumor activity of Sym015 when administered at the 
Q2W RP2D. This will be assessed by the primary 
endpoint for Part 2, documented OR in the Basket 
Cohort, defined as documented PR or CR and assessed 
by RECIST v1.1 at any time during trial participation 
by Investigator assessment. The assessment will be 
performed after completion of Part 2 of the trial. 
 
Number and percentages of patients with documented 
OR will be presented including corresponding 95% 
exact Confidence Intervals (CI). 
The primary objective of Part 2 is to evaluate the 
antitumor activity of Sym015 when administered at the 
Q2W RP2D. The primary endpoint is documented, 
confirmed OR, defined as documented PR or CR and 
assessed by RECIST v1.1 at any time during trial 
participation by Investigator assessment. The 
assessment will be performed after completion of Part 
2 of the trial. 
 
Number and percentages of patients with documented 
OR will be presented including corresponding 90% 
exact Confidence Intervals (CI), separately for each 
cohort. 
10.5.1 Efficacy 
Endpoints and 
Analyses 
Number and percentages of patients with documented 
OR in the dose-escalation part will be presented 
including corresponding 95% exact CI. All 
documented ORs (Part 1 and 2) will be listed including 
duration (in days) of OR, measured from time of first 
PR or CR to PD. 
 
Time to disease progression (TTP), PFS, and OS will 
Number and percentages of patients with documented 
OR in the dose-escalation part will be presented 
including corresponding 90% exact CI. All 
documented ORs (Part 1 and Part 2) will be listed 
including duration (in days) of OR, measured from 
time of first PR or CR to PD. 
 
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be summarized using the product-limit method and 
Kaplan-Meier plots. The median TTP, PFS, and OS, 
including 95% CI, will be calculated. 
be summarized using the product-limit method and 
Kaplan-Meier plots. The median TTP, PFS, and OS, 
including 90% CI, will be calculated. 
10.6 Interim 
Analysis 
All relevant safety and toxicity data will be reviewed 
on an ongoing base throughout the trial. Refer to 
Section 12. 
During Part 1, clinical and laboratory safety data will 
be assessed when the first patient in a 3-patient cohort 
has completed the first dose of Sym015, when 3 
patients have completed Cycle 1, and if the cohort is 
expanded, when 6 patients have completed Cycle 1. 
Based on an overall evaluation of Part 1 of the trial, the 
Q2W RP2D and highest safe dose tested will be 
determined. 
In Part 2 an assessment of futility will be performed 
when 20 patients evaluable for OR have been included 
in the Basket Cohort. The trial will be stopped for 
futility if less than 3 of the evaluable patients have 
documented OR. 
No interim analysis is planned. 
14. Data Handling 
and Record 
Keeping 
Data will be handled according to good data 
management practices and comply with Federal 
regulations including, but not limited to, 21 CFR Part 
11 and ICH GCP E6(R2). 
Study data collection, processing, transfer, and 
reporting, as well as handling of study personnel 
information, will be done in compliance with ICH 
E6(R2) GCP and all applicable data protection 
regulations, including Regulation (EU) 2016/679 of the 
European Parliament and of the Council of 27 April 
2016 on the protection of natural persons with regard 
to the processing of personal data and on the free 
movement of such data (General Data Protection 
Regulation; GDPR). 
14.3 Case Report 
Form 
 
The Investigator or designee will be responsible for 
entering trial data in the CRF provided. It is the 
responsibility of the Investigator to ensure the accuracy 
of the data entered in the CRF. 
All collected data will be entered into a validated 
database. 
Text removed; section replaced (see below) 
14.3 Data 
Processing 
The process of entering or uploading of data from trial 
sites will assure the accuracy of data entry into the 
database and include a validation at data entry time 
(real time validation). Entry or electronic transfer of 
other data than those directly from trial sites (e.g. 
imports of laboratory results) will follow the Sponsor 
requirements for data flow and transfer. 
 
The Sponsor or designee will be responsible for data 
processing in accordance with the applicable data 
management SOPs. A Data Management Plan will be 
generated for this trial. 
 
Database lock will occur once quality control 
procedure, and quality assurance procedures (if 
applicable) have been completed.  
 
The PDF files of the CRFs will be provided to the 
Investigator before access to the CRF is revoked. 
A Data Management Plan (DMP) will be prepared for 
this trial. The Sponsor (or designee) will be responsible 
for data processing in accordance with applicable Data 
Management SOPs and the trial DMP. 
 
Once recorded within the electronic CRF, study data 
will pass through a set of preprogrammed data 
validation checks designed to identify inconsistencies 
and other data errors, and will undergo an additional 
study-specific data review process.  Data issues will be 
queried via the electronic data capture (EDC) system 
and query resolutions will be documented.  
 
Entry and processing of data other than those directly 
recorded on electronic CRFs by trial sites (e.g., imports 
of laboratory results) will follow vendors’ SOPs. 
Transfer of such data from vendors to Sponsor (or 
designee) will be handled according to vendors’ data 
transfer SOPs and the Sponsor data transfer 
requirements with full compliance to applicable 
regulations. 
 
Database Lock will occur upon reaching the predefined 


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data cut-off for primary analysis and completion of 
Sponsor’s (or designee’s) quality control and quality 
assurance procedures. 
 
Portable Document Format (PDF) files of the 
electronic CRFs will be provided to the Investigator 
upon removal of access to the electronic CRFs. 
14.4 Clinical Trial 
Report 
Not applicable 
Following study completion, a final integrated 
clinical/statistical CTR will be prepared. 
14.5 Compliance 
with the General 
Data Protection 
Regulation 
Not applicable 
The applicable EU data protection legislation requires 
that parties enter into a written contract if one party 
(data processor) processes personal data on behalf of 
the other party (data controller). This written contract 
must regulate the subject-matter and duration of the 
processing, the nature and purpose of the processing, 
the types of personal data and categories of data 
subjects, as well as the obligations and rights of the 
data controller…  
17 Changes to the 
Final Clinical Trial 
Protocol 
Changes to the CTP will not be implemented without 
agreement from the Sponsor and prior review and 
written approval from the HA and IRB/EC, except 
where necessary to eliminate an immediate hazard to 
the patient. No protocol waivers will be allowed. 
Changes to the protocol will not be implemented 
without agreement from the Sponsor and prior review 
and written approval from the appropriate Health 
Authority (as indicated) and the IRB/EC, except where 
necessary to eliminate an immediate hazard to the 
patients. No protocol waivers will be allowed.  
Protocol changes to eliminate an apparent hazard to 
trial patients may be implemented by the Investigator 
immediately. The Investigator must then, without 
delay, inform the local IRB/EC, and the Sponsor (or 
designee) will immediately notify local governing 
Health Authorities. 
 
 



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