Conditions: Locally Advanced Solid Tumor Metastatic Solid Tumor Pancreatic Cancer Lung Cancer Head and Neck Cancer Breast Cancer Kidney Cancer Colorectal Cancer Bladder Cancer Ovarian Cancer Sarcoma Gallbladder Cancer Bile Duct Cancer Esophageal Cancer Uterine Cancer Cholangiocarcinoma Prostate Cancer
Keywords: NRG1 Neuregulin 1 Gene fusion
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

Brief summary:
This study is an open-label, international, multi-center, Phase 2 study in adult patients with recurrent, locally-advanced or metastatic solid tumors, which harbor the NRG1 gene fusion.

Detailed description:

Arms:
arm 1: A minimum of 55 adult advanced solid tumor patients harboring NRG1 gene fusions, who have received prior standard treatment, excluding prior ERBB-directed therapy.

Seribantumab 1-h IV infusion at various doses once weekly, every 2 weeks and every 3 weeks, during the induction, consolidation and maintenance dosing phases, respectively. arm 2: Up to 10 adult advanced solid tumor patients harboring NRG1 gene fusions, who have received prior standard treatment, including prior ERBB-directed therapy.

Seribantumab 1-h IV infusion at various doses once weekly, every 2 weeks and every 3 weeks, during the induction, consolidation and maintenance dosing phases, respectively. arm 3: Up to 10 adult advanced solid tumor patients harboring NRG1 gene fusions lacking an EGF-like domain, who have received prior standard treatment, which may have included prior ERBB-directed therapy.

Seribantumab 1-h IV infusion at various doses once weekly, every 2 weeks and every 3 weeks, during the induction, consolidation and maintenance dosing phases, respectively.

Interventions: intervention 1: Seribantumab
Intervention descriptions: intervention 1: Anti-HER3 monoclonal antibody

Protocol document:
Prot_000.pdf: 
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Proprietary and Confidential 
Page 1 of 80 
 
 
 
 
CRESTONE: A Phase 2 Study of Seribantumab in Adult 
Patients with Neuregulin-1 (NRG1) Fusion Positive  
Locally Advanced or Metastatic Solid Tumors 
Elevation Oncology, Inc. 
 
 
Protocol Number: ELVCAP-001-01 
Investigational Product: Seribantumab 
IND Number: 100605 
Protocol Version: 7.0 (21 September 2022) 
Replaces Protocol Version 6.0 (15 August 2022) 
 
 
 
 
 
 
 
Sponsor: 
Elevation Oncology, Inc.  
888 Seventh Avenue 
12th Floor 
New York, NY 10106 
 
 
Confidentiality Statement 
This document, and the information it contains, are confidential and the proprietary  
property of Elevation Oncology. The information is not to be disclosed or transmitted  
to any party without the express approval of Elevation Oncology, or its agents,  
and any such unauthorized use or disclosure is expressly prohibited. 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
LIST OF ABBREVIATIONS ..........................................................................................................7 
STUDY SYNOPSIS ........................................................................................................................9 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
NRG1 Overview .........................................................................................................19 
1.2. 
NRG1 Fusions ............................................................................................................19 
1.3. 
Rationale for Targeting the HER3 Pathway in NRG1 Fusion Dependent 
Cancer .........................................................................................................................21 
1.4. 
Seribantumab ..............................................................................................................23 
1.5. 
Seribantumab Nonclinical Experience in NRG1 Fusion Models ...............................23 
1.6. 
Clinical Experience with Seribantumab to Date .........................................................28 
1.6.1. 
Prior Clinical Development of Seribantumab .............................................................29 
1.6.2. 
Clinical Development of Seribantumab in NRG1 Fusion Positive Cancer ................29 
1.6.3. 
Rationale for 3,000 mg Once Weekly Dosing ............................................................29 
1.7. 
Risk/Benefit Assessment for 3,000 mg Once Weekly Dosing ...................................30 
2. 
OBJECTIVES .............................................................................................................31 
2.1. 
Primary Objective .......................................................................................................31 
2.2. 
Secondary Objectives .................................................................................................31 
2.3. 
Exploratory Objectives ...............................................................................................31 
3. 
STUDY DESIGN .......................................................................................................32 
3.1. 
Overview of Study Design ..........................................................................................32 
3.2. 
Safety Review Committee ..........................................................................................33 
3.3. 
Expanded Safety Review Committee for Interim Futility Analysis ...........................33 
4. 
STUDY POPULATION .............................................................................................33 
4.1. 
Inclusion Criteria ........................................................................................................34 
4.2. 
Exclusion Criteria .......................................................................................................35 
4.3. 
Archival or Fresh Tumor Specimen Requirements ....................................................36 
5. 
STUDY TREATMENT ..............................................................................................37 
5.1. 
Treatment Assignment ................................................................................................37 


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5.2. 
Seribantumab ..............................................................................................................37 
5.2.1. 
Seribantumab Formulation, Packaging, and Labeling ................................................37 
5.2.2. 
Seribantumab Product Storage and Stability ..............................................................37 
5.2.3. 
Seribantumab Dosing, Preparation and Administration .............................................37 
5.2.3.1. 
Seribantumab Dosing ..................................................................................................37 
5.2.3.2. 
Preparation and Administration ..................................................................................38 
5.2.4. 
Management of Toxicity Related to Seribantumab ....................................................38 
5.2.4.1. 
Dose Limiting Toxicity ...............................................................................................38 
5.2.4.2. 
Management of Infusion Related Reactions ...............................................................39 
5.2.4.3. 
Toxicity Management Guidelines ...............................................................................40 
5.2.5. 
Potential Toxicities with Seribantumab ......................................................................41 
5.3. 
Dose Modifications .....................................................................................................41 
5.4. 
Study Treatment Discontinuation ...............................................................................42 
5.4.1. 
Study Treatment Beyond Progression ........................................................................43 
5.5. 
Concomitant and Prohibited Therapies ......................................................................43 
5.5.1. 
Concurrent Palliative Radiotherapy and Elective Procedures ....................................44 
5.6. 
Accountability of Study Drug .....................................................................................44 
6. 
SCHEDULE OF ASSESSMENTS .............................................................................45 
6.1. 
COVID-19 Public Health Emergency Impact on Protocol Assessments ...................45 
6.2. 
Schedule of Assessments ............................................................................................46 
6.3. 
Screening and Baseline Visit ......................................................................................48 
6.4. 
On-Study Visits ..........................................................................................................48 
6.5. 
End of Treatment Visit ...............................................................................................48 
6.6. 
Survival Follow-up .....................................................................................................48 
7. 
CLINICAL PROCEDURES AND ASSESSMENTS ................................................49 
7.1. 
Medical History and Demographics ...........................................................................49 
7.2. 
Adverse Event and Hospitalization Assessment Reporting ........................................49 
7.3. 
Physical Examination and Performance Status Assessment ......................................49 
7.4. 
Vital Signs ..................................................................................................................49 
7.5. 
Electrocardiogram .......................................................................................................49 
7.6. 
Collection of Quality of Life (EORTC QLQ-C30) Questionnaire .............................49 
7.7. 
Disease Evaluation ......................................................................................................50 


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7.7.1. 
Independent Central Review of Scans ........................................................................50 
8. 
LABORATORY PROCEDURES AND ASSESSMENTS ........................................50 
8.1. 
Complete Blood Count ...............................................................................................50 
8.2. 
Serum Chemistry ........................................................................................................51 
8.3. 
Urine or Serum Pregnancy Test ..................................................................................51 
8.4. 
Pharmacokinetic Testing ............................................................................................51 
8.4.1. 
Seribantumab PK samples ..........................................................................................51 
8.5. 
Anti-seribantumab Immunogenicity ...........................................................................51 
8.6. 
Biomarker Samples .....................................................................................................51 
8.6.1. 
Archived Tumor Sample / Tumor Biopsy ..................................................................51 
8.6.2. 
Whole Blood for cell free DNA ..................................................................................52 
9. 
ADVERSE EVENTS AND REPORTING ................................................................52 
9.1. 
Adverse Events ...........................................................................................................52 
9.2. 
Grading and Intensity of Adverse Events ...................................................................53 
9.3. 
Relationship to Study Drug ........................................................................................53 
9.4. 
Serious Adverse Event Reporting ...............................................................................54 
9.5. 
Serious Adverse Event Follow-up ..............................................................................55 
9.6. 
Pregnancy Reporting ..................................................................................................55 
10. 
STATISTICAL METHODS .......................................................................................56 
10.1. 
Study Endpoints ..........................................................................................................56 
10.2. 
Analysis Populations ..................................................................................................56 
10.2.1. 
Cohort 1 Primary Efficacy Analysis Population ........................................................57 
10.2.2. 
Cohort 2 and Cohort 3 Efficacy Analysis Population ................................................57 
10.2.3. 
Safety Analysis Population .........................................................................................57 
10.3. 
Determination of Sample Size ....................................................................................57 
10.4. 
Statistical Considerations ............................................................................................57 
10.5. 
Efficacy Analysis ........................................................................................................58 
10.5.1. 
Primary Efficacy Endpoint for Cohort 1 ....................................................................58 
10.5.2. 
Secondary Efficacy Endpoints for Cohort 1 ...............................................................58 
10.5.3. 
Exploratory Efficacy Analysis for Cohorts 2 and 3 ....................................................59 
10.6. 
Safety Analysis ...........................................................................................................59 
10.7. 
Interim Analysis ..........................................................................................................60 


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10.8. 
Covariates and Subgroups ..........................................................................................60 
10.9. 
Pharmacokinetic Analysis ..........................................................................................60 
10.10. 
Exploratory Analysis ..................................................................................................60 
11. 
STUDY ADMINISTRATION ...................................................................................61 
11.1. 
Pre-Study Documentation ...........................................................................................61 
11.2. 
Source Documents ......................................................................................................61 
11.3. 
Study Ethics ................................................................................................................61 
11.4. 
Patient Informed Consent ...........................................................................................62 
11.5. 
Investigational Review Board Approval ....................................................................62 
11.6. 
Monitoring ..................................................................................................................62 
11.7. 
Confidentiality ............................................................................................................63 
11.7.1. 
Confidentiality of Biomarker Samples .......................................................................63 
11.8. 
Protocol Amendments ................................................................................................64 
11.9. 
Records Retention .......................................................................................................64 
11.10. 
Study Termination ......................................................................................................64 
12. 
INVESTIGATOR SIGNATURE PAGE ....................................................................66 
13. 
REFERENCES ...........................................................................................................67 
APPENDIX A: PREVIOUS CRESTONE DOSING SCHEDULES ..........................................70 
APPENDIX B: MOST/CRESTONE COUNTRY SPECIFIC APPENDIX 
(AUSTRALIA ONLY) ...............................................................................................72 
 


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LIST OF TABLES 
Table 1: 
Clinical Case Reports for ERBB/HER Directed Treatment of NRG1 Fusion 
Positive Cancers ..........................................................................................................22 
Table 2: 
Summary of PK Simulations for Initial CRESTONE Regimen and Extended 
Weekly Regimens .......................................................................................................30 
Table 3: 
Dose Modification – Weekly Dosing .........................................................................41 
Table 4: 
Schedule of Assessments ............................................................................................46 
 
LIST OF FIGURES 
Figure 1: 
Study Schema of Patient Flow in the CRESTONE Clinical Study ............................18 
Figure 2: 
Incidence of NRG1 gene fusions by tumor type ........................................................20 
Figure 3: 
In Vitro Effects of Seribantumab on NRG1 Gene Fusion Positive  Breast 
Cancer Cell Lines .......................................................................................................24 
Figure 4: 
Seribantumab HER2/HER3  Dimer Inhibition ...........................................................24 
Figure 5: 
Seribantumab HER2, HER3,   HER4 + AKT/ERK Inhibition ...................................24 
Figure 6: 
Efficacy of single-dose seribantumab in a NSCLC (SLC3A2-NRG1 fusion) 
PDX model. ................................................................................................................25 
Figure 7: 
Seribantumab Effectively Inhibits Growth of LUAD-0061AS3 PDX NRG1 
Dependent Tumors ......................................................................................................26 
Figure 8: 
Efficacy of seribantumab in CLU-NRG1 ovarian cancer PDX model. ......................27 
Figure 9: 
Efficacy of seribantumab in APP-NRG1 pancreatic cancer PDX model. ..................28 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AE 
Adverse event 
AKT 
Protein kinase B 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
Cavg 
Average serum concentration 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum serum concentration 
Cmin 
Minimum serum concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CRO 
Contract research organization 
CT  
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
ErbB 
Epidermal growth factor family of receptor tyrosine kinases 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
ERK 
Extracellular signal-regulated kinases 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in-situ hybridization 
GCP 
Good Clinical Practice 
HER2 
Human epidermal growth factor receptor 2 
HER3 
Human epidermal growth factor receptor 3 
ICH 
International conference on harmonization 
Ig 
Immunoglobulin 
IMA 
invasive mucinous lung adenocarcinoma 
INTS9 
Integrator Complex Subunit 9 
IRB 
Institutional Review Board 
IRR 
Infusion-Related Reaction 
IV 
Intravenous(ly) 
MAPK 
Mitogen-activated protein kinase 


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM-121 
Seribantumab  
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
NCI 
National Cancer Institute 
NGS 
Next generation sequencing 
NRG 
Neuregulin 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall survival 
PCM1 
Pericentriolar Material 1 
PCR 
Polymerase chain reaction 
PDAC 
Pancreatic ductal adenocarcinoma 
PDX 
Patient derived xenograft 
PFS 
Progression-free survival 
PI3K 
Phosphatidylinositol-3-kinase 
PK 
Pharmacokinetic(s) 
PMEPA1 
Prostate Transmembrane Protein, Androgen Induced 1 
PR 
Partial response 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
QLQ-C30 
Quality of Life Questionnaire-Core 30 
RECIST  
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse events 
TKI 
Tyrosine kinase inhibitor 
ULN 
Upper limit of normal 
US 
United States 
 
 


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STUDY SYNOPSIS 
Sponsor: 
Elevation Oncology, Inc. 
888 Seventh Avenue, 12th Floor 
New York, NY 10106 
Protocol Title: A Phase 2 Study of Seribantumab in Adult Patients with Neuregulin-1 
(NRG1) Fusion Positive Locally Advanced or Metastatic Solid Tumors  
Protocol 
Number: ELVCAP-001-01 (CRESTONE) 
Phase of 
Development: Phase 2 
Study Locations: International 
Number of sites: Approximately 40-50 sites worldwide. 
Patient 
Population: 
Patients with locally advanced or metastatic solid tumors that harbor 
NRG1 gene fusion as assessed by local molecular assays, such as PCR, 
NGS (RNA or DNA) or Fluorescence in situ hybridization (FISH) testing. 
Patients must have progressed on or after at least one prior standard 
therapy appropriate for their tumor type and stage of disease, with no 
further available curative therapy options. Patients who discontinued prior 
therapy due to intolerance or unacceptable toxicity may be eligible after 
discussion with the Sponsor. 
Estimated 
Number of 
Patients: 
An estimated 90 patients will be enrolled.  
Primary 
Objective: 
To determine the objective response rate (ORR) by independent radiologic 
review to single agent seribantumab (anti-HER3 targeted therapy; 
3,000 mg weekly) in patients with centrally confirmed NRG1 gene fusion 
positive advanced cancer according to Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1. 
Secondary 
Objectives: 
• To determine the overall efficacy of single agent seribantumab in 
NRG1 fusion positive patients with various solid tumors through the 
assessment of the following clinical outcome parameters: 
• Duration of Response (DoR) by independent radiologic review  
• ORR and DoR by investigator assessment 
• Progression-free Survival (PFS) by independent radiologic review 
and investigator assessment 
• Overall Survival (OS) 
• Clinical Benefit Rate (CR, PR, SD ≥ 24 weeks) by independent 
radiologic review and investigator assessment 
• To describe the safety profile of seribantumab.  


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Exploratory 
Objectives: 
• To evaluate the pharmacokinetics of the seribantumab dosing schedule 
in patients with NRG1 gene fusion positive advanced solid tumors.  
• To evaluate if mechanistically linked exploratory biomarkers from 
tumor tissue or blood samples correlate with clinical outcomes. 
• To evaluate changes from baseline in quality of life, as measured by 
the European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30). 
Study Design: 
This study is an open-label, international, multi-center, Phase 2 study in 
adult patients with locally advanced or metastatic solid tumors, which 
harbor the NRG1 gene fusion based upon local testing. The design of the 
study is summarized in Figure 1. 
All patients will be determined to be NRG1 gene fusion positive based on 
local testing of tumor tissue per local laboratory directed analyses prior to 
initiating further screening procedures. After all screening procedures and 
determination of eligibility for study treatment (including local NRG1 
fusion positive testing result) have been completed, eligible patients will 
be assigned by the Sponsor to the appropriate cohort based upon prior 
treatment history. Patients will be assigned to Treatment Cohorts as 
follows: 
Cohort 1: Patients with NRG1 gene fusions who are ERBB/HER2/HER3 
treatment-naïve AND harbor NRG1 gene fusions with an EGF-like 
domain intact. Cohort 1 will include at least 55 patients who have received 
≥ 1 prior standard first-line therapy in the locally advanced or metastatic 
setting. 
Cohort 2: Enrollment to Cohort 2 was closed under Protocol Version 
5.0/Protocol Administrative Letter 8.0. Patients with NRG1 gene fusions 
with an EGF-like domain intact, who received ≥ 1 prior standard first-line 
therapy in the locally advanced or metastatic setting including at least one 
ERBB/HER2/HER3 directed treatment are ineligible for study 
participation. 
Cohort 3: Enrollment to Cohort 3 was closed under Protocol Version 5.0 
and later. Patients with NRG1 fusions without an EGF-like domain 
(including but not limited to NRG1-PMEPA1, NRG1-STMN2, PCM1-
NRG1 and INTS9-NRG1) and patients with NRG1 fusions and other 
molecular aberrations lacking standard treatment options, AND patients 
unable to provide tissue for central confirmation of NRG1 gene fusion 
status are ineligible for study participation under Protocol Version 5.0.  
 
One cycle of treatment consists of 28 days. Dosing begins at the Cycle 1 
Week 1 (C1W1) visit.   
 
Treatment consists of seribantumab 3,000 mg 1-h IV once weekly until 
patients meet one or more protocol-specific treatment discontinuation 
criteria. Dose modifications (Section 5.3) and/or treatment interruptions 


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(Section 5.2.4.3) to manage treatment related toxicities are permitted 
during weekly dosing. After 12 months of weekly dosing, patients who 
have tumor response (CR or PR) per RECIST v1.1 may transition from 
treatment with seribantumab 3,000 mg once every week to once every 
2 weeks (Q2W) after discussion with and approval from the Sponsor.  
Note: Previous dosing regimens for patients enrolled under prior protocol 
versions are described in detail in Appendix A. 
Patients are expected to be treated until investigator-assessed progressive 
disease or unacceptable toxicity. Treatment beyond progression is 
permitted if the Investigator determines that the patient may derive clinical 
benefit from continued exposure to seribantumab. Tumor assessments will 
be measured and recorded by the local radiologist beginning at weeks 6, 
12, 18 and 24 with a ± 2-week window and subsequently every 8 weeks 
(± 2 weeks) through Week 48, followed by every 12 weeks (± 2 weeks) 
beginning at Week 60 until disease progression and evaluated using the 
RECIST guidelines (version 1.1). Patients that discontinue study treatment 
for reasons other than disease progression including due to toxicities will 
continue to receive tumor assessments as outlined above until initiation of 
next anti-cancer therapy, clinical disease progression, death, or withdrawal 
of consent. In addition, an independent central review of scans will be 
conducted. All images will be submitted to a central imaging facility for 
this purpose and will be assessed by independent reviewers in accordance 
with the Imaging Charter. After patients discontinue seribantumab 
treatment, survival information and information about subsequent 
therapies will be collected until death or study closure, whichever occurs 
first. An optional biopsy may be obtained at the time of progression to 
explore mechanisms of seribantumab resistance.  
Inclusion 
Criteria: 
To be eligible for participation in the study, patients must meet the 
following inclusion criteria: 
• Locally advanced or metastatic solid tumor with an NRG1 gene fusion 
identified through molecular assays, such as PCR, NGS (RNA or 
DNA) or FISH, by a CLIA-certified or similarly accredited laboratory.  
• Availability of fresh or archived formalin-fixed, paraffin-embedded 
tumor sample to be submitted to a central laboratory for 
post-enrollment confirmation of NRG1 gene fusion status.  
• Patients must have progressed on or after at least one prior standard 
therapy appropriate for their tumor type and stage of disease, with no 
further available curative therapy options. Patients who discontinued 
prior therapy due to intolerance or unacceptable toxicity may be 
eligible after discussion with the Sponsor. 
•  Age ≥ 18 years. 
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 
1 or 2. 


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• Patients must have at least one measurable extra-cranial lesion as 
defined by RECIST v1.1 (Eisenhauer et al., 2009). 
• Adequate organ function defined as: 
• Serum aspartate aminotransferase (AST) and serum alanine 
aminotransferase (ALT) < 2.5 × upper limit of normal (ULN), or 
AST and ALT < 5 × ULN if liver function abnormalities due to 
underlying malignancy. 
• Total bilirubin < 2.0 × ULN. Patients with a known history of 
Gilbert’s Disease and an isolated elevation of indirect bilirubin are 
eligible. Patients with documented hepatic involvement are eligible 
if total bilirubin is ≤ 3.0 × ULN. 
• Estimated glomerular filtration rate ≥ 30 mL/minute using the 
Cockcroft-Gault formula: 
(140 – age) x body weight (kg) × 0.85 (if female) 
Serum creatinine (mg/dL) × 72 
• Absolute neutrophil count ≥ 1.0 × 109/L not requiring growth factor 
support for at least 7 days prior to C1W1, and 
• Platelet count ≥ 75 × 109/L not requiring transfusion support for at 
least 7 days prior to C1W1. 
• Hemoglobin ≥ 8.0 g/dL not requiring transfusion support for at 
least 7 days prior to C1W1. 
• Able to provide informed consent or have a legal representative able 
and willing to do so. 
• Ability to comply with outpatient treatment, laboratory monitoring, 
and required clinic visits for the duration of study participation. 
• Willingness of men and women of reproductive potential to observe 
conventional and effective birth control for the duration of treatment 
and for 3 months following study completion. Please refer to 
Section 4.1 for detailed criteria for men and women of reproductive 
potential.  
Exclusion 
Criteria: 
To be eligible for participation in the study, patients must not meet any of 
the following exclusion criteria: 
• Additional alterations in known oncogenes other than NRG1 fusion 
that could confer resistance to seribantumab monotherapy treatment, 
including alterations for which there are approved targeted therapies. 
Genomic testing reports from locally obtained molecular testing 
documenting NRG1 fusion must be submitted to the Sponsor for 
review during the screening period. 
• Life expectancy < 3 months  
• Pregnant or lactating 
• Prior treatment with pan-ERBB or any ERBB/HER2/HER3 directed 
therapy (exclusion for Cohort 1 only).  
• Symptomatic or untreated brain metastases  


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o Note: Patients with asymptomatic brain metastases treated with 
radiation or surgery and without evidence of progression by 
imaging at screening are eligible to participate in the study, 
including those on a stable [i.e., same dose for ≥ 2 weeks] low-dose 
corticosteroid regimen. Refer to Section 5.5. 
o Note: Patients with history of brain metastases or if clinically 
indicated will require brain imaging at baseline and subsequent 
serial scans if brain metastases are present at baseline. 
• Received other systemic anticancer therapy (investigational or 
standard chemotherapy, immunotherapy, or targeted therapy) within 
28 days prior to planned start of seribantumab or 5 half-lives, 
whichever is shorter.  
• Prior to initiation of seribantumab treatment, patients must have 
recovered from clinically significant toxicities from prior anticancer or 
investigational therapy or acute radiation toxicities. 
• Any other active malignancy requiring systemic therapy.  
• Known hypersensitivity to any of the components of seribantumab or 
previous CTCAE grade 3 or higher hypersensitivity reactions to fully 
human monoclonal antibodies. 
• Clinically significant cardiac disease, including symptomatic 
congestive heart failure, unstable angina, acute myocardial infarction 
within 6 months of planned first dose, or unstable cardiac arrhythmia 
requiring therapy (including torsades de pointes), or prolongation of 
the QT interval corrected for heart rate (QTcF) > 470 ms on at least 2 
of 3 consecutive electrocardiograms (ECGs), and mean QTcF 
> 470 ms on all three ECGs during screening. Correction of suspected 
drug-induced QTcF prolongation may be attempted at the 
investigator’s discretion if considered clinically safe. 
• Active uncontrolled systemic bacterial, viral, or fungal infection. 
• Patients who are not appropriate candidates for participation in this 
clinical study for any other reason as deemed by the investigator. 
Length of Study: 
It is intended that patients will be treated until radiographic disease 
progression per RECIST v1.1, death or intolerable toxicity, as assessed by 
the investigator. It is estimated that enrollment to Cohort 1 (a minimum of 
55 patients with centrally confirmed NRG1 gene fusion positive cancer) 
will require 36 months. 
Investigational 
Product: 
Seribantumab is a fully human IgG2 monoclonal antibody that binds to 
human epidermal growth factor receptor 3 (ERBB3/HER3). Seribantumab 
is a clear liquid solution, supplied in sterile, single-use vials for injectable 
use at a concentration of 25 mg/mL. Seribantumab drug product should be 
stored at 2-8°C. 
Sample Size: 
At least 55 patients with centrally confirmed NRG1 gene fusion positive 
cancer will be enrolled in the Cohort 1 primary efficacy analysis 
population. This sample size will provide approximately 90% power for 


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the lower bound of the 95% CI to exclude 20% assuming the ORR is 40% 
with seribantumab treatment. 
With the release of Protocol Version 5.0, Cohort 3 was closed to 
enrollment. Under Protocol Version 5.0/Protocol Administrative Letter 
8.0, Cohort 2 was closed to enrollment. 
Statistical 
Considerations 
and Data 
Reporting: 
General: 
In general, all analyses will follow the multi-cohort nature of the study 
design. Categorical variables will be summarized by frequency 
distributions (number and percentages of patients) and continuous 
variables will be summarized by descriptive statistics (mean, standard 
deviation, median, minimum, maximum). 
Analysis Populations: 
The analysis populations to be used for the planned statistical analyses 
include: 
Efficacy Analysis Populations 
• Cohort 1 primary efficacy analysis population 
Analyses of the Cohort 1 primary efficacy analysis population will be 
intended to support a potential registration. It will include Cohort 1 patients 
enrolled in this study who meet all criteria listed below: 
• Centrally confirmed NRG1 gene fusion.  
• Received at least one dose of seribantumab at 3,000 mg QW dosing 
regimen (starting with Protocol Version 3.0 and later). Patients in 
the safety-run in (enrolled under Protocol Version 2.0 or earlier) 
will be included if they received seribantumab at 3,000 mg QW 
beyond induction/re-induction. 
• Received at least one prior standard therapy in the locally advanced 
or metastatic setting. 
• At least one measurable lesion at baseline as assessed per RECIST 
v1.1 based on independent central review. 
• Cohort 2 and Cohort 3 efficacy analysis population 
These populations will be used for exploratory efficacy analysis by 
investigator-assessments for each cohort, respectively. All patients 
enrolled in each cohort who received at least one dose of seribantumab and 
had at least one measurable lesion at baseline assessed per RECIST 1.1 
based on investigator assessments will be included in the analysis. With 
the release of Protocol Version 5.0, Cohort 3 was closed to enrollment. 
Under Protocol Version 5.0/Protocol Administrative Letter 8.0, Cohort 2 
was closed to enrollment. 
Safety analysis population: The safety analysis population includes 
patients receiving at least one dose of seribantumab therapy across any of 
the three treatment cohorts (e.g., Cohort 1, 2, and 3) and across any of the 


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seribantumab dosing regimens. The safety population will be used for the 
overall safety analysis. 
 
Primary Efficacy Analysis:  
ORR is determined by RECIST v1.1 (confirmed CR+PR) and will be 
assessed by independent radiographic review. To be assigned a status of 
confirmed PR or CR, changes in tumor measurements must be confirmed 
by repeated assessments at least 4 weeks (28 days) after the criteria for 
response are first met. The point estimate of the ORR along with the 
2-sided 95% CI exact Clopper-Pearson CI will be presented. For the 
Cohort 1 primary efficacy analysis population, the lower bound of the 
95% CI will be compared with the 20% threshold.  
 
Secondary Efficacy Analysis: 
ORR based on the investigator assessments will be analyzed similarly as 
described for the primary efficacy analysis. This is considered a sensitivity 
analysis.  
DoR is defined as the time from the start date of CR or PR (whichever 
response status is observed first and subsequently confirmed), to the date 
of first documented radiographical progression of disease using RECIST 
v1.1, or death from any cause, whichever comes first. DoR will be 
calculated for patients who are responders, i.e., those who achieve a 
confirmed CR or PR. The initiation of new anticancer therapy will mean 
the end of the response for the calculation of DoR. 
PFS is defined as the time from the date of seribantumab treatment 
initiation (Dose 1) to the first documented radiographical progression of 
disease using RECIST 1.1, or death from any cause, whichever comes first. 
The Kaplan-Meier method will be used to estimate PFS for each treatment 
cohort. 
OS is defined as the time from the date of seribantumab treatment initiation 
(Dose 1) to the date of death from any cause. The Kaplan-Meier method 
will be used to estimate OS for each treatment cohort. In addition to 
estimating the overall distribution for OS, the median and the 12-month 
survival rate will be estimated. 
Additional sensitivity analyses may be conducted for the efficacy 
endpoints and the details are specified in the statistical analysis plan. 
Safety Analysis: 
The safety analysis will be based on the Safety Analysis Population and 
will be presented by cohort and all cohorts combined. Patient incidence of 
all treatment-emergent adverse events (TEAE) will be tabulated by 
Medical Dictionary for Regulatory Activities (MedDRA) system organ 
class and preferred term. Summary tables of TEAEs that are fatal, serious, 
treatment-related, Grade 3 or 4, TEAEs leading to dose reduction or 


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interruption of study drug, and TEAEs leading to permanent 
discontinuation of study drug will be provided. Changes in lab values and 
vital signs over time will be summarized. Summary of treatment exposure 
will be provided to include treatment duration, number of doses, actual 
total dose administered, and relative dose intensity. 
Safety Review Committee: 
A Safety Review Committee (SRC) has been established to monitor study 
conduct and to assess the safety and tolerability and PK (if available) of 
seribantumab. The SRC initially convened after the first 6 patients 
completed treatment with Induction Regimen 1 and once again after the 
next 6 patients completed treatment with Induction Regimen 2. Beginning 
with the first patient enrolled to the 12-week Target Induction Regimen 
under Clinical Protocol Version 3.0, and subsequently for patients enrolled 
to the weekly dosing regimen under Protocol Versions 4.0 and later, the 
SRC meetings will occur on a monthly basis for 6 consecutive months to 
ensure the safety and tolerability of the 3,000 mg 1-h IV once weekly 
dosing regimen. Overall safety analyses (adverse events and laboratory 
analyses) will be performed using the safety population. Adverse events 
will be coded using the latest MedDRA dictionary. Severity will be graded 
according to the NCI CTCAE Version 5.0. Treatment-emergent adverse 
events (TEAEs), TEAE grade 3 and higher, TEAE-related, serious adverse 
events (SAEs), and discontinuation due to AE will be reported by 
frequency and percent summaries. Adverse events will be summarized by 
System Organ Class and preferred term. All adverse event data will be 
listed by patient. Laboratory, vital signs, and ECG data will be summarized 
according to parameter type. 
An expanded SRC will be convened to conduct an interim analysis after 
20 patients have been enrolled and treated in Cohort 1 and followed for at 
least one post-baseline tumor assessment (i.e., 6 weeks ± 2 weeks). The 
expanded SRC will consist of the SRC members described in Section 3.3, 
which details the addition of two independent members consisting of one 
clinician and one biostatistician. Following the interim analysis, the 
Sponsor will revert to the original SRC to continue monitoring of the safety 
and conduct of the study. 
Exploratory Analyses: 
Biomarker Analysis: Biomarker data from collected tissue and whole 
blood will be used to evaluate if biomarkers from tumor tissue or blood 
samples correlate with clinical outcomes. Efficacy outcomes considered in 
these exploratory analyses will include ORR, OS, and PFS. Kaplan Meier 
methods will be used in these descriptive analyses. 
PK 
and 
Anti-seribantumab 
Immunogenicity 
Analysis: 
Plasma 
concentrations by patient, cycle, day, and time will be obtained and 
documented prior to and following seribantumab dosing at timepoints 
specified in Section 6.2. Serum samples to assess immunogenicity and the 


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presence of anti-seribantumab immunogenicity will be collected at 
timepoints specified in Section 6.2. 
Quality of Life Analysis: The QLQ-C30 will be administered at visits 
associated with disease assessments as specified in Section 6.2 to assess 
changes from baseline in quality of life. 
 


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Figure 1: 
Study Schema of Patient Flow in the CRESTONE Clinical Study 
 
 
EGF = epidermal growth factor; ERBB = receptor tyrosine-protein kinase erbB-3; HER = human epidermal growth factor receptor; NRG1 = Neuregulin-1 
 


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1. 
INTRODUCTION 
1.1. 
NRG1 Overview 
Neuregulin-1 or NRG1 (formerly known as heregulin or HRG) is a cell adhesion molecule that is 
encoded by the NRG1 gene found on the short arm of chromosome 8 (8p12) in humans. The gene 
encodes a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the 
growth and development of multiple organ systems (Online Mendelian Inheritance in Man 
database entry accessed 29 August 2019). 
There are four neuregulin genes [NRG1-4], and approximately 30 different neuregulin isoforms, 
which are generated through alternative splicing of their mRNA. These different isoforms probably 
have different roles in different tissues. Type I NRG1, contains an N-terminal immunoglobulin 
(Ig)-like domain prior to the EGF-like domain, which is followed by a specific hydrophobic stretch 
and a unique C-terminal domain (Trombetta et al., 2017).  
Neuregulin 1 (NRG1) is the predominant binding ligand for the v-erb-b2 erythroblastic leukemia 
viral oncogene homolog 3 (ErbB3 or HER3), an oncogene that is overexpressed in a variety of 
cancers and is associated with tumor pathogenesis and resistance to therapy. ErbB3/HER3 is one 
member of a family of 4 human growth factor receptors: HER3, HER4, ErbB1 (EGFR) and ErbB2 
(HER2). All family members consist of a glycosylated extracellular domain, a single hydrophobic 
transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein 
kinase domain, and a carboxyterminal tail (Roskoski 2014). Upon binding their cognate ligand, 
the receptors homo- or heterodimerize, which activates downstream signaling pathways. HER2 
does not have a ligand, but rather partners preferentially with HER3 when other ERBB family 
members are ligand-activated (Dimou et al., 2019).  
Thus, under normal circumstances wild-type NRG1 binds to the extracellular domain of HER3 
and induces its heterodimerization with HER2, its preferential dimerization partner. Following 
auto-and trans-phosphorylation of intracellular tyrosine residues, downstream effector kinases of 
the Mitogen-activated protein kinase/ extracellular signal-regulated kinases (MAPK/ERK) and 
Phosphoinositide 3-kinases, Protein kinase B (PI3K-AKT) pathways then become active. Any 
dysregulation of this tightly controlled process can lead to pathologic signaling via MAPK and 
other canonical pathways, leading to unregulated cellular proliferation.  
1.2. 
NRG1 Fusions 
Rearrangement of the neuregulin-1 gene (NRG1) leading to a DOC4-NRG1 fusion was first 
identified in a breast cancer cell line in 1997 (Schaefer et al., 1997). The molecular change was 
then shown to be present in breast cancer samples (Huang et al., 2004), in invasive mucinous 
adenocarcinomas (IMA) of the lung [CD74–NRG1, (Fernandez-Cuesta et al., 2014)] and other 
tumor types (Jonna et al., 2019). Over the past 5 years, general knowledge related to the biology, 
incidence and prevalence of NRG1 genomic alterations has increased considerably. The most 
comprehensive study of the incidence of NRG1 fusions across multiple tumor types is derived 
from molecular testing of 21,858 tumor specimens collected from September 2015-December 
2018 (Jonna et al., 2019). As depicted in Figure 2, comprehensive RNA-based next generation 
sequencing (NGS) testing identified the presence of NRG1 fusions across a broad array of solid 


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tumors including non-small cell lung carcinoma (NSCLC), gallbladder cancer, renal cell 
carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine 
tumor, sarcoma, and colorectal cancer. While this comprehensive study suggests the overall 
incidence of NRG1 fusions is approximately 0.2%, the prevalence of NRG1 fusions appears to be 
enriched in certain solid tumor settings, including patients with IMA (7-27%; Shim HS et al., 2015 
and Shin DH et al., 2016) as well as those diagnosed with KRAS wild-type pancreatic ductal 
adenocarcinoma (6%; Jones et al., 2019).  
 
Figure 2: 
Incidence of NRG1 gene fusions by tumor type  
In addition to its role as an oncogenic driver, NRG1 fusions have also been identified as a mediator 
of resistance to alectinib in anaplastic lymphoma kinase (ALK)-rearranged NSCLC (McCoach et 
al., 2018). The largest category of NRG1 fusions identified mostly involve the upstream gene 
CD74 and contain the active EGF-like domain encoded by exon 6. Although at least 4 fusions 
have also been reported without an active EGF-like domain, NRG1-PMEPA1, NRG1-STMN2, 
PCM1-NRG1 (Drilon et al., 2018) and INTS9 (Ke et al., 2019), these are unlikely to be oncogenic, 
as the EGF domain has been shown to be essential for oncogenic transformation (Shin et al., 2016).  
NRG1 fusions as primary drivers are mutually exclusive with most other known oncogenic drivers 
such as EGFR, KRAS, ALK, ROS1 and RET in nearly all tumor samples tested. This is supported 
by case reports of NRG1 fusions in pancreatic adenocarcinoma and lung cancer with wild-type 
KRAS phenotype. Heining et al., 2018 reported four wild-type KRAS patients of which 3 out of 4 
harbored an NRG1 fusion, whereas a recent article described 3/47 or 6% of pancreatic 
adenocarcinoma patients with wild-type KRAS who also tested for NRG1 fusions (Jones et 
al., 2019). 


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1.3. 
Rationale for Targeting the HER3 Pathway in NRG1 Fusion 
Dependent Cancer 
NRG1 is a ligand for HER3, and generation of NRG1 fusion proteins disrupts normal cellular 
signaling pathways. NRG1 fusion pathogenesis has been shown to occur through the 
indiscriminate heterodimerization of HER3/ERBB3 with a defective NRG1 gene, which leads to 
constitutive activation of the ERBB2/ERBB3 signaling pathway and downstream activation of 
growth 
and 
survival 
pathways, 
which 
drive 
tumor 
formation 
and 
progression 
(Fernandez-Cuesta 2014).  
Preventing NRG1 from binding HER3 and initiating a signaling cascade that drives tumorigenesis, 
represents a promising concept of targeting NRG1-induced oncogenesis. Anti-HER3 monoclonal 
antibodies inhibit NRG1 fusion proteins, containing active EGF-like domains, from binding to 
HER3, thus halting the formation of active HER2/HER3 complexes and preventing downstream 
signaling and uncontrolled growth and proliferation of cancer cells. In contrast, anti-HER2 
antibodies are only able to prevent heterodimerization of HER3 with HER2, thereby still allowing 
NRG1 binding to HER3 and heterodimerize with other HER family member (e.g., HER1/EGFR 
or HER4). Inhibition of HER2 pathway signaling alone does not adequately suppress growth and 
signaling pathways in NRG1 fusion positive patients. More recently, tyrosine kinase inhibitors 
(TKIs) targeting HER2 and other ERBB family members, such as the pan-ERBB inhibitor afatinib, 
have been evaluated in NRG1 fusion positive patients. In one multicenter, global registry 
experience, afatinib produced a 33% response rate (3 partial responses [PRs], 1 complete response 
[CR]) in 12 patients with metastatic lung cancer, however 50% of patients progressed within 
2 months of treatment initiation and two of the four responders experienced short-lived responses 
of 2.0 and 4.4 months, respectively (Duruisseaux et al., 2019). In addition to this report from the 
NRG1 Global Registry, Table 1 highlights several published case reports related to the use of 
afatinib in NRG1 positive patients with various advanced solid tumors. Similar to the findings in 
the global registry, afatinib was associated with short-lived partial responses of < 3 months in the 
majority of these published case reports.  
In contrast to the experience with afatinib, one case report exists where a patient who had 
progressed following exposure to four lines of prior chemotherapy and immunotherapy, developed 
a prolonged PR (19 months) following treatment with an anti-HER3 directed antibody 
(GSK2849330). Coupled with the encouraging preclinical findings for anti-HER3 approaches, this 
case report suggests a potentially important role for HER3 directed therapy over HER2 or 
pan-ERBB directed therapy in NRG1 fusion positive patients (Drilon et al., 2018).  
Targeting tumors harboring NRG1 fusions by using either a HER3 mAb and/or a combination of 
anti-HER3 and HER2 treatments, represent the most encouraging therapeutic strategies for rare 
NRG1 fusion driven cancers. A summary of published case reports, including experience with the 
pan-ERBB inhibitor afatinib, is summarized in Table 1. 
 


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Table 1: 
Clinical Case Reports for ERBB/HER Directed Treatment of NRG1 Fusion 
Positive Cancers 
Drug(s) 
Tumor  
Type 
HER/ERBB 
targeted drug 
NRG  
mutation 
Response 
Response 
Duration 
(months) 
Reference 
Afatinib 
NSCLC 
Pan-HER TKI 
SDC4-
NRG1fusion 
PR 
12 
Jones 2017 
Afatinib 
Cholangio-
carcinoma 
Pan-HER TKI 
ATP1B1-
NRG1fusion 
PR 
8 
Jones 2017 
Afatinib 
NSCLC 
Pan-HER TKI 
SLC3A2-NRG1 
fusion 
PR 
12 
Gay 2017 
Afatinib 
NSCLC 
Pan-HER TKI 
CD74-NRG1 
fusion 
PR 
10 
Gay 2017 
Afatinib 
IMA 
Pan-HER TKI 
CD74–NRG1 
fusion 
PR 
6 
Cheema 
2017 
Afatinib 
Pancreatic 
Pan-HER TKI 
ATP1B1–NRG1 
fusion 
PR 
3 
Heining 
2018 
Afatinib 
Colorectal 
Pan-HER TKI 
NRG1-POMK 
fusion 
SD 
9+ 
Weinberg 
2019 
Afatinib 
Liver 
cancer 
Pan-HER TKI 
APP-NRG1 
fusion 
PR 
7+ 
Weinberg 
2019 
Afatinib 
Prostate/ 
colon 
Pan-HER TKI 
ATP1B1-NRG1 
fusion 
PR 
5.5 
Weinberg 
2019 
Erlotinib/ 
pertuzumab 
Pancreatic 
EGFR TKI +  
anti-HER2 
mAb 
SARAF-NRG1 
fusion 
PR 
3 
Heining 
2018 
Erlotinib/ 
Lumretuzumab 
IMA 
EGFR TKI +  
anti-HER3 
mAb 
NRG1-SLC3A2 
fusions 
SD 
4 
Kim  
2018 
Erlotinib/ 
Lumretuzumab 
IMA 
EGFR TKI +  
anti-HER3 
mAb 
NRG1-SLC3A2 
fusions 
SD 
4 
Kim  
2018 
GSK2849330 
IMA 
Anti-HER3 
mAb 
CD74-NRG1 
fusion 
PR 
19 
Drilon 
2018 
MCLA-128 
PDAC 
HER2/HER3  
bispecific mAb 
ATP1B1-NRG1 
fusion 
PR 
7+ 
Schram 
2019 
MCLA-128 
PDAC 
HER2/HER3  
bispecific mAb 
ATP1B1-NRG1 
fusion 
SD 
7+ 
Schram 
2019 
MCLA-128 
NSCLC 
HER2/HER3  
bispecific mAb 
CD74-
NRG1fusion 
PR 
4.5+ 
Schram 
2019 
CR = complete response; EGFR = Epidermal growth factor receptor; HER = human epidermal growth factor 
receptor; IMA = invasive mucinous adenocarcinoma; NRG = neuregulin; NSCLC = non-small cell lung 
carcinoma; PDAC = pancreatic ductal adenocarcinoma; PR = partial response; SD = stable disease; TKI = tyrosine 
kinase inhibitor 


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1.4. 
Seribantumab 
Seribantumab (formerly MM-121) is a fully human, monoclonal IgG2 antibody that binds to the 
NRG1 domain of the ErbB3 receptor with single digit nanomolar affinity. By preventing NRG1 
from binding to the ErbB3 receptor, seribantumab effectively blocks heterodimer formation of the 
ErbB3 (HER3) receptor with ErbB2 (HER2) and EGFR (HER1) and as such potently blocks 
downstream signaling activation and cancer cell survival.  
In addition to the extensive nonclinical characterization and testing, seribantumab has been 
intravenously (IV) administered as described in Section 1.6. Prior to its redirected development 
for NRG1 fusion driven cancers, seribantumab had been primarily studied in advanced cancer 
patients (e.g., NSCLC, breast, ovarian) with NRG1 amplified cancer. All future development of 
seribantumab will focus on NRG1 gene fusion positive cancers. 
1.5. 
Seribantumab Nonclinical Experience in NRG1 Fusion Models  
Extensive prior nonclinical testing has demonstrated that seribantumab is a sub-nanomolar 
inhibitor of ligand-dependent ERBB3/HER3 signaling, inhibits HER3 dimerization with HER2 
and other HER family members (EGFR/HER1), and downregulates the expression of ERBB3 
across many different cancers alone and in combination (Schoeberl et al., 2017). In NRG1 fusion 
driven cancers, ERBB3 inhibition may be more optimal than ERBB2 or pan-ERBB inhibition 
(Drilon et al., 2018). The effects of seribantumab in NRG1 fusion positive in vitro and in vivo 
models have been explored to support the redirected development of seribantumab in the NRG1 
gene fusion population and this ongoing phase 2 study. Please refer to the current version of the 
Investigator’s Brochure for a more comprehensive description of the nonclinical results 
demonstrating the potential of seribantumab for the treatment of patients with tumors harboring 
NRG1 gene fusions. 
The effects of seribantumab were recently evaluated in NRG1 fusion dependent cell lines 
(Odintsov et al., 2021a). As depicted in Figure 3, seribantumab was associated with potent growth 
inhibition (IC50: 0.008 µM – shown; IC90: 2.86 µM – not shown) in the MDA-MB-175-VII breast 
cancer cell line (DOC4/NRG1 fusion dependent cell line known to be sensitive to HER3 and HER2 
inhibition), yet was not associated with growth inhibition in the MCF-7 breast cancer cell line 
which does not harbor the NRG1 fusion. In this same MDA-MB-175-VII cell line, seribantumab 
effectively inhibited HER2-HER3 dimerization and downregulated the expression of HER3 
(Figure 4). Furthermore, seribantumab demonstrated complete inhibition of HER2, HER3 and 
HER4 downstream signaling (e.g., AKT/ERK) in this NRG1-dependent model (Figure 5), 
indicating the potential for HER3 directed therapy to have profound effects on ERBB pathway 
activity.  
In an experiment evaluating the effects of seribantumab in a NRG1 lung cancer xenograft model, 
a single flat dose of seribantumab (0.6 mg, 0.75 mg or 1 mg per mouse) was administered and 
tumors were removed at 2-, 24-, or 168-hours post-drug administration, to determine impact on 
HER2 and HER3 phosphorylation and downstream signaling activity. As shown in (Figure 6), all 
doses of seribantumab resulted in reduced phosphorylation of HER2, HER3, AKT, and ERK1/2 
by the 2h time point, with higher doses being more effective at the longer time points. However, 
at the 24h and 168h time points, reactivation of HER3, AKT and ERK1/2 protein phosphorylation 
was observed, despite consistent inhibition of HER2. These results suggest the frequency of initial 


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seribantumab administration to patients harboring oncogenic NRG1 fusions may require weekly 
dosing, in order achieve maximal, durable inhibition of HER3/NRG1 oncogenesis. (Odintsov et 
al., 2021a).  
 
Figure 3: 
In Vitro Effects of Seribantumab on NRG1 Gene Fusion Positive  
Breast Cancer Cell Lines 
 
Figure 4: Seribantumab HER2/HER3  
Dimer Inhibition 
 
Figure 5: Seribantumab HER2, HER3,  
 HER4 + AKT/ERK Inhibition 


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Figure 6: 
Efficacy of single-dose seribantumab in a NSCLC (SLC3A2-NRG1 fusion) PDX 
model.  
 
The LUAD-0061AS3 patient derived xenograft (PDX) model was developed from a lung cancer 
specimen with a SLC3A2-NRG1 fusion and this model was used to test repeat dosing of 
seribantumab in vivo (Odintsov et al., 2021b). Notably, this specimen was derived from a patient 
who had progressed after prior standard therapy and progression on afatinib therapy. In this study, 
PDX tumors (approximately 3 mm3) were implanted subcutaneously into the flanks of 
immunodeficient mice. Treatment was initiated when the tumors reached a volume of 100-150 
mm3. Each treatment group consisted of seven mice while five mice were used in the vehicle 
control group. Treatment started on day 14 of the experiment and consisted of vehicle (phosphate 
buffered saline), seribantumab (0.6, 0.75, or 1 mg per dose bi-weekly, which based upon allometric 
scaling for a 70 kg patient represents a human dose range of 156 – 260 mg), or afatinib (5, 10, or 
15 mg/kg once daily). Figure 7 shows a dose-related decline in tumor volume across all doses of 
seribantumab, with the best response observed with the 1 mg dose where maximal tumor 
regression was approximately 60%. Notably, the pan-ErbB family inhibitor afatinib was not 
associated with tumor regression at the clinically equivalent dose of 5 mg/kg, however tumor 
regression of approximately 30% was observed at a dose of 15 mg/kg, which is approximately 
3-fold higher than the clinically equivalent dose of 40 mg/day in humans. (Odintsov et al., 2021a). 


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Figure 7: 
Seribantumab Effectively Inhibits Growth of LUAD-0061AS3 PDX NRG1 
Dependent Tumors 
In a separate experiment, the antitumor effects of higher doses of seribantumab (1 mg, 2.5 mg, 
5 mg, or 10 mg BIW), which based upon allometric scaling for a 70 kg patient represents a human 
dose range of 260 – 2,600 mg, were assessed in a CLU-NRG1 ovarian cancer xenograft model. As 
shown in Figure 8, near complete and complete tumor regressions were observed across the entire 
dose range, with complete tumor regressions observed in nearly all animals at the highest dose 
level of 10 mg BIW, which is similar to a human dose of 2,600 mg or 2.6 grams (Odintsov et al., 
2021a). In a related study, using this same ovarian CLU-NRG1 xenograft model, a single-dose 
pharmacokinetics (PK) study was performed at doses of 1 mg, 5 mg and 10 mg. Results from this 
single-dose PK study indicate the seribantumab trough (Cmin) concentrations ranged from 
200 mg/L to 880 mg/L, with an average trough concentration of 508.4 mg/L at the 10 mg dose 
level. With biological activity observed across the entire dose range and noting the 10 mg dose is 
similar to the recommended 3,000 mg human dose, these results suggest the target trough 
concentration should be in the range of 500 mg/L to achieve optimal target inhibition.  
 


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Figure 8: 
Efficacy of seribantumab in CLU-NRG1 ovarian cancer PDX model. 
BIW = biweekly; H&E = Hematoxylin and eosin; IHC = immunohistochemistry; QD = once daily; WT = wild-type 
(A) Immunohistochemical characterization of the OV-10-0050 PDX model. Hematoxylin and eosin staining, WT1 
and TP53 IHC (left to right). 
(B) Mice bearing OV-10-0050 PDX tumors (5-8 animals per group) were treated with vehicle,  
or afatinib (5mg/kg QD) or the doses of seribantumab shown (BIW). Treatment was terminated on day 27 and 
animals were monitored for tumor regrowth until tumors reached maximum allowable size or until 90 days after 
treatment initiation. Results represent the mean tumor volume ± SE. The right panel shows a zoom-in view on 
tumor volumes during the last 40 days of monitoring of seribantumab-treated groups. The highest dose of 
seribantumab blocked tumor regrowth after cessation of treatment. 
(C) Change in volume of individual tumors (day 27 vs volume at start of treatment). 
In a separate experiment, the anti-tumor activity of seribantumab was assessed in the APP-NRG1 
pancreatic cancer PDX model. In this model, where the doubling time of the tumor in vehicle 
control was 7.3 days, the anti-tumor activity of seribantumab at 5 mg and 10 mg BIW was 
significantly greater than afatinib at a dose of 5 mg/kg. As shown in Figure 9, the tumor growth 
inhibition (TGI) for seribantumab was similar at both dose levels (102% and 105% at day 20, 
respectively), when repeat doses were administered over several weeks. These results demonstrate 
that frequent, repeat doses of seribantumab may achieve and maintain inhibition of HER3 pathway 
signaling and downstream activity. These results suggest that weekly seribantumab dosing may be 
necessary to achieve optimal HER3 / NRG1 inhibition. (Odinstov et al., 2021b). 
 


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Figure 9: 
Efficacy of seribantumab in APP-NRG1 pancreatic cancer PDX model. 
Combined, these nonclinical results demonstrate that seribantumab is effective at both in vitro and 
in vivo inhibition of NRG1-dependent tumorigenesis in breast, lung, ovarian and pancreatic cancer 
models (Odintsov et al., 2021a; Odintsov et al., 2021b). These results support the ongoing clinical 
evaluation of seribantumab in NRG1 fusion positive advanced solid tumors with the optimized 
dosing regimen consisting of seribantumab 3,000 mg 1-h IV once weekly, as outlined in 
Section 5.2.3.1. 
1.6. 
Clinical Experience with Seribantumab to Date 
Overall, as of May 2021, seribantumab has been administered to 869 patients in ongoing and 
completed studies across Merrimack’s 12 studies including monotherapy treatment (n = 43), in a 
single patient IND as monotherapy (n = 1), and in combination with other anticancer treatment 
(n = 803), as well as Elevation Oncology’s CRESTONE study (n = 15) and Investigator Sponsored 
INDs (n = 7) in patients with tumors harboring NRG1 gene fusions. The PK and safety findings 
indicate that seribantumab is well tolerated as monotherapy and in combination therapy with 
targeted therapies, antiestrogen, and other standard chemotherapy (see current version of 
Investigator’s Brochure). 


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1.6.1. 
Prior Clinical Development of Seribantumab 
Previously, seribantumab was being developed by Merrimack Pharmaceuticals to investigate the 
effects of seribantumab as combination therapy with standard anticancer therapies. The focus of 
these studies were tumors where NRG1 was overexpressed or amplified, and not tumors harboring 
NRG1 gene fusions. Please refer to the current version of the Investigator’s Brochure for additional 
information regarding the previous development of seribantumab under Merrimack or the single 
patient IND study, as well as a safety summary of identified risks to date for seribantumab in 
combination with other anticancer therapies.  
1.6.2. 
Clinical Development of Seribantumab in NRG1 Fusion Positive Cancer 
The current Sponsor, Elevation Oncology, redirected the clinical development activities for 
seribantumab to focus exclusively on the treatment of NRG1 gene fusion driven cancers with 
seribantumab monotherapy. In September 2020, Elevation Oncology treated the first patient in the 
phase 2 CRESTONE study to evaluate the effects of seribantumab monotherapy in patients with 
NRG1 fusion positive advanced solid tumors that have received ≥1 prior standard first-line therapy 
in the metastatic setting.  
The final safety run-in cohort of six (6) patients has completed full induction treatment with 
Induction Regimen 2 and no DLT was reported. After formal review, the Safety Review 
Committee (SRC) recommended treatment with Induction Regimen 2, for all subsequently 
enrolled patients. 
Safety findings are discussed in Section 5.2.5. Refer to the current version of the Investigator’s 
Brochure for additional details. 
1.6.3. 
Rationale for 3,000 mg Once Weekly Dosing  
The dosing regimen (3,000 mg, once weekly) for the CRESTONE study was selected based on the 
non-clinical findings in NRG1 fusion models (Section 1.5), safety considerations from prior 
clinical studies of seribantumab, two PK simulation studies, and clinical PK data observations in 
NRG1 fusion patients treated with seribantumab (refer to the current version of the Investigator’s 
Brochure for additional details). The following has been demonstrated: 
• In non-clinical mouse data, HER3 pathway activity rebounds within 24 to 168 hours 
following a single dose of seribantumab (Figure 6). 
• Multiple repeat doses of seribantumab on a weekly basis are required to produce 
sustained tumor growth inhibition and ongoing HER3 pathway inhibition (Figure 9).  
• Seribantumab has demonstrated activity across a range of doses and tumor models, 
with results indicating higher doses are associated with maximal tumor regression and 
inhibition of HER3 / NRG1 oncogenesis. 
• In a single-dose PK study in the ovarian cancer PDX model, the seribantumab trough 
concentration ranged from 200 mg/L (1 mg/mouse dose) to 880 mg/L (10 mg/mouse 
dose), with an average trough concentration equal to 508.4 mg/L at the 10 mg dose 
level. The 10 mg dose level in this model is similar to a 2,600 mg human dose, based 
upon allometric scaling for a 70 kg patient, suggesting that optimal target inhibition 


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may require trough concentrations ≥ 500 mg/L in patients harboring oncogenic NRG1 
gene fusions. 
• Clinical PK data (steady-state trough concentrations of seribantumab) obtained in 
16 patients confirmed the accuracy of the PK simulation predictions (Table 2 [Data on 
file, Feb 2021; PK Simulation Report]) – trough seribantumab levels associated with 
the dose of 3,000 mg weekly at steady-state were approximately 550 mg/L, which 
achieved the preclinical efficacy exposure target; lower or less frequent dosing yielded 
lower trough. 
• Based upon the preliminary PK findings, there were no correlations observed between 
exposure (Cmax or Cmin) and frequency or grade of TEAEs.  
Based upon these non-clinical and clinical observations, the dosing regimen for the CRESTONE 
study is being modified as outlined in Section 5.2.3.1. The revised treatment regimen will consist 
of seribantumab 3,000 mg 1-h IV weekly until progressive disease, toxicity or other treatment 
discontinuation criteria are met. The switch to the weekly dosing regimen is supported by the 
clinical observations to date, where weekly dosing for the initial 4 weeks (induction regimen 
dosing) has been safe and very well tolerated at the fixed 3,000 mg 1-h IV weekly dose. A 
summary of simulation results for select dosing scenarios is presented in Table 2 (Data on file, 
Feb 2021; PK Simulation Report): 
Table 2: 
Summary of PK Simulations for Initial CRESTONE Regimen and Extended 
Weekly Regimens 
Dosing Regimena 
Dosing Perioda 
Ctrough,avg (95% 
CI) (mg/L) 
Css,avg (95% CI) 
(mg/L) 
Cmax,avg (95% CI) 
(mg/L) 
Initial CRESTONE regimen  
(Protocol v2.0) 
Weeks 4-18 (Q2W) 
Weeks 18-28 (Q3W) 
285 (72-612) 
199 (31-468) 
682 (362-1141) 
539 (264-893) 
1128 (319-2445) 
912 (190-2270) 
12-week Induction 
(3,000 mg QW x 12 weeks); 
3,000 mg Q2W maintenance 
Weeks 4-12 (QW) 
Weeks 12-28 (Q2W) 
592 (223-1122) 
314 (75-720) 
1321 (703-2186) 
753 (437-1133) 
2207 (1133-3571) 
1255 (362-2626) 
16-week Induction 
(3,000 mg QW x 16 weeks); 
3,000 mg Q2W maintenance 
Weeks 4-16 (QW) 
Weeks 16-28 (Q2W) 
594 (208-1172) 
329 (75-747) 
1324 (705-2171) 
771 (358-1323) 
2213 (1132-3705) 
1275 (358-2644) 
a Each dosing regimen includes the same initial treatment consisting of 3,000 mg IV weekly (QW) x 4 doses 
(Weeks 0 to 3) 
1.7. 
Risk/Benefit Assessment for 3,000 mg Once Weekly Dosing 
Based upon the safety, tolerability and clinical experience with Induction Regimen 1 (n=6) and 
Induction Regimen 2 (n=6) through April 2021, the seribantumab dosing regimen has been 
modified for all subsequently enrolled patients to 3,000 mg 1-h IV once weekly. 
This optimized seribantumab regimen, consisting of 3,000 mg once weekly dosing, is expected to 
be safe and well tolerated, while offering NRG1 fusion patients the opportunity to rapidly achieve 
and maintain optimal seribantumab exposure and maximal inhibition of HER3 / NRG1 
oncogenesis. With this weekly dosing regimen, patients will be observed more frequently during 


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their weekly clinic visits and safety monitoring and oversight will occur more frequently by the 
SRC, as outlined in Section 3.2. 
2. 
OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is to determine the objective response rate (ORR) by 
independent radiologic review to single agent seribantumab (anti-HER3 targeted therapy; 
3,000 mg weekly) in patients with centrally confirmed NRG1 gene fusion positive advanced 
cancer according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
2.2. 
Secondary Objectives 
The secondary objectives of this study include the following:   
• To determine the overall efficacy of single agent seribantumab in NRG1 gene fusion 
positive patients with various solid tumors through the assessment of the following 
clinical outcome parameters: 
− Duration of Response (DoR) by independent radiologic review  
− ORR and DoR by investigator assessment 
− Progression-free Survival (PFS) by independent radiologic review and investigator 
assessments 
− Overall Survival (OS) 
− Clinical Benefit Rate (CR, PR, SD ≥ 24 weeks) by independent radiologic review 
and investigator assessment 
• To describe the safety profile of seribantumab  
2.3. 
Exploratory Objectives 
The exploratory objectives for this study are: 
• To evaluate the pharmacokinetics of the seribantumab dosing schedule in patients with 
NRG1 gene fusion positive advanced solid tumors  
• To evaluate if mechanistically linked exploratory biomarkers from tumor tissue or 
blood samples correlate with clinical outcomes 
• To evaluate changes from baseline in quality of life, as measured by the European 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) 


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3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
This study is an open-label, international, multi-center, phase 2 study in adult patients with 
advanced or metastatic solid tumors, which harbor the NRG1 gene fusion based upon local testing. 
All patients will be determined to be NRG1 gene fusion positive based on local testing of tumor 
tissue per local laboratory directed analyses prior to initiating further screening procedures. After 
all screening procedures and determination of eligibility for study treatment (including local NRG1 
fusion positive testing result) have been completed, eligible patients will be assigned by the 
Sponsor to the appropriate cohort based upon prior treatment history. Patients will be assigned to 
Treatment Cohorts as follows: 
Cohort 1: Patients with NRG1 gene fusions who are ERBB/ HER2/HER3 treatment-naïve AND 
harbor NRG1 gene fusions with an EGF-like domain intact. Cohort 1 will include at least 
55 patients who have received ≥1 prior standard first-line therapy in the locally advanced or 
metastatic setting. 
Cohort 2: Enrollment to Cohort 2 was closed under Protocol Version 5.0/Protocol Administrative 
Letter 8.0 Patients with NRG1 gene fusions with an EGF-like domain intact, who have received 
≥1 prior standard first-line therapy in the locally advanced or metastatic setting including at least 
one ERBB/HER2/HER3 directed treatment are ineligible for study participation. 
Cohort 3: Enrollment to Cohort 3 was closed under Protocol Version 5.0 and later. Patients with 
NRG1 fusions without an EGF-like domain (including but not limited to NRG1-PMEPA1, 
NRG1-STMN2, PCM1-NRG1, and INTS9-NRG1) and patients with NRG1 fusions and other 
molecular aberrations lacking standard treatment options AND patients unable to provide tissue 
for central confirmation of NRG1 gene fusion status are ineligible for study participation under 
Protocol Version 5.0.  
One cycle of treatment consists of 28 days. Dosing begins at the Cycle 1 Week 1 (C1W1) visit. 
Treatment with seribantumab will be as described in Section 5.2.3.1. Dose modifications 
(Section 5.3) and/or treatment interruptions (Section 5.2.4.3) to manage treatment related toxicities 
are permitted during weekly dosing. After 12 months of weekly dosing, patients who have tumor 
response (CR or PR) per RECIST v1.1 may transition from treatment with seribantumab 3,000 mg 
once every week to once every 2 weeks (Q2W) after discussion with and approval from the 
Sponsor. Previous dosing regimens for patients enrolled under prior protocol versions are 
described in detail in Appendix A. 
Patients are expected to be treated until Investigator-assessed progressive disease or unacceptable 
toxicity. Treatment beyond progression is permitted if the Investigator determines that the patient 
may derive clinical benefit from continued exposure to seribantumab. Tumor assessments will be 
measured and recorded by the local radiologist beginning at weeks 6, 12, 18, and 24 with a 
± 2-week window and subsequently every 8 weeks (± 2 weeks) through Week 48, followed by 
every 12 weeks (± 2 weeks) beginning at Week 60 until disease progression. Tumor assessments 
will be evaluated using the RECIST v1.1 guidelines. Patients that discontinue study treatment for 
reasons other than disease progression including due to toxicities will continue to receive tumor 
assessments as outlined above until initiation of next anti-cancer therapy, clinical disease 


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progression, death, or withdrawal of consent. In addition, an independent central review of scans 
will be conducted. All images will be submitted to a central imaging facility for this purpose and 
will be assessed by independent reviewers in accordance with the Imaging Charter. After patients 
discontinue seribantumab treatment, survival information and information about subsequent 
therapies will be collected until death or study closure, whichever occurs first. An optional biopsy 
may be obtained at the time of progression to explore mechanisms of seribantumab resistance. 
3.2. 
Safety Review Committee 
A SRC has been established to monitor study conduct and to assess the safety and tolerability and 
PK (if available) of seribantumab. The SRC initially convened after the first 6 patients completed 
dosing with Induction Regimen 1 and once again after the next 6 patients completed treatment 
with Induction Regimen 2. Beginning with the first patient enrolled to the 12-week Target 
Induction Regimen under Clinical Protocol Version 3.0 and subsequently for patients enrolled to 
the once weekly dosing regimen under Clinical Protocol Versions 4.0 and later, the SRC meetings 
will occur on a monthly basis for 6 consecutive months to ensure the safety and tolerability of the 
3,000 mg 1-h IV once weekly dosing regimen. Safety analyses are described in Section 10.6. 
Further details will be provided in the SRC Charter.  
3.3. 
Expanded Safety Review Committee for Interim Futility Analysis 
An expanded SRC will be convened to review data from a pre-planned interim analysis. The 
interim analysis based on ORR will be conducted after 20 patients have been enrolled and treated 
in Cohort 1 and followed for at least one post-baseline tumor assessment (i.e., 6 weeks ± 2 weeks). 
The expanded SRC will be composed of the current members of the SRC with the addition of one 
independent clinician and one independent biostatistician for the interim analysis only. Following 
the interim analysis, the Sponsor will revert to the original SRC to continue monitoring of the 
safety and conduct of the study. 
Enrollment may continue while the expanded SRC is evaluating the data from the first 20 patients 
in Cohort 1. Should four or more objective responses be observed at the time of the pre-planned 
interim analysis, enrollment to Cohort 1 will continue until a minimum of 55 patients with 
centrally confirmed NRG1 gene fusion have been consented, screened, and treated with 
seribantumab. The interim analysis is described in Section 10.7.  
4. 
STUDY POPULATION 
The target population for this study will be NRG1 gene fusion positive patients with locally 
advanced or metastatic solid tumors. Patients must have progressed on or after at least one prior 
standard therapy appropriate for their tumor type and stage of disease, with no further available 
curative therapy options. Patients who discontinued prior therapy due to intolerance or 
unacceptable toxicity may be eligible after discussion with the Sponsor. The investigator or his/her 
designee must ensure that all patients meet the following inclusion and exclusion criteria before 
being enrolled in the study.  


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4.1. 
Inclusion Criteria 
To be eligible for participation in the study, patients must meet the following criteria.  
a. Locally advanced or metastatic solid tumor with an NRG1 gene fusion identified 
through molecular assays, such as PCR, NGS (RNA or DNA) or fluorescence in situ 
hybridization (FISH), by a Clinical Laboratory Improvement Amendments 
(CLIA)-certified or similarly accredited laboratory. 
b. Availability of fresh or archived formalin-fixed, paraffin-embedded tumor sample to 
be submitted to a central laboratory for post-enrollment confirmation of NRG1 gene 
fusion status (see also Section 4.3). 
c. Patients must have progressed on or after at least one prior standard therapy appropriate 
for their tumor type and stage of disease, with no further available curative therapy 
options. Patients who discontinued prior therapy due to intolerance or unacceptable 
toxicity may be eligible after discussion with the Sponsor. 
d. Age ≥ 18 years. 
e. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 
f. Patients must have at least one measurable extra-cranial lesion as defined by 
RECIST v1.1  
g. Adequate organ function defined as:  
− Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) 
< 2.5 × upper limit of normal (ULN), or AST and ALT < 5 × ULN if liver function 
abnormalities due to underlying malignancy 
− Total bilirubin < 2.0 × ULN. Patients with a known history of Gilberts Disease and an 
isolated elevation of indirect bilirubin are eligible. Patients with documented hepatic 
involvement are eligible if total bilirubin ≤ 3.0 × ULN. 
− Estimated glomerular filtration rate ≥ 30 mL/minute using the Cockcroft-Gault formula: 
(140 – age) x body weight (kg) × 0.85 (if female) 
Serum creatinine (mg/dL) × 72 
− Absolute neutrophil count ≥ 1.0 × 109/L at Screening and not requiring growth factor 
support for at least 7 days prior to C1W1, and 
− Platelet count ≥ 75 × 109/L at Screening not requiring transfusion support for at least 
7 days prior to C1W1 
− Hemoglobin ≥ 8.0 g/dL at Screening and not requiring transfusion support for at least 
7 days prior to C1W1 
h. Able to provide informed consent or have a legal representative able and willing to do 
so 
i. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic 
visits for the duration of study participation  
j. Willingness of men and women of reproductive potential to observe conventional and 
effective birth control for the duration of treatment and for 3 months following study 
completion. 
Notes: 


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• A postmenopausal woman will be defined as having no menses for 12 months without 
an alternative medical cause. Male sterility will be defined as only men sterilized 
surgically. For male patients with a pregnant partner, a condom should be used for 
contraception. For male patients with a non-pregnant female partner of child-bearing 
potential and woman of child-bearing potential one of the following birth control 
methods with a failure rate of less than 1% per year when used consistently and 
correctly are recommended: 
o Combined estrogen and progestogen containing hormonal contraception 
associated with inhibition of ovulation given orally, intravaginally, or transdermally 
o Progestogen-only hormonal contraception associated with inhibition of ovulation 
given orally, by injection, or by implant 
o Intrauterine device 
o Intrauterine hormone-releasing system 
o Bilateral tubal occlusion/ligation 
o Vasectomized partner 
o Sexual abstinence 
 Sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments.  The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the patient. 
• Birth control methods unacceptable for this clinical study are: 
o Periodic abstinence (calendar, symptothermal, or post-ovulation methods) 
o Withdrawal (coitus interruptus) 
o Spermicide only 
o Lactational amenorrhea method 
4.2. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in this study:  
k. Additional alterations in known oncogenes other than NRG1 fusion that could confer 
resistance to seribantumab monotherapy treatment, including alterations for which 
there are approved targeted therapies. Genomic testing reports from locally obtained 
molecular testing documenting NRG1 fusion must be submitted to the Sponsor for 
review during the screening period  
l. Life expectancy < 3 months  
m. Pregnant or lactating 
n. Prior treatment with pan-ERBB or any ERBB/HER2/HER3 directed therapy (exclusion 
for Cohort 1 only) 
o. Symptomatic or untreated brain metastases  


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− Note: Patients with asymptomatic brain metastases treated with radiation or 
surgery and without evidence of progression by imaging at screening are eligible to 
participate in the study, including those on a stable [i.e., same dose for ≥ 2 weeks] 
low-dose corticosteroid regimen. Refer to Section 5.5. 
− Note: Patients with history of brain metastases or if clinically indicated will require 
brain imaging at baseline and subsequent serial scans if brain metastases are present 
at baseline. 
p. Received other systemic anticancer therapy (investigational or standard chemotherapy, 
immunotherapy, or targeted therapy) within 28 days prior to planned start of 
seribantumab or 5 half-lives, whichever is shorter 
q. Prior to initiation of seribantumab treatment, patients must have recovered from 
clinically significant toxicities from prior anticancer or investigational therapy or acute 
radiation toxicities 
r. Any other active malignancy requiring systemic therapy  
s. Known hypersensitivity to any of the components of seribantumab or previous National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
grade 3 or higher hypersensitivity reactions to fully human monoclonal antibodies 
t. Clinically significant cardiac disease, including symptomatic congestive heart failure, 
unstable angina, acute myocardial infarction within 6 months of planned first dose, or 
unstable cardiac arrhythmia requiring therapy (including torsades de pointes), or 
prolongation of the QT interval corrected for heart rate (QTcF) > 470 ms on at least 
2 of 3 consecutive ECGs, and mean QTcF > 470 ms on all three ECGs during 
screening. Correction of suspected drug-induced QTcF prolongation may be attempted 
at the investigator’s discretion if considered clinically safe  
u. Active uncontrolled systemic bacterial, viral, or fungal infection 
v. Patients who are not appropriate candidates for participation in this clinical study for 
any other reason as deemed by the investigator 
4.3. 
Archival or Fresh Tumor Specimen Requirements 
This study will only enroll patients with NRG1 gene fusion positive tumors. A patient’s tumor 
NRG1 fusion status will be identified by a molecular assay such as PCR, NGS (RNA or DNA) or 
FISH as routinely performed by a CLIA-certified or other similarly accredited laboratory. For 
patients who do not have adequate archived tumor tissue available for testing, a fresh tumor biopsy 
will be obtained in advance of study participation, if it can be safely performed per Section 8.6.1. 
The local NRG1 fusion testing methodologies may vary for qualified sites.  
In addition, an adequate archival or fresh tumor sample will also be required for NRG1 gene fusion 
confirmation using a qualified RNA-based NGS test performed by a central laboratory following 
enrollment and assignment to Cohort 1. Tissue obtained from exploratory Cohort 2 will support 
development of companion diagnostic and future exploratory biomarker research. Refer to the 
Laboratory Manual for additional details on tumor tissue collection. 


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5. 
STUDY TREATMENT 
5.1. 
Treatment Assignment  
If a patient is determined to be NRG1 gene fusion positive based upon local testing, investigators 
will determine if the patient meets all other eligibility criteria. A copy of the redacted molecular 
pathology report identifying the NRG1 gene fusion per local testing used for eligibility and a list 
of the patient’s prior anti-cancer treatments with dates must be submitted for Sponsor review prior 
to patient enrollment. Once all study enrollment criteria have been fulfilled, patients will be 
assigned to the appropriate treatment cohort based upon prior ERBB treatment history. Following 
enrollment, investigators and/or site staff will submit the required tumor samples to a central 
laboratory for confirmation of NRG1 fusion status per the laboratory manual. 
5.2. 
Seribantumab  
5.2.1. 
Seribantumab Formulation, Packaging, and Labeling 
Seribantumab is supplied for IV administration as a sterile, colorless liquid at 25 mg/mL. It is 
packaged in sterile, single-use, clear borosilicate Type 1 glass vials that are closed with a coated 
rubber stopper and flip-off cap with flange.  
Multiple vials of seribantumab will be packaged in a cardboard container. The individual vials, as 
well as the outside of the cardboard container, will be labeled in accordance with regulatory 
requirements and in compliance with country-specific guidelines. Additional details are provided 
in the study pharmacy binder. 
5.2.2. 
Seribantumab Product Storage and Stability 
Seribantumab drug product must be stored refrigerated (2-8°C) with protection from light. Light 
protection is not required during preparation or infusion. Seribantumab must not be frozen. 
Based on available stability data, the concentrate for solution for injection is stable for at least 
36 months when stored according to conditions specified in the clinical supply label. Continued 
stability data are being generated, and longer stability may be available during the course of the 
study. The date of expiration or retest date will be noted on the drug label, or via other pharmacy 
notifications as required by local regulation. Seribantumab should not be used beyond the date of 
expiration. 
5.2.3. 
Seribantumab Dosing, Preparation and Administration 
5.2.3.1. 
Seribantumab Dosing 
Patients enrolled will initiate treatment with seribantumab 3,000 mg 1-h IV once weekly until 
patients meet one or more protocol-specific treatment discontinuation criteria. 
In the setting of weekly dosing, it is expected that during the course of treatment patients may need 
to miss doses for non-adverse event related reasons; for example, due to weather conditions 
making travel to the clinic difficult, due to holidays or vacation, etc. After the patient has been on 
treatment for at least 6 cycles, occasional missed doses during weekly dosing for non-adverse 
event related reasons would not constitute protocol deviations. No more than one missed dose in 


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an 8 week period is permissible. A discussion should be held with the Sponsor if the patient falls 
below 80% compliance with the assigned dosing regimen. 
Dose modifications (Section 5.3) and/or treatment interruptions (Section 5.2.4.3) to manage 
treatment related toxicities are permitted during weekly dosing.   
After 12 months of weekly dosing, patients who have tumor response (CR or PR) per RECIST 
v1.1 may transition from treatment with seribantumab 3,000 mg once every week to once every 
2 weeks (Q2W) after discussion with and approval from the Sponsor.  
For previous seribantumab dosing schedules, see Appendix A.   
5.2.3.2. 
Preparation and Administration 
Administration of seribantumab will require multiple vials, all of which should originate from the 
same lot number. Seribantumab should be brought to room temperature prior to mixing with 0.9% 
normal saline. Vials should not be shaken. The appropriate quantity of study drug will be removed 
from the vial and further diluted with 0.9% normal saline to a final total volume of 250 mL and 
administered over 60 minutes (±15 minutes) using a low protein binding 0.20 or 0.22 micron 
in-line filter. All infusions should be administered over 60 minutes (±15 minutes) in the absence 
of infusion related reactions. The line should be flushed before and after the study drug infusion. 
Study drug should not be administered as a bolus or a push. Seribantumab should be administered 
no less than 7 days after the previous dose.   
5.2.4. 
Management of Toxicity Related to Seribantumab 
5.2.4.1. 
Dose Limiting Toxicity 
Patients will be monitored during weekly dosing for a period of 28 days (i.e., throughout C1W1, 
C1W2, C1W3, and C1W4) for the occurrence of DLTs. Any Grade 3 or 4 hematologic or 
non-hematologic toxicity considered related to seribantumab will be considered dose limiting. A 
DLT is defined as any AE meeting the criteria listed below, occurring during weekly treatment 
with seribantumab, where the relationship to seribantumab cannot be ruled out. The grading of 
AEs will be based on the CTCAE Version 5.0.  
Hematologic toxicity 
• Febrile neutropenia 
• Neutropenic infection 
• Grade 4 neutropenia > 7 days 
• Grade ≥ 3 thrombocytopenia for > 7 days 
• Grade ≥ 3 thrombocytopenia with clinically significant bleeding 
• Grade 4 thrombocytopenia 
• Grade ≥ 3 anemia > 7 days 
Non-hematologic toxicity 


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• Grade ≥ 3 nausea, vomiting, or diarrhea lasting more than 72 hours despite optimal 
medical support with anti-emetics or anti-diarrheals 
• Grade 4 (life-threatening) vomiting, or diarrhea should be considered DLTs 
irrespective of duration  
• Any other grade ≥ 3 AE, except Grade ≥ 3 fatigue and anorexia lasting for < 7 days or 
Grade ≤ 2 infusion related reactions (IRR; for grade 3 or higher IRRs, seribantumab 
must be permanently discontinued) 
Any toxicity, regardless of CTCAE grade, resulting in discontinuation or dose reduction of 
seribantumab treatment during the 28-day DLT evaluation period, with the exception of symptoms 
related to disease progression, will be considered a DLT. 
All events qualifying as a DLT, regardless of seriousness, should be submitted through the defined 
SAE reporting requirements as described in Section 9.4 and followed through proper resolution as 
outlined in Section 9.5. 
5.2.4.2. 
Management of Infusion Related Reactions 
Like other IV infusions of monoclonal antibodies, seribantumab administration may be associated 
with IRRs. Infusion related reactions will be defined according to the National Cancer Institute 
CTCAE (Version 5.0) definition of an allergic reaction/infusion reaction and anaphylaxis. In past 
clinical studies (n=847 patients treated), IRRs with seribantumab have been rare with < 1% of 
patients experiencing an IRR, of which all were Grade 1 or 2. Study site policies or the following 
treatment guidelines shall be used for the management of infusion reactions. 
Grade 1 
• Slow infusion rate by 50% 
• Monitor patient every 15 minutes for worsening of condition 
Grade 2 
• Stop infusion 
• Administer diphenhydramine hydrochloride 50 mg IV, acetaminophen 500-650 mg 
orally, and oxygen 
• Resume infusion at 50% of the prior rate once infusion reaction has resolved 
• Monitor patient every 15 minutes for worsening of condition 
• For all subsequent infusions, pre-medicate with dexamethasone 10 mg orally or IV  
Grade 3 
• Stop infusion and disconnect infusion tubing from patient 
• Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV, 
bronchodilators for bronchospasm, and other medications or oxygen as medically 
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• No further treatment with seribantumab will be permitted 
Grade 4 
• Stop the infusion and disconnect infusion tubing from patient 
• Administer epinephrine, bronchodilators, or oxygen as indicated for bronchospasm 
• Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV 
• Consider hospital admission for observation 
• No further treatment with seribantumab will be permitted 
For patients who experience a Grade 1 or Grade 2 infusion reaction, at the discretion of the 
investigator, future infusions may be administered over 90 minutes. In addition, for patients who 
experience a subsequent Grade 1 or 2 infusion reaction, administer dexamethasone 10 mg IV. All 
subsequent infusions should be pre-medicated with diphenhydramine hydrochloride 50 mg IV, 
dexamethasone 10 mg IV, and acetaminophen 500-650 mg orally.  
For patients who experience a Grade 3 or 4 infusion reaction, an anti-seribantumab antibody titer 
will be taken as close to the onset of the infusion reaction as possible. An anti-seribantumab 
antibody titer should also be obtained at the resolution of the event and 28 days (± 2 days) 
following the event. 
5.2.4.3. 
Toxicity Management Guidelines 
When a patient experiences any Grade 3 or Grade 4 hematologic or non-hematologic toxicity, 
excluding infusion related reactions (Section 5.2.4.2) related to seribantumab, the following 
toxicity management guidelines should be followed:  
Dose Interruptions and Reductions for Hematologic Toxicity 
For ≥ Grade 3 hematologic toxicity, seribantumab dosing will be held until resolving to ≤ Grade 2 
or the patient’s baseline. Once the hematologic toxicity resolves to ≤ Grade 2 or the patient’s 
baseline, seribantumab will be restarted at a 25% reduction of the original dose. 
For recurrence of a ≥ Grade 3 hematologic toxicity, seribantumab will be held again until resolving 
to ≤ Grade 2 or the patient’s baseline. Once the hematologic toxicity resolves to ≤ Grade 2 or the 
patient’s baseline, seribantumab will be restarted at a 50% reduction of the original dose. 
For patients who have had dose reductions of seribantumab due to hematologic toxicity, 
investigators may restart seribantumab at the original assigned dose, provided the toxicity has 
resolved to ≤ Grade 1 on the reduced dose for at least one cycle of treatment. The Investigator 
should consult with the Medical Monitor and Sponsor prior to any planned dose re-escalation.  
Seribantumab should be permanently discontinued if the patient experiences a recurrent Grade 3 
or higher treatment related hematologic toxicity, despite a 50% dose reduction. 
Dose Interruptions and Reductions for Non-Hematologic Toxicity 
For ≥ Grade 3 non-hematologic toxicity, seribantumab dosing will be held until resolving to 
≤ Grade 1 or the patient’s baseline. Once the non-hematologic toxicity resolves to ≤ Grade 1 or 
the patient’s baseline, seribantumab will be restarted at a 25% reduction of the original dose. 


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For recurrence of a ≥ Grade 3 non-hematologic toxicity, seribantumab will be held again until 
resolving to ≤ Grade 1 or the patient’s baseline. Once the non-hematologic toxicity resolves to 
≤ Grade 1 or the patient’s baseline, seribantumab will be restarted at a 50% reduction of the 
original dose. 
For patients who have had dose reductions of seribantumab due to non-hematologic toxicity, 
investigators may restart seribantumab at the original assigned dose, provided the toxicity has 
resolved to ≤ Grade 1 on the reduced dose for at least one cycle of treatment. The Investigator 
should consult with the Medical Monitor and Sponsor prior to dose re-escalation.   
Seribantumab should be permanently discontinued if the patient experiences a recurrent Grade 3 
or higher treatment related non-hematologic toxicity, despite a 50% dose reduction. 
Dose re-escalation is not permitted for patients who experience: 
• Recurrent Grade 3 AEs determined to be clinically significant by the Investigator 
despite dose-reduction 
• Recurrent Grade 4 AEs despite dose-reduction 
Seribantumab should be permanently discontinued for patients who experience life-threatening 
Grade 4 AEs. 
5.2.5. 
Potential Toxicities with Seribantumab 
Overall, seribantumab has been administered IV to 869 patients in ongoing and completed studies. 
In the CRESTONE study, as of 08May2021, diarrhea (8 patients, 53.3%), hypokalemia (5 patients, 
33.3%), and fatigue (5 patients, 33.3%) were the most commonly reported TEAEs. Grade 3 TEAEs 
were experienced by 3 (20.0%) patients. A total of two SAEs have been reported in one patient. 
Both SAEs were Grade 2, resolved, and considered not related to seribantumab. Both events were 
associated with the patient’s concurrent illness of non-serious AE of COVID-19 infections. 
For additional information on the safety associated with seribantumab as a monotherapy and in 
combination with standard anticancer treatments, as well as for safety observations in Investigator 
sponsored single patient INDs, please refer to the current version of the Investigator’s Brochure. 
5.3. 
Dose Modifications 
Patients who experience a clinically significant AE (Grade ≥ 3), may have seribantumab dosing 
held for up to 3 weeks to allow for recovery. Upon restarting treatment with study drug, the 
seribantumab dose will be reduced by either 25% (first occurrence) or 50% (recurrence) per 
Section 5.2.4.3, as follows:  
Table 3: 
Dose Modification – Weekly Dosing  
Original dose level 
3,000 mg 
25% dose reduction 
2,250 mg 
50% dose reduction 
1,500 mg 
 
For patients who meet criteria to transition to Q2W dosing, please discuss with and obtain approval 
from the Sponsor before reducing the dose. Patients who experience clinically significant AEs 


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related to seribantumab during Q2W dosing must have seribantumab withheld until the AE 
resolves according to Section 5.2.4.3. 
Seribantumab should be permanently discontinued for patients who experience life-threatening 
grade 4 AEs. Seribantumab should also be permanently discontinued for patients who experience 
clinically significant, drug-related AEs requiring a recovery period of longer than 3 weeks, unless 
there is compelling, objective radiological evidence of response and no alternative treatment. The 
Sponsor and Investigator must agree that continuation of seribantumab is in the best interest of the 
patient, and the patient agrees.  
5.4. 
Study Treatment Discontinuation 
A patient may withdraw from the study at any time and for any reason. Over the course of the 
study, the Investigator and/or Sponsor should withdraw a patient from treatment for any of the 
following reasons: 
• Disease progression (as assessed using RECIST v1.1). Note: Patients with disease 
progression per RECIST v1.1 who, in both the Investigator’s and Sponsor’s opinions, 
may continue to derive clinical benefit, and who meet the criteria listed in Section 5.4.1, 
may be allowed to continue treatment with written approval from the Sponsor. 
• Clinically significant drug-related toxicity requiring a recovery period of longer than 
3 weeks, unless there is compelling, objective radiological evidence of response, no 
alternative treatment, and the Sponsor and Investigator agree that continuation of 
seribantumab is in the best interest of the patient, and the patient agrees  
• Intercurrent illness compromising the ability to fulfill protocol requirements 
• Requirement for alternative treatment in the opinion of the Investigator 
• Significant non-compliance to protocol 
• Withdrawal of consent by the patient 
• Patient is lost to follow-up 
• Death 
When a patient is discontinued from treatment for any reason, they are to undergo the assessments 
in the End of Treatment visit within 4 weeks of the last dose and prior to initiating any subsequent 
anti-cancer therapy. All patients who discontinue treatment as a result of an adverse event (AE) 
must be followed until resolution or stabilization of the AE. At the time a patient withdraws from 
study treatment, an attempt should be made to determine the reason(s) for discontinuation.  
Upon withdrawal from treatment, the patient will continue to be followed for survival and 
subsequent disease and treatment information every 3 months after completion of the End of 
Treatment visit. If a patient does not return to the clinic for the end of treatment visit or is not 
reached for overall survival follow-up, at least 3 documented attempts, including one via certified 
mail, should be made to contact the patient. If the patient does not respond to these requests, the 
date of death should be captured from public records.  


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5.4.1. 
Study Treatment Beyond Progression 
As noted in Section 5.4, patients with disease progression per RECIST v1.1 who, in the 
Investigator’s and Sponsor’s opinions, may continue to derive clinical benefit, may be eligible to 
continue in the study if they meet the criteria outlined below: 
• absence of clinical symptoms or signs indicating clinically significant disease 
progression; 
• no decline in the ECOG performance status; 
• absence of rapid disease progression or threat to vital organs or critical anatomical 
sites (e.g., central nervous system metastasis, respiratory failure due to tumor 
compression, spinal cord compression) requiring urgent alternative medical 
intervention; 
• no significant, unacceptable, or irreversible toxicities related to the trial treatment; 
• have written approval of the Sponsor; 
• have signed an ICF agreeing to continue treatment; and 
• no other treatment discontinuation criteria are met. 
Patients must permanently discontinue seribantumab treatment if subsequent imaging 
demonstrates further disease progression of ≥ 10% in the target lesions, unequivocal or further 
progression in non-target lesions, and/or the appearance of new lesions. 
5.5. 
Concomitant and Prohibited Therapies 
Standard supportive medications may be used in accordance with institutional guidelines and 
Investigator discretion. These may include hematopoietic growth factors to treat neutropenia, 
thrombocytopenia or anemia in accordance with American Society of Clinical Oncology (ASCO) 
Guidelines (but not for prophylaxis in Cycle 1), transfusions, anti-emetics, anti-diarrheals, 
antibiotics, antipyretics, and corticosteroids (up to 10 mg per day prednisone or equivalent, unless 
a compelling clinical rationale for a higher dose is articulated by the Investigator and approved by 
the Sponsor; permitted corticosteroid uses include topical/cutaneous, ophthalmic, nasal and 
inhalational steroids, as well as short courses to treat asthma, chronic obstructive pulmonary 
disease, or other non-cancer related conditions).   
All concomitant medications, including transfusions of blood products, will be recorded on the 
appropriate page of the case report form. Concomitant therapy (non-investigational products) 
includes any prescription medication, over-the-counter preparation, herbal therapy, or 
radiotherapy used by a patient between the 28 days preceding study treatment initiation and the 
study treatment discontinuation visit. After the End of Treatment Visit, only anti-cancer therapies 
will be collected in addition to survival information. 
The following therapies are not permitted while on study treatment: 
• Other anti-neoplastic therapy, including cytotoxics, targeted agents, endocrine therapy, 
or other antibodies (patients who have been on gonadotropin-releasing hormone 
analogues for more than 90 days prior to study entry may continue while on study) 


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• Any other investigational therapy  
5.5.1. 
Concurrent Palliative Radiotherapy and Elective Procedures 
Palliative radiotherapy to specific sites of disease is permitted if considered medically necessary 
by the treating physician. Seribantumab treatment should be interrupted during palliative 
radiotherapy, stopping 3 days before and resuming treatment no earlier than 1 day thereafter. In 
general, target lesions being used to measure response should not be irradiated without discussion 
with the Sponsor and may be reason for the patient to be removed from study for progressive 
disease. Irradiated lesions will be considered not evaluable for response but can still be used to 
assess disease progression. The intensities, number, and dates of doses received for allowed 
palliative radiotherapy should be recorded on the appropriate eCRF. 
Although seribantumab is not expected to significantly affect wound healing, any unusual findings 
should be recorded as potential AEs. In the event elective procedures, including surgery, are 
necessary during study participation, seribantumab dosing should be stopped 3 days before surgery 
and resumed no sooner than 24 hours after surgery. 
5.6. 
Accountability of Study Drug 
The investigator and investigational site staff are responsible for maintaining an accurate inventory 
and accounting of study drug. A record of all vials of study drug received and administered will 
be maintained on an investigational drug inventory form provided by the Sponsor or an equivalent 
drug inventory form.  The following information will be recorded: 
• Date, quantity, and lot number(s) of study drug received 
• Date, quantity, and lot number(s) of study drug dispensed from the pharmacy per 
patient 
• Date, quantity, and lot number(s) of study drug administered to each patient 
• Date, quantity, and lot number(s) of study drug destroyed (if prepared and dispensed, 
but not administered for any reason, the study drug may not be returned to inventory) 
• Date, quantity, and lot number(s) of study drug returned to sponsor, if applicable 
Each shipment of study drug will contain an invoice describing the amount of drug shipped to the 
investigational site. The information on the invoice will be verified against the actual amount 
received, after which the investigator or designee will place the invoice in the investigator’s file. 
The Sponsor’s monitor will reconcile the information on the investigational drug inventory form 
with the actual amount of study drug remaining at each site on a routine basis. At the conclusion 
of the study, the monitor will either package and ship all unused vials of study drug back to Sponsor 
for destruction or document the destruction, in accordance with local regulations and institutional 
policy. Following use, empty vials of study drug may be destroyed according to local regulatory 
and environmental requirements. A record of any such destruction will be placed in the 
investigator’s file. 


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6. 
SCHEDULE OF ASSESSMENTS 
6.1. 
COVID-19 Public Health Emergency Impact on Protocol 
Assessments 
During study conduct, challenges may arise, for example, from quarantines, site closures, travel 
limitations, interruptions to the supply chain for the investigational product, or other considerations 
if site personnel or study participants become infected with COVID-19. These challenges may lead 
to difficulties in meeting protocol-specified procedures, including administering the study drug or 
adhering to protocol-mandated visits and laboratory/diagnostic testing. During the course of study 
conduct, protocol modifications may be required, and there may be unavoidable protocol 
deviations due to COVID-19 illness and/or COVID-19 public health control measures. In such 
case, these incidences should be documented in the study case report form(s). 
Since study participants may potentially not be able to come to the investigational site for protocol 
specified visits, alternative methods for safety and efficacy assessments (e.g., phone contact, 
virtual visit, telemedicine, visiting nurse to patient’s residence, alternative location for assessment, 
including local labs or imaging centers) could be implemented when necessary and feasible, and 
would be sufficient to assure the safety of study participants. 


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6.2. 
Schedule of Assessments 
The study schedule of events can be found in Table 4. Detailed information of study assessments 
is provided in Section 7. 
Table 4: 
Schedule of Assessments 
Evaluation / 
Procedure 
 
 
Visit Window 
Screen
ing 
  
(D-28 
to 0) 
Treatment  
  
End of 
Treatment 
Visit 
(EOT)13 
Survival Follow-Up 
Every 3 months 
after EOT15 
Evaluations/Procedures +/-2 days  
Seribantumab Dosing +2 days 
 
± 3 days 
± 1 month 
Informed consent 
X 
 
 
 
Medical, surgical, 
malignancy history 
X 
Archived tumor 
tissue or fresh 
biopsy 
X 
X14 
Urine or serum 
pregnancy test 
X 
Every 28 days 
X 
Physical Exam and 
ECOG PS1 
X 
 
Weekly during C1, then at W1 of every Cycle 
thereafter 
X 
Vital signs 
X8 
X 
X 
CBC 
X2,8 
Weekly during C1, then every 14 days starting 
C2W1 then every 28 days starting after 1 year on 
treatment 
X 
Serum chemistry 
X3,8 
X 
Blood sample(s) 
for PK4 
 
C1W1, C1W3, C2W1, C2W3, C3W1, C3W3, 
C4W1, C5W1, C6W1, and then every even Cycle 
beginning with C8W1 
 
12-lead ECG 
X5 
 
X5 
Serum for anti-
seribantumab 
immunogenicity6 
 
C1W1, C1W3, C2W1, C2W3, C3W1 and C3W3, 
C4W1, C5W1, C6W1, and then every even Cycle 
beginning with C8W1 
X6 
Whole blood for 
cfDNA7 
 
C1W1 and C2W1 
X 
Concomitant 
meds8 
X 
X 
X 
Seribantumab 
dosing9 
 
X 
 
AE/SAE 
assessment and 
reporting10 
                                                          X 
Quality of Life 
Questionnaire 
(EORTC QLQ-
C30) 
 
C1W1, and at W1 of every other Cycle16 
X 
Disease evaluation 
X11 
Week 6, Week 12, Week 18, Week 24;  
then every 8 weeks (through Week 48);  
then every 12 weeks (beginning at Week 60) 
X12 
Overall Survival 
Reporting15 
 
X 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen, C = cycle; CBC = complete blood count; cfDNA = cell free DNA; CT = computerized tomography; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOI = end of 
infusion; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life 


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Questionnaire-Core 30; EOT = end of treatment; GI = gastrointestinal; HEENT = head, eyes, ears, nose, and 
throat; Ig = immunoglobulin; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; 
NSCLC = non-small cell lung cancer; RBC = red blood cell; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event; W = week; WBC = white blood cell 
1 Review of systems: HEENT, extremities, GI/abdomen, lymph nodes, musculoskeletal, respiratory/pulmonary, and 
skin, body weight, and height during Screening. Symptom-directed physical and neurological examinations, 
including measurement of weight, may be performed at other time points. After screening, physical exams should 
occur weekly during Cycle 1 and at Week 1 of every cycle thereafter. 
2 Hemoglobin, hematocrit, RBC count, WBC count with differential (neutrophils [count and percent] and 
lymphocytes, monocytes, eosinophils, basophils [percent], and platelet count).  Samples collected for Screening 
may be used for C1W1 if collection occurs within 2 days of the C1W1 visit.  Ad hoc samples may be requested by 
the Sponsor or at the investigator’s discretion. 
3 Serum or plasma chemistries (non-fasting), including alkaline phosphatase, albumin, ALT, AST, blood urea 
nitrogen (BUN), cholesterol, creatinine, glucose, LDH, uric acid, total and direct bilirubin, total protein, sodium, 
potassium, calcium, chloride, bicarbonate, magnesium and phosphate.  Samples collected for Screening may be 
used for C1W1 if collection occurs within 2 days of the C1W1 visit.  Ad hoc samples may be requested by the 
Sponsor or at the investigator’s discretion. 
4 Seribantumab PK sampling: At C1W1 sampling should occur immediately prior to dosing, at the end of infusion 
(EOI) and 1 hour after EOI.  At C1W3, C2W1, C2W3, C3W1, C3W3, C4W1, C5W1, C6W1, and then every even 
Cycle beginning with C8W1: Samples should be collected immediately prior to each dose and at the EOI. 
Sampling should occur within 15 minutes of starting or completing the seribantumab infusion. Ad hoc PK samples 
may be requested by the Sponsor.  
5 Screening electrocardiogram (ECG) should be performed in triplicate. End of Treatment (EOT) ECG reading 
should be repeated only if the initial reading at the EOT visit showed treatment emergent abnormalities. Ad hoc 
ECGs may be requested by the Sponsor.   
6 Anti-seribantumab immunogenicity samples should be collected prior to dosing at scheduled time points. Should a 
patient experience an infusion reaction on study, an anti-seribantumab antibody assay will be taken within 24 
hours of the event. For patients who experience a grade 3 or 4 infusion reaction, an anti-seribantumab antibody 
titer will be taken as close to the onset of the infusion reaction as possible, upon resolution and 28 days (± 2 days) 
following the event.  
7 Whole blood for cfDNA analysis should be obtained prior to treatment on C1W1 and C2W1. Whole blood for 
cfDNA analysis should be obtained at the EOT visit even if radiographic disease assessment is not performed. 
Whole blood for cfDNA analysis should only be collected at subsequent visits if it was collected prior to treatment 
at C1W1. 
8 Performed prior to seribantumab administration. 
9 Seribantumab dosing will consist of weekly 1-h infusions until study treatment discontinuation criteria are met. 
Seribantumab doses should be administered no less than 7 days apart. 
10All AEs and SAEs are collected and reported from the time of informed consent through the EOT visit or 28 days 
after last dose, whichever occurs later. 
11 Baseline Disease Assessment: Radiographic tumor measurements using CT (computerized tomography) or 
magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis, with additional regions affected by disease 
as appropriate, and CT or MRI of brain (for patients with suspected brain involvement or a history of brain 
metastases) within 28 days of seribantumab dosing (first dose). Contrast should be utilized (excluding CT of the 
chest) unless there is a clear contraindication (e.g., decreased renal function or allergy that cannot be addressed 
with standard prophylactic treatments). Disease assessments will utilize RECIST v1.1. Disease assessments will 
occur prior to seribantumab administration on dosing days and occur within a ± 14-day window. Refer to Section 
7.7 for details on confirmation of response. 
12 All patients that come off treatment for reasons other than progressive disease will have a disease assessment 
performed at the EOT visit.  
13 End of Treatment visit should be completed within 4 weeks of the last dose of study drug administration.  
14 An optional fresh tumor biopsy will be performed at the time of progression and prior to the completion of the 
EOT assessments if feasible to evaluate potential patterns of resistance to seribantumab. 
15 Every survival follow-up should include collection of any new anti-cancer therapies and procedures taken after 
EOT visit. Should patients refuse or drop out of survival follow-up, attempts should be made to obtain any death 
information available via public records. 


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16 European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 
(QLQ-C30) should be conducted prior to dosing at C1W1 and at W1 of every other cycle thereafter, i.e., C3W1, 
C5W1, etc. The questionnaires should be answered by the patient to the best of his/her ability, preferably prior to 
learning the results of the radiologic disease assessment. QOLs should only be performed at subsequent visits if 
they were performed prior to dosing at C1W1.  
6.3. 
Screening and Baseline Visit 
All procedures for screening and baseline are outlined in Section 6.2. Patients who screen fail can 
be rescreened. Rescreened patients will be provided a new patient identification number.  
In discussion with the Sponsor, if a patient is identified who does not have access to local NRG1 
fusion testing, the Sponsor may offer support for testing of enriched patient population as a pre-
screening procedure. Enriched patient population may include patients diagnosed with KRAS 
wild-type IMA, and KRAS wild-type pancreatic ductal adenocarcinoma (PDAC). Additional 
tumor types of interest may be added at the Sponsor’s discretion. For patients diagnosed with IMA 
or PDAC who have not been screened for KRAS status, the Sponsor may provide access to KRAS 
testing under the pre-screening mechanism. The Sponsor may also support testing for patients with 
other tumor types who have exhausted all other options for treatment. For further descriptions of 
the clinical and laboratory assessments required, please refer to Section 7 and Section 8, 
respectively. 
6.4. 
On-Study Visits 
Patients who are confirmed to meet all inclusion and exclusion criteria will be assigned to the 
appropriate treatment cohort based upon prior treatment history. Treatment must be initiated within 
7 days of Enrollment and Cohort Assignment.  
All on-study procedures and assessments are outlined in Section 6.2. 
6.5. 
End of Treatment Visit 
When it is decided that a patient will stop receiving treatment on this study, an End of Treatment 
visit must be completed within 4 weeks of last dose of study drug and prior to the initiation of any 
subsequent anticancer therapy. All End of Treatment procedures and assessments are outlined in 
Section 6.2. 
6.6. 
Survival Follow-up 
Survival data will be collected via written communication (e.g., telephone, email, electronic 
medical record) or clinic visits every 3 months (±28 days) from the date of last treatment until 
death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor. In addition, 
any new anti-cancer therapies and procedures should be collected and documented during every 
survival follow-up. All survival information will be captured using the electronic data capture 
(EDC) system. Should patients refuse or drop out of survival follow-up, attempts should be made 
to obtain any death information via public records whenever possible. 


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7. 
CLINICAL PROCEDURES AND ASSESSMENTS 
All of the following clinical procedures should be performed in accordance with the schedule of 
assessments outline in Section 6.2. 
7.1. 
Medical History and Demographics 
Demographic information including age, date of birth, race, ethnicity and gender will be collected 
at the time of Screening.   
A medical history will be collected including all pertinent prior medical conditions, surgeries or 
other medical procedures, allergies, and concomitant medications.  
7.2. 
Adverse Event and Hospitalization Assessment Reporting 
Investigators should complete all routine and standard of care assessments to evaluate for toxicity 
and symptoms of drug-induced AEs. This may include, but is not limited to, verbal reports from 
the patient and/or caregiver, physical examination and laboratory findings. Adverse events should 
be collected and reported throughout the course of the study, from the time of informed consent 
through the end of treatment (EOT) visit or 28 days after the last dose of seribantumab, whichever 
occurs later, and followed through to resolution as detailed in Section 9.  
In addition, information on patient hospitalizations and/or unscheduled hospital visits should also 
be collected in the eCRF, whether or not associated with an AE. 
7.3. 
Physical Examination and Performance Status Assessment 
Physical examination will include a review of systems: head, eyes, ears, nose, and throat, 
extremities, GI/abdomen, lymph nodes, musculoskeletal, respiratory/pulmonary, and skin, body 
weight, and height during Screening. Symptom-directed physical and neurological examinations, 
including measurement of weight, may be performed at other time points. The ECOG 
performance status will be obtained by the Investigator or his/her designee by questioning the 
patient about their functional capabilities. 
7.4. 
Vital Signs 
Vital signs will be collected at Screening and prior to seribantumab administration at dosing visits 
and should include resting blood pressure, pulse, respiratory rate, and temperature. 
7.5. 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will include a description of the cardiac rate, rhythm, interval 
durations, and an overall impression. The corrected QT interval (QTc) should be calculated using 
the Fridericia method (QTcF). 
7.6. 
Collection of Quality of Life (EORTC QLQ-C30) Questionnaire 
The EORTC QLQ-C30 should begin to be implemented for newly enrolled patients when 
available. Only patients who have completed questionnaires at baseline (prior to dosing at C1W1) 
should complete subsequent questionnaires at the follow up periods.  


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7.7. 
Disease Evaluation 
Tumor response will be evaluated by the local radiologist according to the RECIST v1.1 
(Eisenhauer et al., 2009) to establish disease progression by computerized tomography (CT) or 
magnetic resonance imaging (MRI) of chest, abdomen, and pelvis at minimum, and in additional 
regions such as head, neck, or extremities, as appropriate if disease or symptoms are present. 
Patients enrolled with a history of central nervous system (CNS) metastases should additionally 
have a head CT/MRI scan with contrast performed at each tumor assessment. The same method of 
assessment must be used throughout the study. Please refer to image acquisition guidelines for the 
requirements for image collection and scanner qualification. Independent retrospective central 
reviews of all scans may be conducted in addition to review performed by the local radiologist. 
Investigators should choose target and non-target lesions in accordance with RECIST v1.1 
guidelines. Follow-up measurements and overall response should also be in accordance with these 
guidelines. To be assigned a status of confirmed PR or CR, changes in tumor measurements must 
be confirmed by repeated assessments that should be performed ≥ 28 days after the criteria for 
response are first met. 
Patients that discontinue study drug administration for reasons other than progressive disease 
including due to toxicities will continue to receive tumor assessments beginning at weeks 6, 12, 
18 and 24 with a ± 2-week window and subsequently every 8 weeks (± 2 weeks) through Week 
48, followed by every 12 weeks (± 2 weeks) beginning at Week 60 until disease progression and 
evaluated using the RECIST guidelines (version 1.1). Patients will be evaluated until disease 
progression, initiation of next anti-cancer therapy, death, or withdrawal of consent. 
7.7.1. 
Independent Central Review of Scans 
All treatment decisions will be made by the Investigator using local assessments. All images 
should be submitted to a central imaging facility and may be analyzed centrally by independent 
reviewers in accordance with the Imaging Charter. Please refer to the image acquisition guidelines 
for details on how images must be acquired and how scanners must be qualified. In addition, bone 
scans, x-rays, cytologic data (e.g., relevant cytology reports documenting malignant pleural 
effusions, bone marrow aspirations, cerebral spinal fluid, etc.), and relevant clinical information 
including medical photography will be forwarded to the review facility to aid in the tumor response 
assessment. Full details are listed in the Imaging Charter. 
NOTE: Data from the independent review of tumor measurements will not be sent back to 
investigators. 
8. 
LABORATORY PROCEDURES AND ASSESSMENTS 
8.1. 
Complete Blood Count 
The complete blood count will include the following: hemoglobin, hematocrit, platelet count, red 
blood cell, WBC with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils, 
and other cells).  


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8.2. 
Serum Chemistry 
Serum or plasma chemistry (non-fasting) will include electrolytes (sodium, potassium, calcium, 
chloride, bicarbonate, magnesium, and phosphate), blood urea nitrogen, serum creatinine, 
cholesterol, glucose, total and direct bilirubin, AST, ALT, alkaline phosphatase, lactate 
dehydrogenase, uric acid, total protein, and albumin.  
8.3. 
Urine or Serum Pregnancy Test 
A urine or serum pregnancy test will be obtained for all females of childbearing potential. Exempt 
female patients will include those who have undergone a bilateral oophorectomy or hysterectomy, 
or those who are menopausal (defined as absence of a menstrual cycle for at least 12 consecutive 
months). The reason for exemption should be recorded in the medical history. 
8.4. 
Pharmacokinetic Testing 
8.4.1. 
Seribantumab PK samples 
Plasma samples will be obtained from patients as outlined in Section 6.2. A laboratory manual will 
be provided with instructions for collecting, processing, and shipping these samples.  
8.5. 
Anti-seribantumab Immunogenicity 
Serum samples will be collected prior to dosing at the scheduled time points outlined in Section 6.2 
to determine the presence of an immunologic reaction to seribantumab (i.e., human anti-human 
antibodies; HAHA) and for any patients who experience a Grade 3 or higher infusion reaction 
during seribantumab administration. A laboratory manual will be provided with instructions for 
collecting, processing, and shipping these samples. 
8.6. 
Biomarker Samples 
Biomarker data will be explored from collected tissue (prior to treatment and at the EOT visit for 
those patients who undergo an optional biopsy). Additionally, for patients with tumors where 
collection of tumor markers is clinically relevant (i.e., pancreas cancer, breast cancer, etc.), tumor 
marker values will be collected in the eCRF if they are collected. Efficacy outcomes considered 
for pre-specified mechanistic biomarker analysis will include but not be limited to OS, PFS, and 
ORR. 
8.6.1. 
Archived Tumor Sample / Tumor Biopsy 
If archived tumor tissue is available, it should be submitted in lieu of obtaining a fresh tumor 
biopsy for central confirmation of NRG1 gene fusion status at the time of study enrollment for 
patients assigned to Cohort 1. For patients where adequate archival tissue is not available, tumor 
biopsy procedures performed on an outpatient basis and associated with a low risk of major 
complications, per the recent guidance from ASCO (Levit et al. 2019), may be considered by the 
treating physician, in accordance with site specific consent and standard procedures. Refer to the 
lab manual for additional details about tissue collection requirements.  
Central confirmation of NRG1 gene fusion status will be performed on a retrospective basis by 
Caris Life Sciences, utilizing their RNA-based NGS test, MI Transcriptome™. Patients are enrolled 


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and treated based on local NRG1 fusion testing results. Immediately following enrollment, 
Investigators and study staff will be required to obtain, process and ship the required archival 
tumor tissue for central confirmatory testing. A minimum of 55 patients with centrally confirmed 
NRG1 gene fusion positive tumors based on an RNA-based NGS testing method will be enrolled 
into Cohort 1.  
If central laboratory testing fails to confirm the presence of an NRG1 fusion, or insufficient tumor 
tissue is provided for central testing after enrollment, patients would be permitted to continue 
participating in the study at the Investigator’s discretion, as long as they do not meet criteria for 
treatment discontinuation in Section 1.1.  
Additional directions regarding processing and shipping archival or fresh tissue samples for central 
confirmatory testing (Cohort 1 only), or fresh tissue samples obtained at the time of tumor 
progression (optional biopsy), will be outlined in the laboratory manual. 
8.6.2. 
Whole Blood for cell free DNA 
Whole blood samples will be collected prior to dosing at time points described in Section 6.2. The 
samples will be used to conduct exploratory studies to further characterize and correlate possible 
biomarkers that may help to predict or evaluate response to seribantumab in NRG1 fusion positive 
advanced solid tumor patients. If there is remaining sample available after conducting these 
analyses, it will be used by the Sponsor for future analysis of biomarkers that may be 
mechanistically linked to seribantumab activity. At the time of informed consent, patients will be 
able to refuse storage of these remaining samples.  
Directions for processing and shipping the samples will be outlined in the laboratory manual. 
9. 
ADVERSE EVENTS AND REPORTING 
9.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and does not necessarily have to have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign, including 
abnormal laboratory findings, symptoms, or diseases temporally associated with the use of a 
medicinal product, whether or not considered related to the investigational product.  
All AEs, complaints, or symptoms that occur from the time that written informed consent has been 
obtained through the EOT Visit or 28 days after the last dose of seribantumab, whichever occurs 
later, are to be recorded on the appropriate eCRF (events that occur prior to first dose of study drug 
are considered medical history, events that occur on or after the first dose of study drug are 
considered TEAEs). Documentation must be supported by an entry in the patient’s source medical 
records. Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that 
are detected during the study, or are present at Screening and significantly worsen during the study, 
should be reported as AEs. Each AE is to be evaluated for duration, severity, and causal 
relationship with the investigational product, underlying disease or other factors.  
Worsening of a pre-existing medical condition, (i.e., diabetes, migraine headaches) should be 
considered an AE if there is either an increase in severity, frequency, or duration of the condition 


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or an association with significantly worse outcomes. Disease progression in and of itself is not 
considered an AE or SAE. Events attributed to disease progression should be reported as an SAE 
if they meet any of the SAE reporting criteria listed in Section 9.4. 
Interventions for pretreatment conditions (i.e., elective cosmetic surgery) or medical procedures 
that were planned prior to study enrollment are not considered AEs.  
For an AE leading to death, the outcome should be recorded with the event causing death. AEs 
that are ongoing at the end of study or time of death are to be noted as “continuing”. Classification 
of AEs is to be done by the Investigator in accordance with the NCI CTCAE Version 5.0.  
The Investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. Clinically 
significant abnormal laboratory values occurring during the clinical study will be followed until 
repeat tests return to normal, stabilize, or are no longer clinically significant. Any abnormal test 
that is determined to be an error does not require reporting as an AE.  
 
9.2. 
Grading and Intensity of Adverse Events 
Each AE will be graded according to the NCI CTCAE Version 5.0, which may be found at 
http://ctep.cancer.gov/reporting/ctc.html. For events not listed in the CTCAE, severity will be 
designated as mild, moderate, severe, or life-threatening, or fatal which correspond to Grades 1, 2, 
3, 4, and 5, respectively on the NCI CTCAE, with the following definitions: 
• Mild/Grade 1: an event not resulting in disability or incapacity and which resolves 
without intervention; 
• Moderate/Grade 2: an event not resulting in disability or incapacity, but which 
requires intervention; 
• Severe/Grade 3: an event resulting in temporary disability or incapacity and which 
requires intervention; 
• Life-threatening/Grade 4: an event in which the patient was at risk of death at the 
time of the event; 
• Fatal/Grade 5: an event that results in the death of the patient. 
9.3. 
Relationship to Study Drug  
The Investigator must attempt to determine if there exists reasonable possibility that an AE is 
related to the use of the study drug, according to the following guidelines: 
The Investigator will categorize each AE as to its potential relationship to study drug using the 
categories of Yes (causally related) and No (unrelated) as defined below. The assessment of the 
relationship of an AE to the administration of study drug is a clinical decision based on all available 
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No: 
The time course between the administration of study drug and the occurrence or worsening of the 
AE rules out a causal relationship, while another cause (e.g., concomitant medications, 
comorbidities, disease progression or complications, etc.) is suspected. 
Yes: 
The time course between the administration of study drug and the occurrence or worsening of the 
AE is consistent with a causal relationship and no other cause (e.g., concomitant medications, 
comorbidities, disease progression or complications, etc.) can be identified. 
The following factors should also be considered when the Investigator categorizes each AE: 
• Temporal sequence from treatment 
• Underlying, concomitant, or intercurrent diseases 
• Concomitant medications 
• Clinical and/or nonclinical data regarding whether a particular AE is a class effect 
• Pharmacology and PK for the study drug 
9.4. 
Serious Adverse Event Reporting  
A SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event 
While the term “severe” is often used to describe the intensity (severity) of an event, the event 
itself may be of relatively minor significance (such as a severe headache). This is not the same as 
“serious”, which is based on a patient/event outcome or action criteria usually associated with 
events that pose a risk to a patient’s life or functioning. 
All SAEs occurring from the time that written informed consent has been obtained through the 
EOT Follow-up Visit (within 28 days after the last dose of study drug administration) must be 
reported to Medpace Clinical Safety within 24 hours of the knowledge of the occurrence. All SAEs 
that the Investigator considers related to study drug occurring after the 28-day follow-up period 
must be reported to the Sponsor.   
Elective admissions to the hospital for procedures which were planned prior to entering the trial 
are not SAEs. However, if hospitalization is prolonged for any reason, an SAE form must be 
completed. 
An event attributed to disease progression must be reported as an SAE if it meets any of the SAE 
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after the last dose of study drug, the event term should be listed as “malignant neoplasm 
progression” with the outcome of death.   
To report the SAE, complete the SAE form electronically in the EDC system for the study. When 
the form is completed, Medpace Safety personnel will be notified electronically and will retrieve 
the form. If the event meets serious criteria and it is not possible to access the internet, send an 
email to Medpace Safety at medpace-safetynotification@medpace.com or call the Medpace SAE 
hotline (phone number listed below), and fax the completed paper SAE form to Medpace (fax 
number below) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available.   
Safety Contact Information 
 
Medpace Clinical Safety 
 
Medpace SAE Hotline 
 
 
Telephone: +1-800-730-5779, dial “3” or +1-513-579-9911, dial “3” 
 
 
Fax: +1-866-336-5320 or +1-513-579-0444 
 
 
Email: medpace-safetynotification@medpace.com 
The Investigator will be requested to supply detailed information regarding the event. SAEs must 
also be reported to the Institutional Review Board (IRB) and a copy of that report must be retained 
at the investigative site and filed in the Investigator Site File in accordance with the requirements 
of that institution.  
Although not considered an AE per se, the Sponsor must be notified of any patient or patient’s 
partner who becomes pregnant during a clinical study according to Section 9.6.  
9.5. 
Serious Adverse Event Follow-up 
For all SAEs occurring during the study, the Investigator must submit follow-up reports to the 
Sponsor regarding the status of the SAE and the patient’s subsequent course until the SAE has 
resolved, or until the condition stabilizes or is deemed chronic (in the case of persistent 
impairment), or the patient dies.  
AEs, excluding AEs due to disease progression, that lead to permanent discontinuation of the study 
drug will be followed until resolution to baseline, the condition stabilizes or is deemed chronic, 
withdrawal of consent, or death. 
9.6. 
Pregnancy Reporting 
If the patient or partner of a patient participating in the study becomes pregnant while on study, 
the Investigator should report the pregnancy to the Sponsor’s clinical safety representative within 
24 hours of being notified. The Sponsor’s safety representative will then forward the Pregnancy 
form to the Investigator for completion as outlined in the Study Manual.  
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. The investigator should inform the 
patient of the risks of continuing with the pregnancy and the possible effects on the fetus. 
Monitoring of the patient should continue until conclusion of the pregnancy. At the completion of 
the pregnancy, the investigator will document the outcome of the pregnancy. The Sponsor will 
collect information on the outcome of the pregnancy. If the outcome of the pregnancy meets the 


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criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly), the investigator should follow the 
procedures for reporting an SAE. 
In the event of a pregnancy occurring in the partner of a male patient participating in the study, the 
pregnant partner should be requested to report the pregnancy to the investigator, who in turn should 
report it to the Sponsor. The partner should also be informed of the risks of continuing with the 
pregnancy, and the possible effects on the fetus. 
10. 
STATISTICAL METHODS 
A full Statistical Analysis Plan (SAP) will provide detailed methodology for summary and 
statistical analyses of the data collected in this study. 
10.1. 
Study Endpoints  
Primary 
• Objective response rate as assessed by independent radiologic review according to 
RECIST v1.1  
Secondary 
• Duration of Response by independent radiologic review 
• ORR and DoR by investigator assessment 
• Progression-free Survival by independent radiologic review and investigator 
assessment 
• Overall Survival 
• Clinical Benefit Rate (CR, PR, SD ≥ 24 weeks) by independent radiologic review and 
investigator assessment 
• Safety of seribantumab  
Exploratory 
• PK parameters following weekly, Q2W, and Q3W dosing 
• To explore the association between mechanistically linked biomarkers and clinical 
outcomes 
• Changes from baseline in quality of life, as measured by the EORTC QLQ-C30 
10.2. 
Analysis Populations 
All efficacy analyses will be performed by cohort. Analyses for the Cohort 1 primary efficacy 
analysis population will be intended to support a potential registration. Analyses for Cohort 2 and 
Cohort 3 efficacy analysis population will be exploratory. 


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10.2.1. 
Cohort 1 Primary Efficacy Analysis Population 
The population will be used for the primary analysis of efficacy for registration purpose. It will 
include Cohort 1 patients enrolled in this study who meet all criteria listed below: 
• centrally confirmed NRG1 gene fusion  
• received at least one dose of seribantumab at 3,000mg QW dosing regimen (starting 
with Protocol Version 3.0 and later). Patients in the safety-run in (enrolled under 
Protocol Version 2.0 or earlier) will be included if they received seribantumab at 
3,000 mg QW beyond induction/re-induction 
• received at least one prior standard therapy in the locally advanced or metastatic setting  
• at least one measurable lesion at baseline as assessed per RECIST v1.1 based on 
independent central reviews 
10.2.2. 
Cohort 2 and Cohort 3 Efficacy Analysis Population 
These populations will be used for exploratory efficacy analysis for each cohort, respectively. All 
patients enrolled in each cohort who received at least one dose of seribantumab and had at least 
one measurable lesion at baseline assessed per RECIST 1.1 based on investigator assessments will 
be included in the analysis. With the release of Protocol Version 5.0, Cohort 3 was closed to 
enrollment. Under Protocol Version 5.0/Protocol Administrative Letter 8.0, Cohort 2 was closed 
to enrollment. 
10.2.3. 
Safety Analysis Population 
The safety analysis population includes patients receiving at least one dose of seribantumab 
therapy across any of the three treatment cohorts (e.g., Cohort 1, 2, and 3) and across any of the 
seribantumab dosing regimens. The safety population will be used for the overall safety analysis. 
10.3. 
Determination of Sample Size 
At least 55 patients with centrally confirmed NRG1 gene fusion positive cancer will be enrolled 
in the Cohort 1 primary analysis population as defined in Section 10.2.1. This sample size will 
provide approximately 90% power for the lower bound of the 95% CI to exclude 20% assuming 
the ORR is 40% with seribantumab treatment. 
With the release of Protocol Version 5.0, Cohort 3 was closed to enrollment. Under Protocol 
Version 5.0/Protocol Administrative Letter 8.0, Cohort 2 was closed to enrollment.  
10.4. 
Statistical Considerations 
Categorical variables will be summarized by frequency distributions (number and percentages of 
patients) and continuous variables will be summarized by descriptive statistics (mean, standard 
deviation, median, minimum, maximum).  
Disposition of patients will be summarized, including those screened, treated, and discontinued. 
Reason for discontinuation will be summarized. Demographic and baseline characteristics will be 
summarized. Medical history and prior medications will be tabulated. 


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Due to the ongoing COVID-19 pandemic, additional analyses (e.g., sensitivity analysis) will be 
performed to assess the impact of COVID-19 on clinical study data. Documentation for reasons 
for failing to obtain a protocol specified assessment and/or alternative procedures used to collect 
safety and efficacy data will be required. Further details regarding these planned analyses will be 
described in the Statistical Analysis Plan. 
Data collected from patients enrolled in Australia (MoST/CRESTONE subset) will contribute to 
a separate subgroup analysis in addition to the analyses described below.  Further details on the 
MoST/CRESTONE subset can be found in Appendix B. 
10.5. 
Efficacy Analysis 
10.5.1. 
Primary Efficacy Endpoint for Cohort 1 
Objective response rate (ORR) is the primary efficacy endpoint and will be analyzed based on the 
Cohort 1 primary efficacy analysis population.  
ORR is determined by RECIST v1.1 (confirmed CR+PR) and will be assessed by independent 
radiographic review. To be assigned a status of confirmed PR or CR, changes in tumor 
measurements must be confirmed by repeated assessments at least 4 weeks (28 days) after the 
criteria for response are first met. Tumor assessments after the initiation of new anticancer therapy 
should not be used to derive the ORR. The point estimate of the ORR along with the 2-sided 95% 
exact Clopper-Pearson CI will be presented.   
ORR will also be assessed by subgroups defined by the predefined factors listed in Section 10.8. 
10.5.2. 
Secondary Efficacy Endpoints for Cohort 1  
Secondary efficacy endpoints will be analyzed based on the Cohort 1 primary efficacy analysis 
population.  
Objective Response Rate (ORR): ORR based on the investigator assessments will be analyzed 
similarly as described for the primary efficacy analysis (Section 10.5). This is considered a 
sensitivity analysis.  
Duration of Response (DoR): Duration of response is based on independent radiographic review. 
For patients who achieve a confirmed CR or PR, DoR is defined as the number of months from 
the start date of CR or PR (whichever response status is observed first and subsequently 
confirmed), to the date of first documented radiographical progression of disease using 
RECIST v1.1, or death from any cause, whichever comes first. DoR will be calculated for patients 
who are responders, i.e., those who achieve a confirmed CR or PR. The initiation of new anticancer 
therapy will mean the end of the response for the calculation of DoR. Responders who have not 
experienced disease progression, death, or new anticancer therapy at the time of the analysis will 
be censored at the date of the last tumor assessment. If no tumor assessments are available after 
the date of the first occurrence of response, the patient will be censored on the date of the first 
occurrence of the response. DoR will be estimated using the Kaplan-Meier method. The median 
DoR and the proportion of responders with durable responses at 6 months or 12 months will be 
estimated along with 95% CI. 


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DoR by investigators: DoR based on the investigator assessments will be analyzed similarly as 
described for the respective endpoint based on the independent radiographic reviews. This is 
considered a sensitivity analysis. 
Progression-free Survival (PFS): PFS is defined as the time from the date of seribantumab 
treatment initiation (Dose 1) to the first documented radiographical progression of disease using 
RECIST v1.1, or death from any cause, whichever comes first. The Kaplan-Meier method will be 
used to estimate PFS. In addition to the Kaplan-Meier plot of PFS, the median PFS time, 6-month, 
and 12-month PFS rates will be estimated along with 95% CI. PFS analysis will be performed 
separately based on central radiographic review and investigator assessments. Additional 
sensitivity analysis of PFS may be performed using different censoring rules. These sensitivity 
analyses will be detailed in the SAP. 
Overall Survival: OS is defined as the time from the date of treatment seribantumab treatment 
initiation (Dose 1) to the date of death from any cause. The Kaplan-Meier method will be used to 
estimate OS. In addition to the Kaplan-Meier plot of OS, the median OS time, 6-month, and 
12-month survival rates will be estimated, along with 95% CI. 
Clinical Benefit Rate (CBR): Clinical benefit rate is defined as the proportion of patients who 
achieve PR, CR, or SD which is maintained through at least 24 weeks per RECIST v1.1. Tumor 
assessments after the initiation of new anticancer therapy should not be used to derive the CBR. 
Patients with no baseline disease assessment or no evaluable post-baseline disease assessments 
(i.e., NE) or with ongoing SD but short of 24 weeks at the time of analysis will be considered as 
not having attained clinical benefit and included in the denominator in the calculation of the CBR. 
CBR will be summarized similarly as the ORR with both point estimate and 95% Clopper-Pearson 
CI provided. CBR analysis will be performed separately based on central radiographic review and 
investigator assessments.  
Secondary efficacy endpoints will also be assessed by subgroups defined by the predefined factors 
listed in Section 10.8. 
10.5.3. 
Exploratory Efficacy Analysis for Cohorts 2 and 3 
Efficacy analyses of the primary efficacy endpoint and secondary efficacy endpoints for Cohorts 
2 and 3 will be performed separately using the same methods described above. For the ORR, DoR, 
CBR, and PFS endpoints, investigator assessments will be used.   
10.6. 
Safety Analysis 
Safety analyses (AE and laboratory analyses) will be performed using the safety analysis 
population. Adverse events will be coded using the latest Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. Severity will be graded according to the NCI CTCAE 
Version 5.0.  
Treatment-emergent adverse events (TEAEs), TEAE grade 3 and higher, TEAE-related, SAEs, 
and discontinuation due to AE will be reported by frequency and percent summaries. Adverse 
events will be summarized by System Organ Class and preferred term. All AE data will be listed 
by patient. 
Treatment-emergent adverse events are defined as any event that occurred after the first dose of 
study drug and was not present prior to study drug administration or worsened in severity after 


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study drug administration. Treatment-emergent adverse events will be collected through the end 
of treatment visit.   
Laboratory, vital signs, and ECG data will be summarized according to parameter type. 
A SRC has been established to assess the safety, tolerability, and PK exposure (if available) of 
seribantumab. Refer to Section 3.2 and the SRC Charter for further details.  
10.7. 
Interim Analysis  
A pre-planned interim analysis based on investigator assessed ORR will be conducted after 
20 patients are enrolled and treated in the Cohort 1 and followed for at least one post-baseline 
tumor assessment with sufficient follow-up (at least one post-baseline tumor assessment [i.e., 
6 weeks ± 2 weeks]). Should four or more objective responses be observed at the time of the 
interim analysis, enrollment to Cohort 1 for the primary analysis population will continue until a 
minimum of 55 patients with centrally confirmed NRG1 gene fusion positive cancer. The futility 
analysis will be considered non-binding as factors other than ORR may be factored in (such as 
depth of response, duration of response, tumor type, and fusion partner).  
An expanded SRC will be established to evaluate the interim futility analysis in addition to safety 
as detailed in Section 3.3. 
10.8. 
Covariates and Subgroups 
Predefined covariates and subgroups include:  
• Age, age groups (< 65, ≥ 65 years) 
• Gender 
• Geographic region (US vs non-US) 
• Tumor type 
• Fusion partner  
• Number and/or type of ERBB-directed therapy in cohort 2 
− 1 versus >1 
− TKI versus monoclonal antibody       
Efficacy and safety analyses based on the subgroups may be performed as appropriate. 
10.9. 
Pharmacokinetic Analysis 
Plasma concentrations by patient, cycle, day, and time will be obtained and documented at various 
time points during treatment with seribantumab (refer to Section 6.2). 
10.10. 
Exploratory Analysis 
Biomarker analyses will include summary of the biomarker of interest based on the biomarker 
analysis population. Additional analyses correlating biomarkers with efficacy and safety endpoints 
may be performed.  


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Changes from baseline in quality of life, as measured by the EORTC Quality of Life 
Questionnaire-Core 30 (QLQ‑C30) will be summarized and plotted by visit. 
11. 
STUDY ADMINISTRATION 
11.1. 
Pre-Study Documentation 
Prior to initiating the study, the investigator will provide the Sponsor or designee with the 
following documents: 
• A signed FDA Form 1572 or equivalent document 
• A current (i.e., updated no more than 24 months prior) curriculum vitae for the 
Investigator and each sub-investigator listed on the FDA Form 1572 or equivalent 
document that is signed and dated.  
• A copy of the current medical license for the Investigator and each sub-investigator. 
• A letter from the IRB/Ethics Committee (EC) stipulating approval of the protocol, the 
informed consent document, and any other material provided to potential study 
participants with information about the study (e.g., advertisements) 
• The current IRB/EC membership list for the reviewing IRB/EC, or the multiple project 
assurance number from the U.S. Federal Wide Assurance program where applicable 
• A signed Investigator Protocol Agreement 
• A completed financial disclosure form for the Investigator and all sub-investigators 
• A current laboratory certification for the local reference laboratory  
11.2. 
Source Documents 
The investigator will maintain records separate from the case report forms in the form of clinic 
charts, medical records, original laboratory, radiology and pathology reports, pharmacy records, 
etc. The investigator will document in the clinic chart or medical record the date on which the 
patient signed informed consent prior to the patient’s participation in the study. Source documents 
must completely reflect the nature and extent of the patient’s medical care and must be available 
for source document verification against entries in the case report forms when the Sponsor’s 
monitor visits the investigational site. Source documents regarding procedures such as scans, and 
laboratory evaluations performed as part of the standard of care prior to enrollment in the study 
can be used to fulfill certain screening and baseline assessments. All information obtained from 
source documents will be kept in strict confidentiality. Source data sent to the Sponsor or the 
Sponsor’s representative as supporting documentation for SAEs will be de-identified to preserve 
confidentiality. 
11.3. 
Study Ethics 
The study will be performed according to the principles of the Declaration of Helsinki, the 
International Conference on Harmonization Guidance on Good Clinical Practice and the 


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requirements of the US FDA and/or local regulatory authorities regarding the conduct of human 
clinical studies. 
11.4. 
Patient Informed Consent 
No study related procedures will be performed until a patient or a patient’s legal representative has 
given written informed consent. The Sponsor will provide to the investigator a sample informed 
consent document in addition to a sample pre-screening consent that includes all the requirements 
for informed consent according to the ICH Good Clinical Practice (GCP), U.S. FDA guidelines 
(21 CFR 50) and/or local regulatory guidelines. However, it is up to the investigator to provide a 
final informed consent that may include additional elements required by the investigator’s 
institution. Changes to the Sponsor’s sample informed consent should receive approval from the 
Sponsor or the Sponsor’s representative prior to use in the study. The informed consent document 
must clearly describe the potential risks and benefits of the study, and each prospective participant 
must be given adequate time to discuss the study with the Investigator or site staff and to decide 
whether or not to participate. Each patient who agrees to participate in the study and who signs the 
informed consent form will be given a copy of the signed, dated, and witnessed document. The 
provision of informed consent must be documented in the medical record. 
11.5. 
Investigational Review Board Approval 
The study will not be initiated until there is approval of the protocol, informed consent document 
and any other material used to inform the patient about the nature of the study by the local IRB or 
EC. The IRB or EC should be duly constituted according to local regulatory requirements. 
Approval must be in the form of a letter signed by the Chairperson of the IRB/EC or the 
Chairperson’s designee, must be on IRB/EC stationary and must include the protocol by name 
and/or by designated number. If an investigator is a member of the IRB/EC, the approval letter 
must stipulate that the Investigator did not participate in the final vote, although the investigator 
may participate in the discussion of the study. The investigator will also inform the IRB/EC of any 
SAE that the Sponsor reports to regulatory authorities, will report on the progress of the study at 
least yearly (or more frequently if required by local regulation or guidance) and will provide to the 
IRB/EC a final summary of the results of the study at the conclusion of the study. 
11.6. 
Monitoring 
Overall study monitoring will be conducted through a combination of on-site visit and centralized 
monitoring. A clinical monitor will make regularly scheduled trips to the investigational site to 
review the progress of the study, study data and site processes. At each visit, the monitor will 
review various aspects of the study including, but not limited to: screening and enrollment logs; 
compliance with the protocol and study manuals and with the principles of Good Clinical Practice; 
completion of case report forms; source data verification; study drug accountability and storage; 
facilities and staff. 
The actual frequency of monitoring trips will depend on the enrollment rate and performance at 
each site. The investigator will allow Elevation Oncology, and/or its representatives or designees, 
access to all pertinent medical records, as required by federal regulations, in order to allow for the 
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During scheduled monitoring visits, the investigator and the investigational site staff must be 
available to meet with the study monitor in order to discuss the progress of the study, make 
necessary corrections to case report form entries, respond to data clarification requests and respond 
to any other study-related inquiries of the monitor. In addition to on-site monitoring visits, the 
Sponsor and/or representatives will also be routinely reviewing data. Any queries identified 
through this review will be managed within the systems established for query resolution and 
tracking. Inquiries related to study conduct which require further information or action will be 
discussed within the study team for appropriate and documented escalation plans. It is expected 
that response to data clarification requests and other study-related inquiries will occur throughout 
the course of the study through regular communication with the site monitor, the Sponsor or 
representatives, and review/entry of data into the electronic study database. 
At any time during the course of the study, representatives of the FDA and/or other regulatory 
agencies may review the conduct or results of the study at the investigational site. The investigator 
must promptly inform Elevation Oncology of any audit requests by health authorities and will 
provide Elevation Oncology with the results of any such audits and with copies of any regulatory 
documents related to such audits. 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use 
personal identifiable health information may be required from each patient before commencement 
of research activities. This authorization document must clearly specify what parties will have 
access to a patient’s personal health information, for what purpose and for what duration. 
11.7. 
Confidentiality 
It is the responsibility of the investigator to ensure that the confidentiality of all patients 
participating in the study and all of their medical information is maintained. Case report forms, 
and other documents submitted to the Sponsor must never contain the name of a study patient. All 
patients in the study will be identified by a unique identifier which will be used on all eCRFs and 
any other material submitted to the Sponsor. All case report forms, and any identifying information 
must be kept in a secure location with access limited to the study staff directly participating in the 
study. 
11.7.1. 
Confidentiality of Biomarker Samples 
Blood and tissue samples collected as part of the biomarker analysis will be identified only by a 
number assigned to the patient at the study site; this number will be used in lieu of the patient’s 
name in order to protect the patient’s identity. The samples will be stored at a facility designated 
by the Sponsor. Other than the patient’s unique identifying number, no additional patient 
information will be stored with these samples. Samples will be kept until they are used completely 
for the specified biomarker analyses, or, in the event there is remaining tissue or blood sample 
available, such specimens will be stored indefinitely. At the time of informed consent, patients will 
be able to refuse indefinite storage of these remaining samples. If indefinite storage is refused, any 
remaining samples will be destroyed following the completion of the study. Similarly, patients 
may withdraw approval at any time by submitting a written request to the study site investigator. 
Upon receipt of this withdraw of consent, no further analyses will be completed, and the patient’s 
remaining samples will be destroyed, however, data already collected will not be removed from 
the study dataset.  


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Any samples that a patient consents to be stored indefinitely may be used by the Sponsor for future 
oncological translational and companion diagnostic work, as directed by the findings of the 
exploratory biomarker evaluation and the results of the initial tissue biomarker evaluation. The 
results from these exploratory analyses may not necessarily be shared with the investigators or the 
participating patients. 
11.8. 
Protocol Amendments 
The protocol will only be amended with the consent of the Sponsor and the IRB/EC. Changes to 
the protocol must be in the form of a written amendment; changes other than those of a simple 
administrative nature (e.g., a new telephone number for a medical monitor) must be submitted by 
the investigator to the local IRB/EC and such amendments will only be implemented after approval 
of the requisite IRB/EC. All amendments will also be submitted to the FDA and/or local regulatory 
authorities by the Sponsor.   
Protocol changes to eliminate an immediate hazard to a study patient may be implemented by the 
investigator immediately. The investigator must then immediately inform their IRB/EC and the 
Sponsor will immediately notify applicable regulatory authorities. 
11.9. 
Records Retention 
The investigator will retain the records of the clinical study (including, but not necessarily limited 
to, eCRFs, source documents, informed consent forms, drug accountability records, IRB/EC 
correspondence, Sponsor correspondence, etc.) for 2 years following the date that the last 
marketing application for the study drug is approved (or per local regulatory requirements), or if 
no marketing application is filed, or if such an application is not approved, for 2 years after the 
formal discontinuation of clinical development of the study drug. The Sponsor or designee will 
notify investigators when retention of study records is no longer required. Study records must be 
stored in a safe and secure location permitting timely retrieval, if necessary. 
Study records must be retained as per the GCP guidelines and local regulatory requirements, 
including, but not limited to, case report forms, signed informed consents, correspondence with 
the IRB/EC, study drug dispensing and inventory records, source documents (clinic charts, medical 
records, laboratory results, radiographic reports) and screening/enrollment logs. 
Should the investigator relocate or retire the responsibility for maintaining the study records may 
be transferred to another investigator. The Sponsor must be notified of the identity of the individual 
assuming responsibility for maintaining the study records and the location of their storage. If no 
other individual at the site is willing to assume this responsibility, the Sponsor will assume 
responsibility for maintaining the study records. 
11.10. 
Study Termination 
The Sponsor reserves the right to terminate the study at any site and at any time. Reasons for study 
termination may include, but are not limited to, the following: 
• Investigator non-compliance with the protocol, GCP, or regulatory requirements 
• Insufficient enrollment 
• Safety concerns 


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• Drug supply or manufacturing issues 
• The Sponsor’s decision to modify or discontinue the development of seribantumab 
• A request to discontinue the study by the FDA and/or other regulatory authorities 
The Sponsor will promptly inform all investigators and the FDA and/or other regulatory authorities 
if the study is suspended or terminated for any reason. The investigator will promptly notify the 
IRB/EC if the study is suspended or terminated. 


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12. 
INVESTIGATOR SIGNATURE PAGE 
I have read this protocol and agree that it contains all necessary details for carrying out the study 
as described. I will conduct this study as outlined herein, including all statements regarding 
confidentiality. I will make a reasonable effort to complete the study within the time designated. I 
will provide copies of the protocol and access to all information furnished by the Sponsor to study 
personnel under my supervision. I will discuss this material with them to ensure that they are fully 
informed about the drug and the study. I will identify study personnel conducting study specific 
procedures and appropriately document their training and/or delegated responsibilities. I 
understand that the study may be terminated, or enrollment suspended at any time by the Sponsor, 
with or without cause, or by me if it becomes necessary to protect the best interests of the patients 
in the study. 
I agree to conduct this study in full accordance with all applicable regulations and Good Clinical 
Practice (GCP). 
 
 
_________________________________ 
 
 
 
_______________________ 
Signature of Investigator 
 
 
 
 
 
Date 
 
________________________________ 
 
 
 
 
 
Print Name of Investigator 
 
 
_______________________________ 
 
 
 
_______________________ 
Signature of Sponsor  
 
 
 
 
 
Date 
Valerie Jansen, MD, PhD 
Chief Medical Officer 
Elevation Oncology, Inc. 
888 Seventh Avenue, 12th Floor 
New York, NY 10106 


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13. 
REFERENCES 
Cheema PK, Doherty M, Tsao MS. A Case of Invasive Mucinous Pulmonary Adenocarcinoma 
with a CD74-NRG1 Fusion Protein Targeted with Afatinib. J Thorac Oncol. 2017 
Dec;12(12):e200-e202. 
Data on file. SRC Decision Memo:  Induction Regimen 1.  Elevation Oncology. Feb 2021. 
Data on file.  PK Simulation Report.  Elevation Oncology.  Feb. 2021. 
Data on file. SRC Decision Memo:  Induction Regimen 2.  Elevation Oncology. Apr. 2021. 
Dimou A, Camidge DR. Detection of NRG1 fusions in solid tumors: Rare gold? Clin Cancer 
Res. 2019 Aug 15;25(16):4865-4867.  
Drilon A, Somwar R, Mangatt BP, Edgren H, Desmeules P, Ruusulehto A, et al. Response to 
ErbB3-Directed Targeted Therapy in NRG1-Rearranged Cancers. Cancer Discov 2018;8(6):686-
95.  
Duruisseaux M, Liu SV, Han JY, Gounant V, et al., NRG1 fusion-positive lung cancers: 
Clinicopathologic profile and treatment outcomes from a global multicenter registry published 
online before print May 26, 2019, ASCO 2019. 
Eisenhauer, E. a, Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., … Verweij, J. 
(2009). New response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). European Journal of Cancer (Oxford, England: 1990), 45(2), 228–47.  
Fernandez-Cuesta L, Plenker D, Osada H, Sun R, Menon R, Leenders F, et al. CD74-NRG1 
fusions in lung adenocarcinoma. Cancer Discov 2014;4(4):415-22. 
Gay ND, Wang Y, Beadling C, Warrick A, Neff T, Corless CL, Tolba K. Durable Response to 
Afatinib in Lung Adenocarcinoma Harboring NRG1 Gene Fusions. J Thorac Oncol. 2017 
Aug;12(8):e107-e110. 
Heining C, Horak P, Uhrig S, Codo PL, Klink B, Hutter B, Fröhlich M, Bonekamp D, Richter D, 
Steiger K, Penzel R, Endris V, Ehrenberg KR, Frank S, Kleinheinz K, Toprak UH, Schlesner M, 
Mandal R, Schulz L, Lambertz H, Fetscher S, Bitzer M, Malek NP, Horger M, Giese NA, 
Strobel O, Hackert T, Springfeld C, Feuerbach L, Bergmann F, Schröck E, von Kalle C, 
Weichert W, Scholl C, Ball CR, Stenzinger A, Brors B, Fröhling S2, Glimm H. NRG1 Fusions 
in KRAS Wild-Type Pancreatic Cancer. Cancer Discov. 2018 Sep;8(9):1087-1095. 
Huang HE, Chin SF, Ginestier C, Bardou VJ, Adélaïde J, Iyer NG, Garcia MJ, Pole JC, Callagy 
GM, Hewitt SM, Gullick WJ, Jacquemier J, Caldas C, Chaffanet M, Birnbaum D, Edwards PA. 
A recurrent chromosome breakpoint in breast cancer at the NRG1/neuregulin 1/heregulin gene. 
Cancer Res. 2004 Oct 1;64(19):6840-4. 
Jones MR, Lim H, Shen Y, Pleasance E, Ch'ng C, Reisle C, Leelakumari S, Zhao C, Yip S, Ho J, 
Zhong E, Ng T, Ionescu D, Schaeffer DF, Mungall AJ, Mungall KL, Zhao Y, Moore RA, Ma Y, 
Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic 
cancer. Ann Oncol. 2017 Dec 1;28(12):3092-3097. 
Jones MR, Williamson LM, Topham JT, et al. NRG1 Gene Fusions Are Recurrent, Clinically 
Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma. Clin 
Cancer Res. 2019;25:4674-4681. 


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Jonna S, Feldman RA, Swensen J, Gatalica Z, Korn WM, Borghaei H, et al. Detection of NRG1 
Gene Fusions in Solid Tumors. Clin Cancer Res 2019. 
Ke, H., Shen, W., Hu, A., Ou, Q., & Lu, S. Distribution of NRG1 Gene Fusions in a Large 
Population of Chinese Patients with NSCLC. Journal Thorac Oncol 2019 Dec;14(12):e263-e266 
Kim, H. S., Han, J. Y., Shin, D. H., Lim, K. Y., Lee, G. K., Kim, J. Y., Jacob, W., Ceppi, M., 
Weisser, M., & James, I. (2018). EGFR and HER3 signaling blockade in invasive mucinous lung 
adenocarcinoma harboring an NRG1 fusion. Lung Cancer. 2018 Oct;124:71-75 
McCoach CE, Le AT, Gowan K, Jones K, Schubert L, Doak A, Estrada-Bernal A, Davies KD, 
Merrick DT, Bunn PA Jr, Purcell WT, Dziadziuszko R, Varella-Garcia M, Aisner DL, Camidge 
DR, Doebele RC. Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non-
small Cell Lung Cancer. Clin Cancer Res. 2018 Jul 15;24(14):3334-3347. 
Nakaoku T, Tsuta K, Ichikawa H, Shiraishi K, Sakamoto H, Enari M, et al. Druggable oncogene 
fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res 2014;20(12):3087-93. 
NCR001-01 PK report, Data on File. Feb 2020. 
Odinstov I, Kurth RI, Lui AJW, et al. Preclinical activity of seribantumab in gastrointestinal 
cancers with NRG1 fusions. Presented at: AACR Annual Meeting 2021a; April 10-15, 2021; 
Virtual. Abstract 935. 
Odintsov I, Lui A, Sisso W, et al.  The anti-HER3 monoclonal antibody seribantumab effectively 
inhibits growth of patient-derived and isogenic cell line and xenograft models with oncogenic 
NRG1 fusions. Clin Cancer Res. 2021b.  
Roskoski R Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 
2014 Jan; 79:34-74. 
Schaefer G, Fitzpatrick VD, Sliwkowski MX. Gamma-heregulin: a novel heregulin isoform that 
is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175. Oncogene. 
1997 Sep 18;15(12):1385-94. 
Schoeberl B, Kudla A, Masson K, Kalra A, Curley M, Finn G, Pace E, Harms B, Kim J, Kearns 
J, Fulgham A, Burenkova O, Grantcharova V, Yarar D, Paragas V, Fitzgerald J, Wainszelbaum 
M, West K, Mathews S, Nering R, Adiwijaya B, Garcia G, Kubasek B, Moyo V, Czibere A, 
Nielsen UB, MacBeath G. Systems biology driving drug development: from design to the 
clinical testing of the anti-ErbB3 antibody seribantumab (MM-121). NPJ Syst Biol Appl. 2017 
Jan 5; 3:16034. 
Schram AM, O’Reilly EM, Somwar R, Benayed R, Shameem S, Chauhan T, Torrisi J, Ford J, 
Maussang D, Wasserman E, Ladanyi M, Hyman DM, Sirulnik LA, Drilon A. Clinical proof of 
concept for MCLA-128, a bispecific HER2/3 antibody therapy, in NRG1 fusion-positive cancers 
[abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular 
Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol 
Cancer Ther 2019;18(12 Suppl):Abstract nr PR02. 
Shin DH, Jo JY, Han JY. Dual Targeting of ERBB2/ErbB3 for the Treatment of SLC3A2-
NRG1-Mediated Lung Cancer. Mol Cancer Ther. 2018 Sep;17(9):2024-2033. 


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Trombetta, D, Rossi, A, Fabrizio, FP, Sparaneo, A, Graziano, P, Fazio, VM, & Muscarella, LA. 
NRG1-ErbB Lost in Translation: A New Paradigm for Lung Cancer? Current Medicinal 
Chemistry 2017:24(38):4213–4228.  
Weinberg BA et al., NRG1 fusion-positive gastrointestinal tumours: Afatinib as a novel potential 
treatment option Poster number 291 ESMO 21st World Congress on Gastrointestinal Cancer 
Barcelona, Spain 3-6 July 2019. 


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APPENDIX A: 
PREVIOUS CRESTONE DOSING SCHEDULES 
Prior to IRB/IEC approval for Protocol Version 4.0, treatment for all eligible patients consisted of 
initial Induction (once weekly dosing x 4 weeks) followed by Q2W maintenance dosing with 
seribantumab. (Note: Despite the provision to switch to Q3W dosing under Protocol Version 2.0, 
no patients enrolled to study ever received Q3W seribantumab treatment.)  
The pharmacokinetics of seribantumab were quantified by the former Sponsor across multiple 
phase 1 and 2 studies (n=499) using mixed-effect modeling. The majority of these studies utilized 
the 40/20 mg/kg weekly dosing regimen in combination with other anticancer therapies. Overall, 
the final best-fit model was a two-compartment model with association between (sex, weight) and 
central clearance. The terminal half-life was determined to be approximately 100 hours and 
achievement of steady state occurred after 3-4 repeat doses, as had been described from the initial 
phase 1 monotherapy experience in 43 patients. 
In addition, the former Sponsor conducted dose simulation studies based upon population PK to 
assess weight-based versus fixed dosing. These dose simulation studies confirmed similar 
exposure (Cmax) would be expected between the 40 mg/kg and 3,000 mg fixed-dose, as well as the 
20 mg/kg and a 1,500 mg fixed-dose in average weight patients. The estimated mean Cmax levels 
were approximately 1000 mg/L and the estimated steady state (Cavg) levels were approximately 
600 mg/L with the 40/20 mg/kg weekly dosing regimen. Notably, in a combination study (Study 
MM-121-01-101) with weekly administration of seribantumab and daily erlotinib in an EGFR 
wild-type NSCLC population (e.g., a non-NRG1 fusion population), the achievement of 
seribantumab average concentrations ≥ 500 mg/L appeared to be associated with improved 
efficacy. 
Given that the NRG1 fusion patients to be enrolled in the CRESTONE study are expected to be 
heavily pretreated, metastatic patients who have exhausted standard treatment options, the initial 
dosing regimen was designed to deliver rapid steady state levels with a 4-week induction phase 
consisting of once weekly dosing. This induction treatment course was to be followed by a 
consolidation (3,000mg IV Q2W x 6 doses) and maintenance (3,000 mg IV Q3W) phase of dosing, 
in the initially approved Protocol Version 2.0. These subsequent dosing phases were expected to 
be well tolerated, and they were based on previously defined thresholds (e.g., > 100 mg/L 
minimum and ≥ 500 mg/L average serum concentrations), which were established in non-NRG1 
fusion positive cancer models and patients, which may not be relevant to tumors harboring 
oncogenic NRG1 gene fusions.  
Further PK modeling (Data on file, Feb 2020; NCR001-01 PK Report) was performed prior to the 
initiation of the CRESTONE study to support the initial planned weekly induction dosing regimens 
(e.g., Induction Regimen 1: 3,000 mg IV week 1 followed by 2,000 mg IV weeks 2, 3 and 4; and 
Induction Regimen 2: 3,000 mg IV once weekly x 4 doses). The results from this initial PK 
modeling (Data on file, Feb 2020; NCR001-01 PK Report) indicated the range of predicted Cmax 
and Cavg values with Induction Regimen 1 would be comparable to levels observed in patients 
treated with the 40/20 mg/kg weekly dosing regimen from the initial monotherapy study 
(MM-121-01-100 study), while Induction Regimen 2 would increase exposure during the initial 
4 weeks by approximately 60% compared to the previously studied 40/20 weekly regimen. 


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Prior Induction Regimens 
Induction Regimen 1: Seribantumab 3,000 mg 1-h IV as a loading dose at the C1W1 visit, 
followed by 2,000 mg 1-h IV once weekly at C1W2, C1W3 and C1W4.There were no DLTs 
observed with Induction Regimen 1. Upon review and recommendation by the SRC, the next 
6 patients enrolled and initiated treatment with Induction Regimen 2.  
Induction Regimen 2: Seribantumab 3,000 mg 1-h IV once weekly at the C1W1, C1W2, C1W3 
and C1W4 visits. There were no DLTs observed in the first 6 patients treated with Induction 
Regimen 2. Upon review and recommendation by the SRC, all subsequently enrolled patients 
treated under Protocol Version 2.0 initiated treatment with Induction Regimen 2. 
With IRB/IEC approval of Protocol Version 3.0, subsequently enrolled patients initiated treatment 
with the 12-Week Target Induction Regimen. 
12-Week Target Induction Regimen:  Seribantumab 3,000 mg 1-h IV once weekly for a total of 
12 weeks (C1W1, C1W2, C1W3, C1W4, C2W1, C2W2, C2W3, C2W4, C3W1, C3W2, C3W3, 
and C3W4 visits). Notably, patients enrolled to Induction Regimen 2, who were continuing weekly 
induction phase dosing at the time of IRB approval for Protocol Version 3.0, were switched to the 
extended 12-Week Target Induction Regimen.  
Q2 Week Dosing:  
Prior to IRB/IEC approval of Protocol Version 4.0, all patients who completed induction phase 
dosing with Induction Regimen 1, Induction Regimen 2 or the 12-week Target Induction Regimen, 
who continued study-directed treatment, subsequently received seribantumab 3,000 mg 1-h IV 
once every 2 weeks, initiating approximately 14 days after completion of the final weekly 
induction dosing. For these patients, dosing continued every 2 weeks until patients met one or 
more protocol-specific treatment discontinuation criteria. 
Protocol Version 2.0 included Q2W dosing for 6 doses (consolidation dosing) followed by Q3W 
dosing (maintenance dosing) for the remainder of study participation.  Q3W dosing was removed 
from the protocol with the approval of Protocol Version 3.0.  No patients were treated with Q3W 
dosing.  
  


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APPENDIX B: 
MOST/CRESTONE COUNTRY SPECIFIC APPENDIX 
(AUSTRALIA ONLY) 


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MoST CRESTONE:  
Seribantumab 
 
MoST CRESTONE: Australia Specific Appendix to the International 
CRESTONE Study 
 
Australia Specific Appendix version 5.0 dated XX September 2022, to the 
CRESTONE Trial Protocol version 7.0, dated 21 September 2022 
 
 
Protocol Title 
CRESTONE: A Phase 2 Study of Seribantumab 
in Adult Patients with Neuregulin-1 (NRG1) 
Fusion Positive Locally Advanced or Metastatic 
Solid Tumors 
Short Title: 
MoST CRESTONE 
CTC Protocol Number: 
CTC 0369  
Global Sponsor (CRESTONE): Elevation Oncology 
Australian Sponsor: 
University of Sydney 
Australian Coordinating 
Principal Investigator: 
Subotheni Thavaneswaran 
 
IMPORTANT NOTE 
This appendix is to be read in conjunction with the current approved version of the 
CRESTONE Trial Protocol. This document provides additional information about 
trial structure and conduct specifically in Australia. 


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MoST CRESTONE:  
Seribantumab 
 
Australia-specific protocol information for conduct of the CRESTONE 
study (ELVCAP-001-01) 
“MoST CRESTONE” refers to a subset of up to 16 Australian participants who will receive 
treatment with seribantumab for NRG1 fusion positive locally advanced or metastatic solid 
tumours. MoST CRESTONE represents the Australian patients contributing to the global 
CRESTONE study (ELVCAP-001-01). 
MoST CRESTONE will recruit to the pivotal cohort (Cohort 1). With the release of 
CRESTONE Protocol Version 5.0, exploratory Cohort 3 was closed to enrollment. Under 
Protocol Version 5.0/Protocol Administrative Letter 8.0, exploratory Cohort 2 was closed 
to enrollment. Should recruitment to the global CRESTONE study cease for reasons other 
than futility or safety, it is envisaged that participants will continue to enroll in Australia 
until the target enrollment of 16 participants is reached.  
The following section of this document (Section 3) describes Australian-specific variations 
to the conduct of the global CRESTONE study (ELVCAP-001-01).  
List of Abbreviations for this document 
Abbreviation 
Definition 
HREC 
Human research ethics committee 
IMP 
Investigational medicinal product 
MoST 
Cancer Molecular Screening and Therapeutics  
NHMRC CTC 
NHMRC Clinical Trials Centre, University of Sydney  
OS 
Overall survival 
PFS 
Progression-free survival 
SADR 
Serious adverse drug reaction  
SSI 
Significant safety issue 
SUSAR 
Suspected unexpected serious adverse reaction  
TGA 
Therapeutic Goods Administration  
TMC 
Trial Management Committee 
TTP 
Time to progression  
USM 
Urgent safety measure 
 
IMPORTANT NOTE 
Unless otherwise specified, the information below is in addition to that included in 
the CRESTONE Trial Protocol. Where information in the appendix conflicts with 
that in the CRESTONE Trial Protocol, the appendix will take precedence. 


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Study Synopsis  
Australian Sponsor 
The University of Sydney, NSW 2006, Australia 
CTC Protocol Number: 
CTC 0369 
Estimated Number of 
Patients 
Up to 16 patients will be enrolled in Australia as part of 
MoST CRESTONE. Patients enrolled in Australia may 
contribute to Cohort 1, 2 or 3 of the global CRESTONE 
study.  With the release of CRESTONE Protocol Version 
5.0, exploratory Cohort 3 was closed.  Under Protocol 
Version 
5.0/Protocol 
Administrative 
Letter 
8.0, 
exploratory Cohort 2 was closed. 
Cohort 1: patients with centrally confirmed NRG1 gene 
fusions who are ERBB/HER2/HER3 treatment-naïve 
AND harbor NRG1 gene fusions with an EGF-like 
domain intact.  Cohort 1 will include patients that have 
received ≥ 1 prior standard first-line therapy in the locally 
advanced or metastatic setting. 
Cohort 
2: 
Under 
Protocol 
Version 
5.0/Protocol 
Administrative Letter 8.0, enrollment to Cohort 2 was 
closed. Patients with NRG1 fusions with an EGF-like 
domain intact, who have received ≥ 1 prior standard 
therapy, in the locally advanced or metastatic setting 
including prior ERBB/HER2/HER3 directed treatment. 
Cohort 3: Enrollment to Cohort 3 was closed under 
Protocol Version 5.0.  Patients with NRG1 fusions 
without an EGF-like domain including but not limited to 
NRG1-PMEPA1, NRG1-STMN2, PCM1-NRG1 and 
INTS9-NRG1; patients with NRG1 fusions and other 
molecular aberrations lacking standard treatment 
options. 
Primary objective 
[Note: this section is 
reproduced verbatim from the 
CRESTONE Protocol for 
readability of this appendix] 
To 
determine 
the 
objective 
response 
rate 
by 
independent 
radiologic 
review 
to 
single 
agent 
seribantumab (anti-HER3 targeted therapy) in patients 
with centrally confirmed NRG1 gene fusion positive 
advanced cancer according to RECIST 1.1. 
Secondary Objectives 
Additional secondary objectives for MoST CRESTONE 
population include: 
• The ratio of time to progression (TTP) on MoST 
CRESTONE (TTP2) to TTP in the period prior to 
MoST CRESTONE (TTP1) 
• Progression free survival at 6 months 
• Overall survival at 12 months 
Study Design 
Up to 16 participants will be enrolled to this study in 
Australia as part of MoST CRESTONE. Potential 
participants may be identified via their participation in 
molecular screening programs, such as the MoST 


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Framework Protocol screening program. 
Statistical Considerations 
and Data Reporting 
[Some content in this section 
is reproduced from the 
CRESTONE Protocol for 
readability of this appendix] 
Please refer to Section 10 of the Global CRESTONE 
protocol for information on statistical methods.   
 
MoST CRESTONE will recruit participants in Australia 
to a maximum of 16 participants. Data collected from 
these participants will be included in the overall analysis 
for the global CRESTONE study. Additionally, upon 
completion of recruitment in Australia, the Australian 
treatment outcomes will be described in a subsequent 
and separate sub-group analysis. 
Categorical variables will be summarized by frequency 
distributions (number and percentages of patients) and 
continuous variables will be summarized by descriptive 
statistics (mean, standard deviation, median, minimum, 
maximum). Disposition of patients will be summarized, 
including those screened, treated, and discontinued. 
Reason for discontinuation will be summarized. 
Demographic and baseline characteristics will be 
summarized. 
 
Section 2 Objectives 
Aim: To assess the clinical activity of seribantumab in patients with NRG1 fusion positive 
locally advanced or metastatic solid tumours. 
 
Section 2.1 Primary objective  
[This section is reproduced verbatim from the CRESTONE Protocol for readability of 
this appendix] 
To determine the objective response rate by independent radiologic review to single agent 
seribantumab (anti-HER3 targeted therapy) in patients with centrally confirmed NRG1 
gene fusion positive advanced cancer according to RECIST 1.1. 
Section 2.2 Secondary objectives 
Additional secondary objectives for MoST CRESTONE population include:  
• The ratio of time to progression (TTP) on MoST CRESTONE (TTP2) to TTP in the 
period prior to MoST CRESTONE (TTP1) 
• Progression free survival at 6 months 
• Overall survival at 12 months 
 
Section 3.1 Study Design 
MoST CRESTONE is the subset of patients enrolled to the global multicenter open-label 
phase II clinical study in Australia. Participants must be eligible for one of the actively 
enrolling cohorts described in the global CRESTONE protocol (ELVCAP-001-01). 
MoST CRESTONE will represent the Australian subset of patients contributing to the 
global CRESTONE study (ELVCAP-001-01). MoST CRESTONE will recruit to the pivotal 
cohort (Cohort 1) and the two exploratory cohorts (Cohorts 2 and 3).  With the release of 
CRESTONE Protocol Version 5.0, exploratory Cohort 3 was closed to enrollment. Under 


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Protocol Version 5.0/Protocol Administrative Letter 8.0, exploratory Cohort 2 was closed 
to enrollment.  
Should recruitment to the global CRESTONE study cease for reasons other than futility 
or safety, it is envisaged that participants will continue to enroll in Australia until the target 
enrollment of 16 participants is reached.  
The MoST CRESTONE population will be included in the overall analysis of the global 
CRESTONE study. In addition, the MoST CRESTONE subset of patients will be analysed 
and published subsequently and separately from the global CRESTONE analysis to 
describe the Australian treatment experience and outcomes with seribantumab.  
 
Section 3.4 MoST CRESTONE Coordination 
 
Coordination and statistical analysis of the MoST CRESTONE population will be 
performed by the NHMRC CTC. MoST CRESTONE study results will be a sub-group 
analysis and published as a sub-group of the global CRESTONE study 
(ELVCAP-001-01). Data collected from patients participating in Australia will be included 
in the global CRESTONE analysis and resulting publication.   
Section 4 Study Population 
No exceptions will be made to these eligibility requirements at the time of registration. 
All enquiries about eligibility should be addressed by contacting Elevation Oncology (or 
their nominated delegate) prior to registration.  
 
Section 9.1 Adverse Events 
In Australia the following definitions are used for reporting of safety events; 
• A SIGNIFICANT SAFETY ISSUE (SSI) is defined as is a safety issue that could 
adversely affect the safety of participants or materially impact on the continued 
ethical acceptability or conduct of the trial.  These events may be in addition to the 
current SAE/SADR/SUSAR reports and generally have a consequence related to 
patient safety within the current study protocol, which thus requires some type of 
amendment.   
• An URGENT SAFETY MEASURE (USM) is one type of significant safety issue 
where sponsors or trial investigators act immediately to protect participants from 
an immediate hazard to their health and safety. USMs are often instigated before 
the TGA and HREC are notified. In these cases, it is strongly recommended that 
the sponsor contact the TGA within 24 hours of the measure being taken. 
(Examples include:  
• a serious adverse event that could be associated with the trial procedures and that 
requires modification of the conduct of the trial  
• a hazard to the patient population, such as lack of efficacy of an IMP used for the 
treatment of a life-threatening disease  
• a major safety finding from a newly completed animal study (such as 
carcinogenicity)  
• a temporary halt/termination of a trial for safety reasons  
• recommendations of the Safety Review Committee, where relevant for the safety 
of participants, such as an increase in frequency or severity of an expected 
adverse reaction  


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• single case events (e.g. toxic epidermal necrolysis, agranulocytosis, hepatic 
failure) that lead to an urgent safety measure) 
SSIs or USMs do not necessarily meet all criteria to be considered an SAE. For purpose 
of safety reporting, these events are to be reported in real-time (within 24 hours of 
awareness) to NHMRC CTC and Elevation Oncology (or their nominated delegate) with 
a note that this concerns an SSI or USM. 
A SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) is an SAE 
that is related to the drug or device and is unexpected, i.e. not listed in the investigator 
brochure or approved Product Information; or is not listed at the specificity or severity that 
has been observed; or is not consistent with the risk information described in the 
Participant Information Sheet and Informed Consent Form or elsewhere in the protocol. 
An event is causally related if there is a reasonable possibility that the drug caused the 
AE, i.e. there is evidence to suggest a causal relationship between the drug and the event.  
 
Section 9.4 Serious Adverse Event Reporting  
The investigator is responsible for reporting all SAEs (including SUSARs), SSIs and 
USMs occurring during the study to the global Sponsor within 24 hours of investigational 
site staff becoming aware of the event according to the procedure documented in the 
Study Manual.   
The NHMRC CTC will be responsible for providing reports to the Lead HREC. The 
NHMRC CTC will provide SUSAR, SSIs and USMs reports and SAE line listings to 
Investigators for submission to Human Research Ethics Committees (HRECs) as 
required. The investigator must notify the local site as required.  
The NHMRC CTC will submit ‘reportable safety events’ to the TGA in Australia and to the 
lead site/coordinating centre in other regions, in time to comply with the requisite specified 
regulatory time windows (usually 7 days for fatal/life threatening events with an 8 day 
follow-up report, and 15 days for other events). The lead site/centre will be responsible 
for reporting to the regulatory authorities and Lead Ethics Committees in other 
participating countries for which they are responsible.  
 
Section 10 Statistical Methods 
A full SAP will also be produced for the MoST CRESTONE analyses. Upon completion 
of Australian recruitment, the Australian treatment outcome will be described. 
 
Section 10.6 Secondary Efficacy Analysis 
For the MoST CRESTONE population, additional secondary endpoints are defined as 
follows: 
Time to progression:  
Time to progression is defined as the time interval from the date of seribantumab 
treatment initiation (Dose 1) to the date of first evidence of disease progression on MoST 
CRESTONE (TTP2) or death due to cancer.  
The study will compare the time to progression on MoST CRESTONE (period 2) with the 
time to progression on the most recent therapy on which the patient had just experienced 
progression (period 1). If the ratio of TTP of period 2 over TTP of period 1 (TTP2/TTP1) 
is greater than or equal to 1.3, then the study therapy will be defined as having benefit for 
the patient, as durable stable disease is achieved. This efficacy assessment is based on 


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key elements shared with the WINTHER trial conducted by the WIN consortium 
(NCT01856296). For patients where time to progression prior to trial therapy (TTP1) 
cannot be evaluated, TTP2 exceeding 6 months (i.e. stable disease on study maintained 
for > 6 month) would meet the criteria of benefit.  
Determination of disease progression will follow the RECIST v1.1 criteria where 
comparative baseline scan data is available. If surgical intervention is required on a target 
lesion, this will constitute progression and be censored at the time of surgery. A clinical 
evaluation will be required. 
Progression free survival (PFS) at 6 months:  
PFS at 6 months will also be determined. Progression free survival at 6 months is defined 
as the proportion of patients on study who are alive and progression free at 6 months 
from date of seribantumab treatment initiation (Dose 1) on study. 
Overall survival (OS) at 12 months:  
OS at 12 months is defined as the proportion of patients who are alive at 12 months from 
date of seribantumab treatment initiation (Dose 1) on study to date of death from any 
cause (or the date of last known vital status during follow up within 12 months from date 
of seribantumab treatment initiation (Dose 1)). 
Duration of response and clinical benefit rate are defined as per the global CRESTONE 
protocol. 
 
Section 11.3 Trial Ethics 
In Australia, the study will be conducted according to the Note for Guidance on Good 
Clinical Practice (Integrated Addendum to ICH E6 (R1): Guidelines for Good Clinical 
Practice ICH E6(R2) annotated with TGA comments (Therapeutic Goods Administration 
DSEB July 2000) and in compliance with applicable laws and regulations. The study will be 
performed in accordance with the NHMRC Statement on Ethical Conduct in Research 
Involving Humans 2007, the NHMRC Australian Code for the Responsible Conduct of 
Research (2007, updated 2015 and as amended from time to time), according to NHMRC 
Guidance: “Safety monitoring and reporting in clinical trials involving therapeutic goods- 
Nov2016”, and the principles laid down by the World Medical Assembly in the Declaration 
of Helsinki 2008.  
To this end, no patient will be recruited to the study until all the necessary approvals have 
been obtained and the patient has provided written informed consent. Further, the 
investigator shall comply with the protocol, except when a protocol deviation is required 
to eliminate immediate hazard to a participant. In this circumstance, the NHMRC CTC, 
global Sponsor, principal investigator and HREC must be advised immediately. 
 
Section 11.4 Patient Informed Consent 
A sample pre-screening consent will not be provided in Australia. 
A master participant information sheet and consent form, developed by the sponsor and 
approved by the lead HREC, will be provided to investigators for approval by their local 
HRECs and/or governance offices as required prior to use.  
 
For patients who meet criteria to continue with treatment beyond progression, as 
described in Section 5.4.1 of the main protocol, an addendum Treatment Beyond 
Progression ICF that is developed by the Sponsor and approved by HREC must be signed 


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by the participant prior to continuing treatment beyond disease progression. 
 
Section 11.5 Investigational Review Board Approval 
In Australia, the term “Investigational Review Board” refers to the human research ethics 
committee (HREC) and/or local governance body reviewing this study. There may be site-
specific governance review and approval required at site, in addition to HREC approval. 
Approval letters may take the form of an email (including automatically generated emails), 
and do not require letterhead or formal signature.  
 
Section 11.6 Monitoring 
Authorisation by participants for the use of personal identifiable health information will be 
documented via signature on the main participant information sheet and consent form.  
 
Section 11.7 Confidentiality 
The study will be conducted in accordance with applicable Privacy laws and regulations. 
All data generated in this study will remain confidential. All information will be stored 
securely at the NHMRC CTC, University of Sydney, and Elevation Oncology and 
Medpace, and will only be available to people directly involved with the study and who 
have signed a Confidentiality Agreement. Coded information may be shared with future 
collaborators.  
 
Section 11.8 Protocol Amendments 
Changes and amendments to the protocol can only be made by the Sponsor. Approval 
of amendments by the Institutional HREC is required prior to their implementation. In 
some instances, an amendment may require a change to a consent form. The Investigator 
must receive approval/advice of the revised consent form prior to implementation of the 
change.  In addition, changes to the data collected, if required, will be incorporated in the 
amendment. 
The investigator should not implement any changes to, or deviations from, the protocol 
except where necessary to eliminate immediate hazard(s) to trial participant(s). 
 
Section 11.9 Records Retention 
All study-related documentation at Australian sites will be maintained for 15 years 
following completion of the study, or until 2 years following the date that the last marketing 
application for the study drug is approved, or if no marketing application is filed, or such 
application is not approved, for 2 years after the formal discontinuation of clinical 
development of the study drug – whichever is later.  
Signed consent forms from Australian participants will not be collected by the Sponsor or 
their representative. They must be filed, as appropriate, at each site.  
Section 11.10 Clinical Study Report 
A Clinical Study Report which summarises and interprets all the pertinent study data 
collected for the MoST CRESTONE population (population of patients enrolled in 
Australia) will be issued, which may form the basis of a manuscript intended for 
publication.  

SAP_001.pdf: 
Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
Page 1 
 
STATISTICAL ANALYSIS PLAN 
 
 
CRESTONE: A Phase 2 Study of Seribantumab in Adult 
Patients with Neuregulin-1 (NRG1) Fusion Positive 
Locally Advanced or Metastatic Solid Tumors 
 
Protocol Number: 
ELVCAP-001-01 
Development Phase: 
Phase 2 
Sponsor: 
Elevation Oncology, Inc. 
101 Federal Street 
Suite 1900 
Boston, MA 02110 
Protocol Version Number/ Date: 
v7.0/ 21 September 2022 
SAP Version/ Date: 
v1.0/ 11 March 2024 
 
 
 
 
 
 
 
Confidentiality Statement 
This document, and the information it contains, are confidential and the proprietary 
property of Elevation Oncology. The information is not to be disclosed or transmitted 
to any party without the express approval of Elevation Oncology, or its agents, 
and any such unauthorized use or disclosure is expressly prohibited. 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
Page 2 
 
Protocol: CRESTONE: A Phase 2 Study of Seribantumab in Adult 
Patients with Neuregulin-1 (NRG1) Fusion Positive 
Locally Advanced or Metastatic Solid Tumors 
 
 
Protocol Number: 
ELVCAP-001-01 
Protocol Version: 
V7.0 
SAP Version: 
V1.0 
 
 
 
This Statistical Analysis Plan has been reviewed and approved by: 
 
Electronically signed by: 
Aubrey Benner 
Reason: Approved 
Date: Mar 13, 2024 20:34 EDT 
13-Mar-2024 
 
 
 
Aubrey Benner, MPH 
Date 
Statistical Scientist 
Medpace, Inc. 
Electronically signed by: Juan 
Liang 
Reason: Approved 
Date: Mar 13, 2024 16:28 
EDT 
13-Mar-2024 
 
 
 
Joanne Liang, PhD 
Date 
Director, Biostatistics 
Medpace, Inc. 
Electronically signed by: Lyon 
Gleich 
Reason: Approved 
Date: Mar 13, 2024 16:26 EDT 
 
Lyon Gleich, MD 
Date 
Vice President, Medical Affairs 
Medpace, Inc. 
13-Mar-2024 
Electronically signed by: 
Valerie Jansen 
Reason: Approved 
Date: Mar 13, 2024 13:30 CDT 
 
Valerie Malyvanh Jansen, MD, PhD 
Date 
Chief Medical Officer 
Elevation Oncology, Inc. 
13-Mar-2024 
Juan Liang 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
Page 3 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................. 3 
LIST OF TABLES ........................................................................................................................... 6 
LIST OF FIGURES .......................................................................................................................... 6 
LIST OF ABBREVIATIONS .......................................................................................................... 8 
1. 
INTRODUCTION ...................................................................................................... 10 
2. 
STUDY OBJECTIVES ............................................................................................... 11 
3. 
STUDY OVERVIEW ................................................................................................. 12 
3.1. 
Study Design ............................................................................................................... 12 
3.2. 
Seribantumab Dosing .................................................................................................. 13 
3.3. 
Randomization and Blinding ...................................................................................... 13 
3.4. 
Sample Size Determination ......................................................................................... 13 
3.5. 
Duration of Study ........................................................................................................ 14 
3.6. 
Disease Assessments ................................................................................................... 14 
4. 
ANALYSIS POPULATIONS ..................................................................................... 15 
4.1. 
Efficacy Analysis Populations .................................................................................... 15 
4.2. 
Safety Population ........................................................................................................ 15 
4.3. 
Pharmacokinetic Evaluable Population ...................................................................... 15 
5. 
CLINICAL OUTCOME VARIABLES ...................................................................... 16 
5.1. 
Primary Efficacy Endpoint .......................................................................................... 16 
5.1.1. 
Objective Response Rate (ORR) ................................................................................ 16 
5.2. 
Secondary Efficacy Endpoints .................................................................................... 16 
5.2.1. 
Duration of Response (DoR) ...................................................................................... 16 
5.2.2. 
Progression-free Survival (PFS) ................................................................................. 17 
5.2.3. 
Overall Survival (OS) ................................................................................................. 17 
5.2.4. 
Clinical Benefit Rate (CBR) ....................................................................................... 18 
5.3. 
Safety Endpoints ......................................................................................................... 18 
5.3.1. 
Treatment-emergent Adverse Events (TEAEs) .......................................................... 18 
5.3.2. 
Dose Limiting Toxicities (DLTs) ............................................................................... 18 
5.3.3. 
Exposure to Study Drug .............................................................................................. 18 
5.4. 
Pharmacokinetics ........................................................................................................ 19 
6. 
STATISTICAL ANALYSES ..................................................................................... 20 


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6.1. 
General Statistical Considerations .............................................................................. 20 
6.1.1. 
Baseline Definition ..................................................................................................... 20 
6.1.2. 
Multiple Comparisons ................................................................................................. 21 
6.1.3. 
Handling of Dropouts or Missing Data ....................................................................... 21 
6.2. 
Analysis of Study Population ...................................................................................... 21 
6.2.1. 
Patient Disposition ...................................................................................................... 21 
6.2.2. 
Protocol Deviations ..................................................................................................... 22 
6.2.3. 
Demographics and Baseline Characteristics ............................................................... 22 
6.2.4. 
Medical History .......................................................................................................... 22 
6.2.5. 
Primary Cancer History .............................................................................................. 22 
6.2.6. 
Prior Cancer Therapies ................................................................................................ 23 
6.2.7. 
Prior & Concomitant Medications .............................................................................. 23 
6.2.8. 
Concomitant Medical Procedures ............................................................................... 23 
6.2.9. 
Subsequent Cancer Therapies ..................................................................................... 23 
6.3. 
Efficacy Analyses ....................................................................................................... 24 
6.3.1. 
Objective Response Rate ............................................................................................ 24 
6.3.2. 
Progression-free Survival ............................................................................................ 24 
6.3.3. 
Overall Survival .......................................................................................................... 25 
6.3.4. 
Duration of Response .................................................................................................. 25 
6.3.5. 
Clinical Benefit Rate ................................................................................................... 25 
6.3.6. 
Interim Futility Analysis ............................................................................................. 25 
6.4. 
Safety Analyses ........................................................................................................... 25 
6.4.1. 
Extent of Exposure ...................................................................................................... 25 
6.4.2. 
Adverse Events ........................................................................................................... 26 
6.4.3. 
Clinical Laboratory Evaluations ................................................................................. 26 
6.4.4. 
Vital Signs ................................................................................................................... 27 
6.4.5. 
Electrocardiograms ...................................................................................................... 27 
6.4.6. 
Physical Examinations ................................................................................................ 28 
6.4.7. 
ECOG Performance Status.......................................................................................... 28 
6.4.8. 
Other Safety Assessments ........................................................................................... 28 
6.5. 
Covariates and Subgroups ........................................................................................... 28 
6.6. 
COVID-19 ................................................................................................................... 28 


Elevation Oncology, Inc. 
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6.7. 
Pharmacokinetic Analysis ........................................................................................... 28 
7. 
GENERAL INFORMATION ..................................................................................... 29 
7.1. 
Statistical Software ..................................................................................................... 29 
7.2. 
Format of Tables, Listings, and Figures ..................................................................... 29 
8. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSIS ...................................... 30 
9. 
REFERENCES ............................................................................................................ 31 


Elevation Oncology, Inc. 
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LIST OF TABLES 
Table 1: 
Progression Free Survival Censoring Rules ......................................................... 17 
 
LIST OF FIGURES 
Figure 1: 
Study Schema of Patient Flow in the CRESTONE Clinical Study ...................... 13 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
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Version History 
 
Version and Date 
Description 
Version 1.0 (11 March 2024) 
Initial version 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
Page 8 
 
LIST OF ABBREVIATIONS 
 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of Response 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
EGF 
Epidermal Growth Factor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
ERBB 
Epidermal Growth Factor Family of Receptor Tyrosine Kinases 
MedDRA 
Medical Dictionary for Regulatory Activities 
HER2 
Human Epidermal Growth Factor Receptor 2 
HER3 
Human Epidermal Growth Factor Receptor 3 
IV 
Intravenous 
MoST 
Molecular Screening and Therapeutics Study 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NON-CR 
Non Complete Response 
NON-PD 
Non Progressive Disease 
NRG1 
Neuregulin-1 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCM1 
Pericentriolar Material 1 
PD 
Progressive Disease 
PFS 
Progression-free Survival 
PK 
Pharmacokinetic 
PMEPA1 
Prostate Transmembrane Protein, Androgen Induced 1 
PR 
Partial Response 
PT 
Preferred Term 
QTcF 
QT Interval Corrected According to Fredericia’s Method 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
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ABBREVIATION 
DEFINITION 
SOC 
System Organ Class 
STMN2 
Stathmin 2 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
WHO 
World Health Organization 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical methodology and analyses to be 
conducted for Elevation Oncology, Inc. protocol ELVCAP-001-01 (Version 7.0). Any 
deviations from this analysis plan will be substantiated by sound statistical rationale and will 
be documented in the final clinical study report. The clinical study report will include all 
planned analyses defined in this SAP and any deviations from the planned analyses. 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
Page 11 
 
2. 
STUDY OBJECTIVES 
Primary Objective: the primary objective of this study is to determine the objective response 
rate (ORR) by independent radiologic review to single agent seribantumab (anti-HER3 
monoclonal antibody therapy; 3,000 mg IV weekly) in patients with centrally confirmed 
Neuregulin-1 (NRG1) gene fusion positive advanced cancer according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
Secondary Objectives: the secondary objectives of this study include the following: 
• To determine the overall efficacy of single agent seribantumab in NRG1 gene fusion 
positive patients with various solid tumors through the assessment of the following 
clinical outcome parameters: 
• Duration of Response (DoR) by independent radiologic review 
• ORR and DoR by investigator assessment 
• Progression-free Survival (PFS) by independent radiologic review and investigator 
assessment 
• Overall Survival (OS) 
• Clinical Benefit Rate (CBR) [Complete Response (CR), Partial Response (PR), Stable 
Disease (SD) ≥24 weeks] by independent radiologic review and investigator 
assessment 
• To describe the safety profile of seribantumab 
Exploratory Objectives: the exploratory objectives for this study are: 
• To evaluate the pharmacokinetics (PK) of the seribantumab dosing schedule in 
patients with NRG1 gene fusion positive advanced solid tumors 
• To evaluate if mechanistically linked exploratory biomarkers from tumor tissue or 
blood samples correlate with clinical outcomes 
• To evaluate changes from baseline in quality of life, as measured by the European 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) 


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ELVCAP-001-01 Statistical Analysis Plan 
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3. 
STUDY OVERVIEW 
3.1. 
Study Design 
This study is an open-label, international, multi-center, Phase 2 study in adult patients with 
advanced or metastatic solid tumors, which harbor the NRG1 gene fusion based upon local 
testing. The design of the study is summarized in Figure 1. 
All patients will be determined to be NRG1 gene fusion positive based on local testing of 
tumor tissue per local laboratory directed analyses prior to initiating further screening 
procedures. After all screening procedures and determination of eligibility for study 
treatment have been completed, eligible patients will be assigned by the Sponsor to the 
appropriate cohort based upon prior treatment history. Patients will be assigned to Treatment 
Cohorts as follows: 
Cohort 1: Patients with NRG1 gene fusions who are ERBB/HER2/HER3 treatment-naïve 
AND harbor NRG1 gene fusions with an EGF-like domain intact. Cohort 1 will include at 
least 55 patients with tumors that progressed on or are intolerant to ≥1 prior standard first- 
line therapy in the metastatic setting. 
Cohort 2: Enrollment to Cohort 2 was closed under Protocol Version 5.0/Protocol 
Administrative Letter 8.0. Patients with NRG1 gene fusions with an EGF-like domain intact, 
who received ≥ 1 prior standard first-line therapy in the locally advanced or metastatic 
setting including at least one ERBB/HER2/HER3 directed treatment are ineligible for study 
participation. 
Cohort 3: Enrollment to Cohort 3 was closed under Protocol Version 5.0 and later. Patients 
with NRG1 fusions without an EGF-like domain (including but not limited to NRG1- 
PMEPA1, NRG1-STMN2, PCM1-NRG1 and INTS9-NRG1) and patients with NRG1 
fusions and other molecular aberrations lacking standard treatment options, AND patients 
unable to provide tissue for central confirmation of NRG1 gene fusion status are ineligible 
for study participation under Protocol Version 5.0. 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
Page 13 
 
Figure 1: Study Schema of Patient Flow in the CRESTONE Clinical Study 
 
 
EGF = epidermal growth factor; ERBB = receptor tyrosine-protein kinase erbB-3; HER = human epidermal growth factor receptor; NRG1 = Neuregulin-1 
 
 
 
3.2. 
Seribantumab Dosing 
Starting with Protocol Version 4.0 and later, eligible patients will receive seribantumab 
3,000 mg 1-h IV once weekly until patients meet one or more protocol specific study 
treatment discontinuation criteria. 
Prior to Protocol Version 4.0, treatment for all eligible patients consisted of an initial 
Induction (Induction Regimen 1: 3,000 mg x 1 week followed by 2, 000 mg once weekly 
dosing x 3 weeks; Induction Regimen 2: 3,000 mg once weekly dosing x 4 weeks) followed 
by Q2W maintenance dosing with 3,000 mg seribantumab. 
3.3. 
Randomization and Blinding 
This is an open-label non-randomized study. 
3.4. 
Sample Size Determination 
The trial is designed to provide statistically persuasive evidence of a clinically meaningful 
effect of seribantumab if the lower boundary of a 2-sided 95% exact binomial confidence 
interval (CI) about the estimated ORR exceeds a minimal threshold of 20%. This threshold 
for level of evidence for benefit would be consistent with the standard used for approved 
targeted therapies for genomically defined populations of patients who stop responding to 
previous standard therapies. A sample size of 55 patients with central confirmation of NRG1 
gene fusion status, who have been enrolled and treated with either the 12-Week Target 
Induction Regimen and transitioned without interruption to weekly dosing (Clinical Protocol 
Version 3.0), or once weekly dosing from the time of enrollment (Clinical Protocol 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
Page 14 
 
Version 4.0 or later) is planned in the cohort 1 primary efficacy analysis population. Patients 
in the safety run-in (enrolled under Clinical Protocol Version 2.0 or earlier) will be included 
if they received seribantumab at 3,000 mg QW beyond induction/re-induction. This sample 
size will provide approximately 90% power for the lower bound of the 95% CI to exclude the 
pre-specified threshold of 20% for positivity assuming the ORR is 40% with seribantumab 
treatment. 
3.5. 
Duration of Study 
The expected duration of the study is 3 years. 
3.6. 
Disease Assessments 
For all consented patients assigned to one of the treatment cohorts after eligibility 
confirmation, treatment must start within 7 days following cohort assignment. Patients are 
expected to be treated until investigator-assessed progressive disease or unacceptable 
toxicity. Tumor assessments will be measured and recorded by the local radiologist 
beginning at weeks 6, 12, 18 and 24 (+/- 2 weeks) and subsequently every 8 weeks 
(+/- 2 weeks) through Week 48, followed by every 12 weeks (+/- 2 weeks) thereafter until 
disease progression and evaluated using the RECIST guidelines (version 1.1). All patients 
that discontinue treatment for reasons other than disease progression will have a scan 
performed at the time of the End of Treatment (EOT) visit. 
In addition, an independent central review of scans may be conducted for patients assigned to 
cohort 1. All images may be submitted to a central imaging facility and may be assessed by 
independent reviewers in accordance with the Imaging Charter. After patients discontinue 
seribantumab treatment, survival information and information about subsequent therapies 
will be collected until death or study closure, whichever occurs first. 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
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4. 
ANALYSIS POPULATIONS 
This section defines the analysis populations to be used for the planned statistical analyses. 
4.1. 
Efficacy Analysis Populations 
Cohort 1 primary efficacy analysis population 
The population will be used for the primary analysis of efficacy for registration purpose. It 
will include cohort 1 subjects enrolled in this study who meet all criteria listed below: 
• Centrally confirmed NRG1 gene fusion 
• Received at least one dose of seribantumab with the 3,000 mg IV QW dosing regimen 
(starting with Protocol Version 3.0 and later). Patients in the safety-run in (enrolled 
under Protocol Version 2.0 or earlier) will be included if they received seribantumab 
at 3,000 mg QW beyond induction/re-induction. 
• Received at least one prior standard therapy in the locally advanced or metastatic 
setting 
• 
At least one measurable lesion at baseline as assessed per RECIST Version 1.1 
 
4.2. 
Safety Population 
The Safety Population includes patients receiving at least one dose of seribantumab therapy 
across any of the three treatment cohorts (e.g., cohort 1, 2 and 3) and across any of the 
seribantumab dosing regimens. The safety population will be used for the overall safety 
analysis. 
4.3. 
Pharmacokinetic Evaluable Population 
The PK Evaluable Population includes all eligible patients who have at least one dose of 
seribantumab therapy, and from whom results of plasma concentrations are obtained for at 
least one sampling point which is suitable for analysis. The PK Evaluable Population will be 
used for PK analysis. 


Elevation Oncology, Inc. 
ELVCAP-001-01 Statistical Analysis Plan 
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5. 
CLINICAL OUTCOME VARIABLES 
This section provides endpoint definitions. For endpoints based on tumor assessments, such 
as ORR, DoR, PFS, and CBR, the definitions are the same for each endpoint whether the 
independent radiographic review assessments or investigator assessments are used per 
RECIST v1.1. 
5.1. 
Primary Efficacy Endpoint 
5.1.1. 
Objective Response Rate (ORR) 
ORR is defined as the proportion of patients whose overall response is a confirmed CR or PR 
per RECIST v1.1. To be assigned a status of confirmed PR or CR, changes in tumor 
measurements must be confirmed by repeated assessments at least 4 weeks (28 days) after 
the criteria for response are first met. Tumor assessments after the initiation of new 
anticancer therapy should not be used to derive the ORR. 
Patients with no evaluable post-baseline disease assessments (i.e., NE) will be considered 
non-responders and included in the denominator in the calculation of the ORR. 
ORR based on independent radiologic review assessments is the primary efficacy endpoint in 
this study. 
5.2. 
Secondary Efficacy Endpoints 
5.2.1. 
Duration of Response (DoR) 
Duration of response is defined as the time from the start date of CR or PR (whichever 
response status is observed first and subsequently confirmed), to the date of first documented 
radiographical progression of disease using RECIST v1.1, or death from any cause, 
whichever comes first. DoR will be calculated for patients who are responders, i.e., those 
who achieve a confirmed CR or PR. 
DoR in days will be calculated as: 
• DoR (days) = Date of PD or death (whichever is earlier) or Date of censoring – first 
date of PR/CR + 1 
DoR in months will be calculated as: 
• DoR (months) = 12*DoR (days)/365.25 
 
DOR will follow the same censoring rules as PFS primary analysis in Table 1 in section 
5.2.2. 


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5.2.2. 
Progression-free Survival (PFS) 
Progression-free survival is defined as the time from the date of seribantumab treatment 
initiation (Dose 1) to the first documented radiographical progression of disease using 
RECIST v1.1, or death from any cause, whichever comes first. 
PFS in days will be calculated as: 
• PFS (days) = Date of PD or death (whichever is earlier) or Date of censoring – first 
dose date + 1 
PFS in months will be calculated as: 
• PFS (months) = 12*PFS (days)/365.25 
The following table summarizes the PFS censoring rules: 
Table 1: Progression Free Survival Censoring Rules 
 
Primary analysis 
(Censoring rules) 
Sensitivity analysis 
(Censoring rules) 
No PD, no death, no NACT 
initiated 
Censored at last tumor 
assessment. If no evaluable 
tumor assessment, censored 
on the first dose date. 
Censored at last tumor 
assessment. If no evaluable 
tumor assessment, censored on 
the first dose date. 
No PD, no death, NACT 
initiated 
Censored at the last tumor 
assessment prior to NACT. If 
no evaluable tumor 
assessment, censored on the 
first dose date. 
Censored at last tumor 
assessment regardless of NACT. 
If no evaluable tumor 
assessment, censored on the first 
dose date. 
PD or death, no NACT 
initiated 
PFS event at the date of PD or 
death 
PFS event at the date of PD or 
death 
PD or death prior to or on date 
NCAT initiated if patient 
received the NACT 
PFS event at the date of PD or 
death 
PFS event at the date of PD or 
death 
PD or death after NACT 
Censored at the last tumor 
assessment prior to NACT 
PFS event at the date of PD or 
death 
PD or death after 1 missed 
tumor assessment 
PFS event at the date of PD or 
death 
PFS event at the date of PD or 
death 
PD or death after 2 or more 
missed tumor assessment 
Censored at last tumor 
assessment prior to PD or 
death 
PFS event at the date of PD or 
death 
Abbreviations: PD = progressive disease; PFS = progression-free survival; NACT = new anticancer therapy 
5.2.3. 
Overall Survival (OS) 
Overall survival is defined as the time from the date of seribantumab treatment initiation 
(Dose 1) to the date of death from any cause. 
OS in days will be calculated as: 
• OS (days) = Date of death – first dose date + 1 
OS in months will be calculated as: 


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• OS (months) = 12*OS (days)/365.25 
Patients who are alive at the time of database lock or lost to follow-up will be censored on 
the date the patient was last known to be alive based on data collected in the database. 
5.2.4. 
Clinical Benefit Rate (CBR) 
Clinical benefit rate is defined as the proportion of patients who achieve PR, CR, or SD 
which is maintained through at least 24 weeks per RECIST v1.1. Tumor assessments after 
the initiation of new anticancer therapy should not be used to derive the CBR. 
Patients with no evaluable post-baseline disease assessments (i.e., NE) or with ongoing SD 
but short of 24 weeks at the time of analysis will be considered as not having attained clinical 
benefit and included in the denominator in the calculation of the CBR. 
5.3. 
Safety Endpoints 
5.3.1. 
Treatment-emergent Adverse Events (TEAEs) 
Adverse events (AE) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary v26.0 or later. Severity will be graded according to the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 
All AEs, complaints, or symptoms that occur from the time that written informed consent has 
been obtained through the EOT visit are to be recorded on the appropriate case report form 
(CRF). 
TEAEs are defined as any event that occurred after the first dose of study drug and 28 days 
after the last dose of seribantumab that was not present prior to study drug administration or 
worsened in severity after study drug administration. TEAEs will be summarized in the 
safety analysis. 
5.3.2. 
Dose Limiting Toxicities (DLTs) 
Patients will be monitored during weekly dosing for a period of 28 days (i.e., throughout 
C1W1, C1W2, C1W3, and C1W4) for the occurrence of dose limiting toxicities (DLTs). Any 
Grade 3 or 4 hematologic or non-hematologic toxicity considered related to seribantumab 
will be considered dose limiting. A DLT is defined as any AE meeting specific criteria, 
occurring during weekly treatment with seribantumab, where the relationship to 
seribantumab cannot be ruled out. The full list of criteria for determination of DLTs is given 
in Section 5.2.4.1 of Clinical Protocol Version 7.0. 
Any toxicity, regardless of CTCAE grade, resulting in discontinuation or dose reduction of 
seribantumab treatment during the 28-day DLT evaluation period, except for symptoms 
related to PD, will be considered a DLT. 
5.3.3. 
Exposure to Study Drug 
Seribantumab dosing will consist of weekly dosing until study treatment discontinuation 
criteria are met. 


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Total treatment duration: 
• Total treatment duration (days) = date of last dose – date of first dose + 1 
• Total treatment duration (months) = 12*Total treatment duration (days)/365.25 
Actual numbers of completed seribantumab infusions: 
• Actual numbers completed = actual numbers of completed seribantumab infusions 
from the first dose to last dose 
Actual dose of administered seribantumab infusions (mg): 
• Actual dose administered (mg) = actual cumulative dose of administered 
seribantumab up to the date of last dose 
Relative dose intensity (RDI) is the percentage of actual dose administered relative to the 
intended dose planned through to treatment discontinuation. 
RDI will be calculated as follows: 
• RDI = 100% * d/D 
where d (mg) is actual total dose administered and D (mg) is cumulative dose planned. D is 
the total dose that would be administered if there were no modification to dose or schedule. 
5.4. 
Pharmacokinetics 
The PK of seribantumab will be assessed from plasma samples taken at time indicated in the 
Schedule of Assessments. 


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6. 
STATISTICAL ANALYSES 
This section describes the statistical analyses to be conducted in relation to the primary, 
secondary, and exploratory objectives of the study. 
6.1. 
General Statistical Considerations 
In general, analyses specified will follow the multi-cohort nature of the study design. 
Specifically, analysis of safety (Section 6.4) will be presented by cohort (cohort 1 primary 
efficacy analysis population, cohort 1, cohort 2, cohort 3) and all cohorts combined based on 
the safety analysis population. Analysis of patient population (Section 6.2) will be 
summarized similarly, except for Patient Disposition, which will be summarized for all 
patients who have signed the informed consent regardless of seribantumab treatment. The 
efficacy analysis (Section 6.3) primary focus will be on the cohort 1 primary efficacy 
analysis population patients. Safety and efficacy analysis will also be performed for non- 
small cell lung cancer (NSCLC) vs other tumors within cohort 1 primary efficacy analysis 
population. 
For continuous variables, the number of observations (n), mean, standard deviation, median, 
minimum, and maximum will be provided as summary statistics. The mean and median will 
be reported to one additional decimal place compared to the original data. The standard 
deviation will be reported to two additional decimal places compared to the original data and 
the minimum and maximum will be reported to the same number of decimal places as the 
original data. 
For categorical variables, the frequency and percentage in each category will be displayed. 
Percentages (e.g., for AEs and concomitant medications) will be calculated out of the 
population total for each cohort. Footnotes will clarify the denominator used in each output if 
other than the analysis set stated in the title. Percentages will be reported to one decimal 
place throughout unless the percentage is 100 (in which case no decimal places will be 
presented) or if the frequency count is zero (in which case no percentage will be presented). 
For time to event data, unless otherwise noted, the median value, 25th percentile and 75th 
percentile will be calculated using the Kaplan-Meier method. In addition, the minimum and 
maximum values of the time to event data will be calculated with an indication of whether 
that value is an event or censored. However, if both an event and a censored observation 
contributes to the minimum or maximum then in the case of the minimum the value would be 
indicated as an event and in the case of a maximum the value would be indicated as censored. 
Furthermore, the Brookmeyer and Crowley method will be used to calculate the CI of the 
median value estimated using the Kaplan-Meier method (Brookmeyer and Crowley 1982). 
Also, the Greenwood formula will be used to calculate the CI of the survival rate (or the rate 
of interest pertaining to the time to event data), at a given time point estimated using the 
Kaplan-Meier method for the time to event data (Kalbfleisch and Prentice 2002). 
6.1.1. 
Baseline Definition 
Unless stated otherwise, the baseline value is defined as the last non-missing measurement 
prior to the first administration of seribantumab. Study Day 1 will be considered as the date 


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of the first dose of seribantumab. The change from baseline for a parameter is calculated as 
(observed value at visit - baseline value). 
6.1.2. 
Multiple Comparisons 
No multiple comparisons adjustment will be applied to the efficacy analysis. 
6.1.3. 
Handling of Dropouts or Missing Data 
Unrecorded data values will be recorded as missing. Only recorded (i.e., complete) data 
values will be used for statistical analyses. In general, invalid or missing values will not be 
imputed unless stated otherwise. 
In cases of missing or incomplete dates (e.g., AEs and concomitant medications), the missing 
component(s) will be assumed as the most conservative value possible. For example, AEs 
with missing start dates, but with stop dates either overlapping into the treatment period or 
missing, will be counted as treatment-emergent, taking the worst-case approach. When 
partial dates are present in the data, both a partial start date and/or a partial stop date will be 
evaluated to determine whether it can be conclusively established that the AE started prior to 
the start of study drug or ended prior to the start of study drug. If the above cannot be 
conclusively established based on the partial and/or present dates, then the AE will be 
considered as treatment-emergent. Actual data values as they appear in the original CRFs 
will be presented in the data listings. 
To be conservative in the case of missing causality assessment for AEs after data querying, 
AEs will be assumed to be related to study drug. If the CTCAE grade is missing after data 
querying it will not be imputed and the patient will be presented in table summaries based on 
the maximum CTCAE grade of all other recorded AEs meeting applicable criteria. 
6.2. 
Analysis of Study Population 
6.2.1. 
Patient Disposition 
Patient disposition will be summarized in terms of counts and percentages for all patients 
who have signed the informed consent regardless of seribantumab treatment. The following 
patient disposition categories will be summarized: 
• Patients screened 
• Patients who enrolled in the study 
• Patients treated with seribantumab 
• Patients discontinued from seribantumab 
• Patients who terminated the study 
For patients who discontinued study treatment, or terminated the study, a summary will be 
provided by reason. 
The number and percentage of patients in each defined analysis population may also be 
tabulated. 


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All patient disposition data will be listed. 
6.2.2. 
Protocol Deviations 
Protocol deviations will be identified and reported by the process described in the current 
version of the study Protocol Deviation Plan. Protocol deviations considered reportable in the 
clinical study report per the study Protocol Deviation Plan will be summarized and listed 
by-patient. 
6.2.3. 
Demographics and Baseline Characteristics 
Demographic characteristics will be collected during the Screening period. Gender, race, and 
ethnicity will be summarized using frequencies and percentages. If female, the frequencies 
and percentages of childbearing potential will be summarized. Age at Screening will be 
summarized using descriptive statistics. Demographic and baseline characteristics will be 
summarized based on the safety population. Additional summaries based on other analysis 
populations may also pe performed. 
Baseline height (cm), body weight (kg) will be summarized with descriptive statistics and 
Eastern Cooperative Oncology Group (ECOG) performance status will be summarized using 
frequencies and percentages. 
Demographics and baseline characteristics will be listed by-patient. 
6.2.4. 
Medical History 
A medical history will be collected during Screening. All pertinent prior medical conditions, 
surgeries or other medical procedures, allergies, and concomitant medications will be 
collected. 
The reported medical history terms will be coded using the MedDRA v26.0 or later. 
Summary analyses for medical history will be based on Safety Population and will be 
summarized by system organ class (SOC) and preferred term (PT). Patients may have more 
than one reported medical history event for each SOC and PT but will be only counted once 
within each SOC and PT classification. 
Reported medical history data will be presented in a by-patient listing. 
6.2.5. 
Primary Cancer History 
Primary cancer history will be collected during Screening. Continuous variables including 
time from initial histologic/cytologic diagnosis (months) and time from last progression will 
be summarized with descriptive statistics. Categorical variables including primary cancer 
type, tumor stage at time of diagnosis, histology/cytology, grade, tumor stage at trial entry, 
NRG1 Fusion detected, NRG1 testing method, and other genomic findings will be 
summarized in count and percentage. 
Primary cancer history data will be presented in a by-patient listing. 


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6.2.6. 
Prior Cancer Therapies 
The analyses will be based on Safety Population. The prior systemic anti-cancer treatments, 
prior cancer radiation therapy, and prior cancer surgery will be collected during Screening. 
For systemic anti-cancer treatments, the number and percentage of patients, the line of 
therapy setting, duration of therapy, best overall response (defined in order of CR, PR, SD, 
PD, NON-CR/NON-PD, NE), and reason for discontinuing will be summarized. The 
reported cancer therapy terms will be coded using the World Health Organization (WHO) 
Drug Dictionary (Version Global B3, March 2020 or later). Prior cancer therapies will be 
summarized by Anatomical Therapeutic Chemical (ATC) and PT. A patient will be counted 
only once within an ATC classification but may contribute to two or more PTs in the same 
classification. 
For prior radiation therapy and prior cancer surgery, the number and percentage of patients, 
the radiation location, duration of radiation therapy, total dose in Gy, surgery intention will 
be summarized. The type of surgery will be coded using MedDRA v26.0 or later. The 
surgeries will be summarized by SOC and PT. A patient will be counted only once within a 
SOC classification but may contribute to two or more PTs in the same classification. 
All prior therapies will be listed, including prior systemic anti-cancer treatments, prior 
radiation therapy and prior cancer surgery. 
6.2.7. 
Prior & Concomitant Medications 
The medications collected will be coded using WHO Drug Dictionary (Version Global B3, 
March 2020 or later). The prior and concomitant medications will be summarized by ATC 
and PT. A patient will be counted only once within an ATC classification but may contribute 
to two or more PTs in the same classification. Frequency ordering will be used for the table 
presentation (i.e. order by the overall grouping in descending frequency for each ATC and 
for each PT within each ATC). 
All prior and concomitant medications will be presented in listings. 
6.2.8. 
Concomitant Medical Procedures 
The number and percentage of patients will be summarized. All medical procedures will be 
coded by using MedDRA v26.0 or later. The medical procedures will be summarized by 
SOC and PT. A patient will be counted only once within a SOC classification but may 
contribute to two or more PTs in the same classification. Frequency ordering will be used for 
the table presentation (i.e. order by the overall grouping in descending frequency for each 
SOC and for each PT within each SOC). 
All concomitant medical procedures will be presented in a data listing. 
6.2.9. 
Subsequent Cancer Therapies 
Subsequent cancer therapies (subsequent cancer therapy, cancer surgery and radiation 
therapy) will be collected during every survival follow-up. 
For subsequent cancer therapy, regimen start/stop dates, and ongoing status will be recorded. 
The number and percentage of patients treated with a subsequent cancer regimen will be 


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summarized. The reported cancer therapy terms will be coded using WHO Drug Dictionary 
(Version Global B3, March 2020 or later). Subsequent cancer therapies will be summarized 
by ATC and PT. A patient will be counted only once within an ATC classification but may 
contribute to two or more PTs in the same classification. 
For subsequent cancer surgery, the number and percentage of patients who have surgery 
therapies, palliative/curative intent will be summarized. For subsequent radiation therapy, the 
number and percentage of patients who have radiation therapies, palliative/ curative intent, 
therapy location, total dose in Gy will be summarized. 
The surgery procedures will be summarized by SOC and PT. A patient will be counted only 
once within a SOC classification but may contribute to two or more PTs in the same 
classification. 
All the subsequent therapies will be listed. 
6.3. 
Efficacy Analyses 
All efficacy analyses will be performed by cohort. Analyses for the cohort 1 primary efficacy 
analysis population will be intended to support a potential registration With the exception on 
the handling of tumor assessments after the initiation of new anticancer therapy as described 
in Sections 5.1 and 5.2, all data from scheduled or unscheduled assessments will be included 
in the efficacy analyses. 
All efficacy analysis will be analyzed by investigator assessments only, independent 
radiographic review was not done due to Sponsor decision to end the study prior to full 
enrollment. 
6.3.1. 
Objective Response Rate 
The point estimate of the ORR along with the 2-sided 95% exact Clopper-Pearson CI will be 
presented. 
The best overall response (CR, PR, SD, PD, NE) will also be tabulated to show the number 
and percentage of patients in each response category. 
6.3.2. 
Progression-free Survival 
PFS will be estimated using the Kaplan-Meier method and will be presented graphically. 
Sensitivity analysis based on the alternative censoring rules described in Table 1 will be 
provided. 
The number and percentage of patients experiencing a PFS event and patients censored will 
be summarized. The median, 25th percentile, 75th percentile, minimum and maximum will 
be provided along with the 95% CI for the median. The proportion and 95% CI for the 
number of patients progression-free at clinically significant time points (e.g., 6 months, 12 
months) from the date of the first dose will be provided. Other clinically relevant timepoints 
may also be included if data warrant. 


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6.3.3. 
Overall Survival 
OS will be estimated using the Kaplan-Meier method along with the Kaplan-Meier plot. The 
number and percentage of deaths and patients censored will be summarized. The median, 
25th percentile, 75th percentile, minimum and maximum will be provided along with the 
95% CIs for the median. The proportion and 95% CI for the number of patients alive at 
clinically significant time points (e.g., 6 months, 12 months) from first treatment will be 
provided. Other clinically relevant timepoints may also be included if data warrant. 
6.3.4. 
Duration of Response 
DoR will be estimated using the Kaplan-Meier method along with the Kaplan-Meier plot. 
The number and percentage of patients experiencing a DoR event and patients censored will 
be summarized. The median, 25th percentile, 75th percentile, minimum and maximum will 
be provided along with the 95% CI for the median. The proportion and 95% CI for the 
number of patients with durable responses at 6 months and 12 months from the onset of 
response will be provided. Other clinically relevant timepoints may also be included if data 
warrant. 
6.3.5. 
Clinical Benefit Rate 
The CBR along with exact Clopper-Pearson 95% CI will be presented. 
6.3.6. 
Interim Futility Analysis 
A pre-planned interim futility analysis based on investigator assessed ORR will be conducted 
after 20 patients are enrolled in the cohort 1 primary efficacy analysis population and have 
been followed for at least one tumor assessment (i.e., 6 weeks +/- 2 weeks). Should four or 
more objective responses be observed at the time of the interim analysis, enrollment to 
cohort 1 for the primary analysis population will continue until a minimum of 55 patients. 
The futility analysis will be considered non-binding as factors other than ORR may be 
factored in (such as depth of response, duration of response, tumor type and fusion partner). 
6.4. 
Safety Analyses 
The assessment of the incidence of adverse events during the study will consist of the 
recording of any AEs, SAEs, DLTs, etc. Safety will also be assessed through clinical 
laboratory evaluations, immunogenicity assessments, vital signs, electrocardiograms (ECGs), 
physical examinations, ECOG performance status, and prior and concomitant medication 
reporting. 
The safety analysis will be based on the Safety Population and will be presented by cohort 
(cohort 1 primary efficacy analysis population, cohort 1, cohort 2, cohort 3) and all cohorts 
combined. 
6.4.1. 
Extent of Exposure 
Descriptive statistics will be provided for total treatment duration, total dose planned, actual 
total dose administered, and relative dose intensity. 


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The number and percentage of patients initiating a given number of treatment cycles and 
seribantumab infusions will be summarized. A cycle will be defined as 28 days. In addition, 
the number and percentage of patients with dose modification, dose interruption, or missed 
dose will be summarized, along with the reason. 
The seribantumab administration data will be presented in a by-patient listing. 
6.4.2. 
Adverse Events 
Patient incidence will be summarized in tables. Frequency ordering will be used for the table 
presentation (i.e. order by the overall grouping in descending frequency for each SOC and for 
each PT within each SOC). 
An overview of adverse events will be provided which summarizes the patient incidence of 
the following. This overview will include the number and percentage of patients with: 
• Any AEs; 
• Any TEAEs; 
• Any drug related TEAEs; 
• Any serious adverse events (SAEs); 
• Any serious TEAE (TESAEs); 
• DLTs; 
• CTCAE grade 3/4/5 TEAEs; 
• CTCAE grade 3/4/5 TEAEs related to seribantumab; 
• TEAEs leading to dose reduction or interruption of study drug; 
• TEAEs leading to discontinuation of study drug; 
• TEAEs resulting in Death. 
The number and percentage of patients with AEs will be tabulated by the highest CTCAE 
Grade, SOC, and PT. DLTs, TEAEs, TEAEs related to study drug will be summarized in the 
same manner. 
TEAEs will also be summarized by SOC and PT. DLTs, CTCAE Grade 3/4/5 TEAEs, 
TESAEs, drug-related TEAEs, drug-related CTCAE Grade 3/4/5 TEAEs, AEs leading to 
dose reduction or interruption of study drug, and AEs leading to discontinuation of study 
drug will be summarized in the same manner. 
For all above summaries, patients with multiple adverse events will be counted only once per 
SOC and PT. 
Listings will be presented for TEAEs and TESAEs. 
 
6.4.3. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be summarized using descriptive statistics for select 
laboratory parameters (e.g. serum or plasma chemistry, complete blood count) including 


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absolute measurements and changes from baseline by scheduled time of evaluation. Changes 
from baseline by scheduled time of evaluation will include EOT visit, maximum post- 
treatment value, and minimum post-treatment value. Both scheduled and unscheduled post- 
treatment visits will be considered for the summaries of the maximum and minimum post- 
treatment values. 
Abnormal laboratory results will be graded according to NCI CTCAE v5.0 as applicable. 
Clinical laboratory evaluations will be listed by patient and abnormal values will be flagged. 
6.4.4. 
Vital Signs 
Descriptive statistics will be provided for vital signs measurements (systolic and diastolic 
blood pressure, pulse rate, respiratory rate, body temperature, and weight). Actual observed 
values and changes from baseline by scheduled evaluation, and maximum and minimum 
post-treatment values will be presented. 
Both scheduled and unscheduled post-treatment values until the EOT will be considered for 
summaries of the minimum and maximum on-treatment values. In addition, box plots of 
change from baseline values by visit for systolic and diastolic blood pressure and pulse rate 
will be produced. 
All vital signs assessments will be presented in a by-patient listing. 
6.4.5. 
Electrocardiograms 
Note that the mean of the triplicate readings will be obtained at Screening for each patient 
prior to summarizing. 
Continuous ECG parameters (Cardiac Rate, PR, RR, QRS, QT, QTcF) will be summarized 
using descriptive for actual values and for changes from baseline by scheduled time of 
evaluation, including the maximum post-treatment value. Both scheduled and unscheduled 
post-treatment values will be considered for summaries of the maximum post-treatment 
values. 
The Fridericia-corrected QT interval (QTcF) will be calculated as QTcF = QT/(RR)^1/3 for 
the above summaries. 
• Increase from baseline QTcF > 30 ms 
• Increase from baseline QTcF > 30 ms and QTcF ≤ 60 ms 
• Increase from baseline QTcF > 60 ms 
Box plots or other graphical summaries may be produced for QTcF absolute and change from 
baseline values if warranted after data review. 
Overall evaluation of ECG is also collected at each visit in terms of normal or abnormal, and 
the relevance of the abnormality is termed as “clinically significant” or “not clinically 
significant”, this information may be summarized. 


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6.4.6. 
Physical Examinations 
The overall physical examination result at each time point (including scheduled and 
unscheduled will be listed by-patient. 
6.4.7. 
ECOG Performance Status 
For patients with ECOG performance status assessments, the performance status at each visit 
on study and worst post-baseline assessment will be presented using frequencies and 
percentages. Both scheduled and unscheduled visits will be considered in determination of 
the worst post-baseline assessment. 
ECOG performance status results will be presented in a by-patient listing. 
6.4.8. 
Other Safety Assessments 
Results from other safety assessments (e.g. pregnancy test) will be presented in by-patient 
listings if applicable. 
6.5. 
Covariates and Subgroups 
The following covariates and subgroups are of interest: 
• Tumor type (NSCLC vs other tumors) 
• Fusion partner (ADAM9, AGRN, APP, ATP1B1, BAG4, CD74, CDH1, COX10- 
AS1, DIP2B, DPYSL2, FUT10, GDF15, HMBOX1, IL1RL2, ITGB1, MDK, 
MRPL13, NOTCH2, PARP8, POMK, RBPMS, RNF169, ROCK1, SDC4, SETD4, 
SLC3A2, TMPRSS3, TNC, TSHZ2, VAMP2, VTCN1, WHSC1L1, ZMYM2) 
Additional efficacy and safety analysis may be performed by subgroups for cohort 1 primary 
efficacy analysis population. Waterfall plot of responses will be provided by fusion partner. 
6.6. 
COVID-19 
Due to the COVID-19 pandemic, additional analyses (e.g., sensitivity analysis) may be 
performed to assess the impact of COVID-19 on clinical trial data. 
Applicable data collected in relation to COVID-19 on the CRF will be summarized as 
appropriate and/or included in data listings. 
Protocol deviations resulting from COVID-19 will be recorded and included in the protocol 
deviation listing. 
6.7. 
Pharmacokinetic Analysis 
Plasma concentrations by patient, cycle, day, and time will be obtained and documented at 
various time points during the treatment with seribantumab. 
If applicable, additional PK analysis and methods will be described in a standalone PK 
analysis plan. 
PK concentration results will be presented in a by-patient listing. 


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7. 
GENERAL INFORMATION 
7.1. 
Statistical Software 
The creation of analysis datasets and statistical analyses will be done using SAS® version 9.4 
or higher. The Medpace standard operating procedures (Medpace Standard Operating 
Procedures GL-DS-02-S4 and GL-DS-03-S3, or newest version at the time of analysis if 
applicable) will be followed for the validation of all SAS programs and outputs. 
7.2. 
Format of Tables, Listings, and Figures 
The format of tables, listings, and figures will be described in a stand-alone programming 
specifications document. The programming specification document will be prepared before 
database lock (or interim data lock for analyses presented at interim analysis). 


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8. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSIS 
An independent central review of scans was not done due to Sponsor decision to end the 
study prior to full enrollment. Therefore, the primary efficacy endpoint and secondary 
efficacy endpoints utilizing independent radiologic review will not be analyzed. 
The following exploratory endpoints in Protocol 7.0 will not be analyzed: 
• To evaluate if mechanistically linked exploratory biomarkers from tumor tissue or 
blood samples correlate with clinical outcomes 
• To evaluate changes from baseline in quality of life, as measured by the European 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) 
For Cohort 1 Primary Efficacy Analysis Population definition, “based on independent central 
reviews” was removed from the last criteria. 
Cohort 2 and Cohort 3 Efficacy Analysis Population, intended for exploratory efficacy 
analysis, will not be analyzed. 


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9. 
REFERENCES 
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