Clinical trial NCT04504916
Conditions: Triple-negative Breast Cancer Non-squamous Non-small-cell Lung Cancer NSCLC Estrogen-receptor-positive Breast Cancer Progesterone-receptor-positive Breast Cancer Estrogen-receptor-negative Breast Cancer ER-negative Breast Cancer Progesterone-receptor Negative Breast Cancer PR-negative Breast Cancer HER2-negative Breast Cancer ER-positive Breast Cancer PR-positive Breast Cancer Platinum-resistant Ovarian Cancer Gastric Cancer Pancreatic Cancer
Sponsor: VelosBio Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Start date: 2020-10-07; Completion date: 2023-06-12
Enrollment: 102 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a study evaluating the efficacy, safety, and pharmacokinetics of zilovertamab vedotin in participants with metastatic solid tumors including previously treated cancers of triple-negative breast cancer (TNBC), non-TNBC human epidermal growth factor receptor 2 (HER2)-negative breast cancer, non-squamous non-small-cell lung cancer (NSCLC), gastric cancer, pancreatic cancer, and platinum-resistant ovarian cancer. The study will evaluate a null hypothesis that the objective response rate (ORR) is ≤5% against the alternative hypothesis that it is ≥20%.

Detailed description:
Participants enrolled prior to Amendment 3 will receive zilovertamab vedotin at 2.5 mg/kg given intravenously on Day 1 of repeated 21-day cycles. Participants enrolled after Amendment 3 will receive zilovertamab vedotin at 1.75 mg/kg given intravenously on Day 1 and Day 8 of repeated 21-day cycles. Treatment will continue until progressive disease or discontinuation.

Arms: arm 1: Participants will receive intravenous (IV) zilovertamab vedotin 2.5 mg/kg on Day 1 of each repeated 21-day cycle (Q1/3W) or 1.75 mg/kg on Day 1 and Day 8 of each 21-day cycle (Q2/3W). Treatment will continue until progressive disease or discontinuation
Interventions: intervention 1: Zilovertamab vedotin
Intervention descriptions: intervention 1: Intravenous infusion

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 2 Study of VLS-101 in Patients with
Solid Tumors.
NCT04504916
September 20, 2022


PRODUCT: MK-2140  
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20-SEP-2022
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2 Study of VLS-101 in Patients with Solid Tumors
Protocol Number: 002-04
Compound Number: MK-2140
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):    
NCT
04504916
IND
151470
Approval Date: 20 September 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 4
20-SEP-2022
Updated the MK-2140 (VLS-101) starting dose, study population inclusion 
criteria, and contraception language and revised the SAP.
Amendment 3
15-NOV-2021
Added ROR1 expression levels; updated with analysis per RECIST 1.1 as 
assessed by BICR; and added cohort-specific eligibility criteria.
Amendment 2
23-MAR-2021
Modified inclusion laboratory values; added Phase 1 clinical data; and adjusted 
visit windows.
Amendment 1
05-AUG-2020
Implement FDA-requested changes for inclusion criteria and study design.
Original Protocol
16-JUN-2020
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment: 04
Overall Rationale for the Amendments:
Updated the MK-2140 (VLS-101) starting dose, study population inclusion criteria, and contraception language and revised the SAP.
Summary of Changes Table: 
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis, Intervention 
Groups
4.3 Justification for Dose
4.3.1 Starting Dose for This 
Study
4.3.2 Maximum Dose/Exposure 
for This Study
6.1 Study Intervention(s) 
Administered, Table 3
6.6 Dose Modification 
(Escalation/Titration/Other)
Increased starting dose to 2.0 mg/kg from 1.75 mg/kg
for most newly consented participants.
Dose updated from previous MTD 
to current RP2D now being used 
for all solid tumors. 
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Section # and Name
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria
• Included de novo metastatic disease in the TNBC
cohort
• Clarified that in the NSCLC cohort, 2 prior lines of 
therapy applies to metastatic disease
• Removed taxane exclusion for treatment of platinum-
resistant disease in the ovarian cancer cohort
• Expanded gastric cancer cohort to allow 2 lines of 
prior therapy and 1 additional line of HER2-directed 
monotherapy for participants with HER2+ disease 
and removed taxane exclusion from prior treatment
• Expanded pancreatic cancer cohort to allow 2 lines of 
prior therapy and locally advanced disease
To allow more participants to be 
eligible for study treatment. 
5.1 Inclusion Criteria
10.4.2 Contraception 
Requirements
Revised contraception requirements based on the half-
life of MK-2140 (VLS-101) and updated contraceptive 
methods that are considered ‘highly effective’.
To provide more clarity to 
contraception language.
9.7 Interim Analyses
Updated language in SAP regarding IA.
To clarify that totality of the data 
will be used to determine further 
action at IA.
Title Page
10.1.1 Code of Conduct for 
Clinical Trials
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. 
underwent an entity name and 
address change to Merck Sharp & 
Dohme LLC, Rahway, NJ, USA. 
This conversion resulted only in an 
entity name change and update to 
the address.
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Section # and Name
Description of Change 
Brief Rationale 
1.2 Schema, Figure 1 Study 
Design
Added figure to depict the study design. 
To provide a concise overview of 
the study design.
1.3 Schedule of Activities 
Updated SoA table to remove redundancy in footnotes 
for information present elsewhere in the protocol and 
clarified presentation.
To provide more clarity and ease of 
use.
1.3 Schedule of Activities
8.1.1 Informed Consent
8.1.1.2 Consent and Collection 
of Specimens for Future 
Biomedical Research
8.1.9.1 Withdrawal From Future 
Biomedical Research
Added information on FBR consent and its withdrawal 
and that the requirement for consent for FBR is 
optional.
To maintain alignment and 
consistency.
6.1 Study Intervention(s) 
Administered, Table 3
Added lyophilized MK-2140 (VLS-101, zilovertamab 
vedotin) formulation.
To update MK-2140 (VLS-101, 
zilovertamab vedotin) product 
reference based on currently 
available formulation options.
4.2.1.6 Planned Exploratory 
Biomarker Research
Updated text to provide further detail for biomarker 
plan for the MK-2140 (VLS-101) program. 
To reflect the biomarker plan for 
the MK-2140 (VLS-101) program 
unique to this particular study.
6.6 Dose Modification 
(Escalation/Titration/Other)
Clarified language regarding limitations on dosing 
delays.
To specify dosing delays due to
AEs and unrelated medical 
procedures.
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Section # and Name
Description of Change 
Brief Rationale 
8.2.1.2 Tumor Imaging and 
Assessment of Disease
Clarified language regarding timing of study imaging.
To clarify that study imaging is to 
be based on calendar days rather 
than treatment cycles.
8 Study Assessments and 
Procedures
Clarified maximum amount of blood to be collected per 
the laboratory manual.
To provide further detail regarding 
amount of blood drawn from 
participants.
Throughout Document
With the transfer of protocol content from the VelosBio 
protocol template to the MSD protocol template, minor 
administrative, formatting, grammatical, and/or
typographical changes were made throughout the 
document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities...........................................................................................22
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................25
2.2
Background ..........................................................................................................25
2.2.1
Receptor Tyrosine Kinase-like Orphan Receptor 1 .....................................25
2.2.2
ROR1 in Solid Tumors ................................................................................26
2.2.3
Summary......................................................................................................27
2.2.4
Chemistry.....................................................................................................28
2.2.4.1
MK-2140 (VLS-101) .........................................................................28
2.2.4.2
Mechanism of Action.........................................................................29
2.2.4.3
Pharmacology ....................................................................................29
2.2.4.3.1
MMAE Pharmacology and Toxicology...................................30
2.2.5
Preclinical and Clinical Studies ...................................................................31
2.2.6
Ongoing Clinical Studies.............................................................................32
2.3
Benefit/Risk Assessment......................................................................................33
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................34
4
STUDY DESIGN............................................................................................................37
4.1
Overall Design......................................................................................................37
4.2
Scientific Rationale for Study Design.................................................................38
4.2.1
Rationale for Endpoints ...............................................................................38
4.2.1.1
Efficacy Endpoints.............................................................................38
4.2.1.2
Safety Endpoints................................................................................39
4.2.1.3
Pharmacokinetic Endpoints ...............................................................39
4.2.1.4
Pharmacodynamic Endpoints.............................................................40
4.2.1.5
Antidrug Antibodies...........................................................................40
4.2.1.6
Planned Exploratory Biomarker Research.........................................40
4.2.1.7
Future Biomedical Research..............................................................42
4.3
Justification for Dose...........................................................................................42
4.3.1
Starting Dose for This Study........................................................................42
4.3.2
Maximum Dose/Exposure for This Study ...................................................43
4.3.2.1
Rationale for Dose Interval................................................................43
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4.4
Beginning and End-of-Study Definition ............................................................43
4.4.1
Clinical Criteria for Early Study Termination .............................................43
5
STUDY POPULATION ................................................................................................44
5.1
Inclusion Criteria.................................................................................................44
5.2
Exclusion Criteria................................................................................................51
5.3
Lifestyle Considerations......................................................................................53
5.3.1
Meals and Dietary Restrictions....................................................................53
5.3.1.1
Diet Restrictions.................................................................................53
5.3.1.2
Fruit Juice Restrictions ......................................................................53
5.4
Screen Failures.....................................................................................................53
6
STUDY INTERVENTION............................................................................................53
6.1
Study Intervention(s) Administered...................................................................54
6.2
Preparation/Handling/Storage/Accountability .................................................56
6.2.1
Dose Preparation..........................................................................................56
6.2.2
Dose Administration....................................................................................56
6.2.3
Handling, Storage, and Accountability........................................................56
6.3
Measures to Minimize Bias: Randomization and Blinding..............................57
6.3.1
Intervention Assignment..............................................................................57
6.3.2
Stratification.................................................................................................57
6.3.3
Blinding........................................................................................................57
6.4
Study Intervention Compliance..........................................................................57
6.5
Concomitant Therapy..........................................................................................57
6.5.1
Antibiotics, Antifungals, Antivirals.............................................................58
6.5.2
Anticancer Therapies Other than the Study Drug........................................58
6.5.3
Anticoagulants .............................................................................................58
6.5.4
Antidiarrheals...............................................................................................58
6.5.5
Antiemetics ..................................................................................................59
6.5.6
Antihistamine, Anti-inflammatory, and Antipyretic Drugs.........................59
6.5.7
Corticosteroids.............................................................................................59
6.5.8
Drugs Known to Inhibit or Induce Cytochrome P450 (CYP)3A4...............59
6.5.9
Drugs Known to Prolong the QT Interval....................................................60
6.5.10
Extravasation Support..................................................................................60
6.5.11
Hematopoietic Support ................................................................................60
6.5.12
Immunization...............................................................................................61
6.5.13
Infusion Reactions .......................................................................................61
6.5.14
Procedures/Surgery......................................................................................62
6.6
Dose Modification (Escalation/Titration/Other)...............................................62
6.7
Intervention After the End of the Study............................................................66
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6.8
Clinical Supplies Disclosure................................................................................67
6.9
Standard Policies..................................................................................................67
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................67
7.1
Discontinuation of Study Intervention...............................................................67
7.2
Participant Withdrawal From the Study...........................................................68
7.3
Lost to Follow-up .................................................................................................68
8
STUDY ASSESSMENTS AND PROCEDURES........................................................69
8.1
Administrative and General Procedures ...........................................................69
8.1.1
Informed Consent.........................................................................................69
8.1.1.1
General Informed Consent.................................................................70
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................70
8.1.2
Inclusion/Exclusion Criteria ........................................................................70
8.1.3
Participant Identification Card.....................................................................70
8.1.4
Medical History ...........................................................................................71
8.1.5
Prior and Concomitant Medications Review ...............................................71
8.1.5.1
Prior Medications...............................................................................71
8.1.5.2
Concomitant Medications..................................................................71
8.1.6
Assignment of Screening Number...............................................................71
8.1.7
Assignment of Treatment/Randomization Number.....................................72
8.1.8
Study Intervention Administration ..............................................................72
8.1.8.1
Timing of Dose Administration.........................................................72
8.1.8.2
Timing of Administration for VLS-101.............................................72
8.1.9
Discontinuation and Withdrawal .................................................................73
8.1.9.1
Withdrawal From Future Biomedical Research ................................73
8.1.10
Participant Blinding/Unblinding..................................................................73
8.1.11
Calibration of Equipment.............................................................................73
8.2
Efficacy Assessments ...........................................................................................74
8.2.1
Tumor Imaging and Assessment of Disease................................................74
8.2.1.1
Initial Tumor Scans............................................................................74
8.2.1.2
Tumor Scans During the Study..........................................................74
8.2.1.3
End-of-Treatment and Follow-up Tumor Scans................................75
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................75
8.3
Safety Assessments...............................................................................................75
8.3.1
Physical Examinations.................................................................................76
8.3.1.1
Full Physical Examination.................................................................76
8.3.1.2
Directed Physical Examination..........................................................76
8.3.2
Vital Signs....................................................................................................76
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8.3.3
Electrocardiograms ......................................................................................77
8.3.4
Clinical Safety Laboratory Assessments .....................................................77
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)..........................................................................................77
8.3.5
Pregnancy Testing........................................................................................78
8.3.6
Eastern Cooperative Oncology Group Performance Status.........................78
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................78
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................79
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......80
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...81
8.4.4
Regulatory Reporting Requirements for SAE .............................................81
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................81
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................82
8.4.7
Events of Clinical Interest............................................................................82
8.5
Treatment of Overdose........................................................................................82
8.6
Pharmacokinetics.................................................................................................83
8.6.1
Blood Collection for Plasma MK-2140 (VLS-101).....................................83
8.6.2
Blood Collection for Antidrug Antibodies ..................................................83
8.7
Pharmacodynamics..............................................................................................83
8.8
Biomarkers ...........................................................................................................83
8.9
Future Biomedical Research Sample Collection...............................................84
8.10
Visit Requirements...............................................................................................84
8.10.1
Screening......................................................................................................84
8.10.2
Treatment Period/Vaccination Visit ............................................................84
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................84
8.10.4
Posttreatment Visit.......................................................................................84
8.10.4.1
Safety Follow-up Visit.......................................................................85
8.10.4.2
Efficacy Follow-up Visits..................................................................85
8.10.4.3
Survival Follow-up Contacts .............................................................85
8.10.5
Vital Status...................................................................................................85
9
STATISTICAL ANALYSIS PLAN .............................................................................85
9.1
Statistical Analysis Plan Summary.....................................................................86
9.2
Responsibility for Analyses/In-house Blinding .................................................86
9.3
Hypotheses/Estimation ........................................................................................86
9.4
Analysis Endpoints...............................................................................................87
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9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..............................87
9.4.2
Safety Endpoints..........................................................................................87
9.4.3
Pharmacokinetics Endpoints........................................................................87
9.5
Analysis Populations............................................................................................88
9.5.1
Full Analysis Set..........................................................................................88
9.5.2
Responding Analysis Set .............................................................................88
9.5.3
Evaluable Analysis Set ................................................................................88
9.6
Statistical Methods...............................................................................................88
9.6.1
Statistical Methods for Efficacy Analysis....................................................88
9.6.2
Statistical Methods for Safety Analysis.......................................................89
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................91
9.6.3.1
Demographic and Baseline Characteristics .......................................91
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis............91
9.7
Interim Analyses ..................................................................................................91
9.8
Multiplicity ...........................................................................................................91
9.9
Sample Size and Power Calculations .................................................................92
9.10
Subgroup Analyses...............................................................................................92
9.11
Compliance (Medication Adherence).................................................................92
9.12
Extent of Exposure...............................................................................................92
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................93
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........93
10.1.1
Code of Conduct for Clinical Trials.............................................................93
10.1.2
Financial Disclosure.....................................................................................95
10.1.3
Data Protection.............................................................................................96
10.1.3.1
Confidentiality of Data ......................................................................96
10.1.3.2
Confidentiality of Participant Records...............................................96
10.1.3.3
Confidentiality of IRB/IEC Information............................................96
10.1.4
Publication Policy........................................................................................97
10.1.5
Compliance with Study Registration and Results Posting Requirements ...97
10.1.6
Compliance with Law, Audit, and Debarment ............................................97
10.1.7
Data Quality Assurance ...............................................................................98
10.1.8
Source Documents .......................................................................................99
10.1.9
Study and Site Closure.................................................................................99
10.2
Appendix 2: Clinical Laboratory Tests............................................................100
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................101
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................101
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10.3.2
Definition of AE ........................................................................................101
10.3.3
Definition of SAE ......................................................................................102
10.3.4
Additional Events Reported in the Same Manner as SAE.........................103
10.3.5
Recording AE and SAE .............................................................................104
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................107
10.4
Appendix 4: Contraceptive Guidance..............................................................109
10.4.1
Definitions..................................................................................................109
10.4.2
Contraception Requirements......................................................................110
10.5
Appendix 5: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................112
10.6
Appendix 6: Country-specific Requirements..................................................117
10.7
Appendix 7: Strong Inhibitors and Inducers of Cytochrome P450 
(CYP)3A4............................................................................................................118
10.8
Appendix 8: Eastern Cooperative Oncology Group.......................................119
10.9
Appendix 9: Abbreviations ...............................................................................120
11
REFERENCES.............................................................................................................125
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LIST OF TABLES
Table 1
Study Schedule of Activities......................................................................22
Table 2
Adequate Organ Function Laboratory Values ...........................................48
Table 3
Study Interventions....................................................................................55
Table 4
Dosing Modification Recommendations ...................................................64
Table 5
VLS-101 Dose Reduction Levels ..............................................................65
Table 6
Zilovertamab Vedotin Infusion Reaction Dose Modification and 
Treatment Guidelines.................................................................................65
Table 7
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................80
Table 8
Protocol-required Safety Laboratory Assessments..................................100
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................21
Figure 2
Schematic view of MK-2140 (VLS-101) Antibody, Linker, and Toxin 
Components ...............................................................................................29
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2 Study of VLS-101 in Patients with Solid Tumors
Short Title: A Phase 2 Study of VLS-101 in Patients with Solid Tumors
Acronym: MK-2140-002
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In male and female participants with advanced/metastatic solid tumors:
[Will be populated by selections made in Section 3 Objectives and Endpoints]
Objectives
Endpoints
Primary
•
To document the proportion of study 
participants who achieve an objective 
tumor response per RECIST 1.1 as 
assessed by blinded independent 
central review (BICR)
•
ORR, defined as the proportion of 
participants who achieve a confirmed 
CR or PR per RECIST 1.1 as assessed 
by BICR
Secondary
•
To document the proportion of study 
participants who achieve an objective 
tumor response per RECIST 1.1 as 
assessed by investigator
•
To characterize the duration of 
antitumor efficacy and to assess 
survival in participants receiving 
VLS-101
•
To document the safety of VLS-101
•
To evaluate the pharmacokinetic 
profile of VLS-101
•
ORR, defined as the proportion of 
participants who achieve a confirmed 
CR or PR per RECIST 1.1 as assessed 
by investigator
•
Time to response (TTR), defined as the 
interval from the start of study therapy 
to the first documentation of objective 
tumor response
•
Duration of response (DOR), defined as 
the interval from the first documentation 
of objective tumor response to the 
earlier of the first documentation of 
disease progression or death from any 
cause
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Objectives
Endpoints
•
Progression-free survival (PFS), defined 
as the interval from the start of study 
therapy to the  earlier of the first
documentation of disease progression or 
death from any cause
•
Time to treatment failure (TTF), defined 
as the interval from the start of study 
therapy to the earliest of the first 
documentation of disease progression, 
the permanent cessation of study drug
due to an AE, or death from any cause
•
Overall survival (OS), defined as the 
interval from the start of study therapy 
to death from any cause
•
Type, frequency, severity, timing of 
onset, duration, and relationship to study 
drug of any treatment-emergent adverse 
events (TEAEs); laboratory 
abnormalities; serious adverse events 
(SAEs); or adverse events (AEs) leading 
to interruption, modification, or 
discontinuation of study treatment 
(referencing the NCI Common 
Terminology Criteria for Adverse 
Events [CTCAE], Version 5.0, for 
grading of the severity of AEs and 
laboratory abnormalities)
•
Derived total VLS-101, total antibody, 
and MMAE pharmacokinetic 
parameters (including, as appropriate for 
the analyte: Cmax and AUC, as 
determined using noncompartmental 
methods)
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Solid Tumors
Population
Male and female participants ≥18 years of age, with 
adequate performance status and organ function who 
have histologically or cytologically confirmed solid 
tumor with metastases that have progressed during or 
following previous treatment with established therapies
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
N/A
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 42 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 30 participants per disease cohort will be allocated to complete the study as 
described in Section 9.1.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin-
istratio
n
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
VLS-101
(MK-2140)
zilovertamab 
vedotin
2.0 mg/kg
Q2/3W
IV 
Infusion
Q2/3W until 1 
discontinuation 
criterion is met
Test 
product
IV=intravenous; Q2/3W=repeated 3-week cycles with a drug infusion on Day 1 and Day 8 of each cycle
Total 
Number of 
Intervention 
Groups/
Arms
6 tumor-specific cohorts
Duration of 
Participation
Each participant will participate in the study for approximately 1-2 years
from the time the participant provides documented informed consent 
through the final contact. After a screening phase of 28 days, each 
participant will receive assigned intervention until disease progression is 
radiographically documented per modified RECIST 1.1, unacceptable 
AEs, intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the participant, noncompliance with 
study treatment or procedure requirements or administrative reasons 
requiring cessation of treatment, or withdrawal of consent.
After the end of treatment, each participant will be followed for the
occurrence of AEs for 30 days.
All participants will be followed for OS until death, withdrawal of 
consent, or end of the study.
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Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations is in Appendix 9.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
2L=second-line; 2-4L=second to fourth-line; 3L=third-line; N/n=number; NSCLC=non–small cell lung cancer; 
Q2/3W=every 2/3 weeks; TNBC=triple-negative breast cancer.
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1.3
Schedule of Activities
Table 1 summarizes the schedule of activities for this study.
Table 1
Study Schedule of Activities
Study Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
EOT/ 
DC
Posttreatment Phase
Notes
Treatment 
Cycle/Title:
Visit 1
1
2
3
≥4
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Treatment Day 
per Cycle:
-28 to -1a
1b
8
15
1
8
15
1
8
15
1
8
30 days from 
last dose 
Every 12 
Weeks
Every 12 
Weeks
Window (days):
±1
±2
±3
±1
±2
±3
±1
±2
±3
±1
±21
+7
±7
±7
Administrative Procedures
Informed Consent
X
Informed Consent 
for Future 
Biomedical 
Research
X
This is optional for 
the participant.
Inclusion/ 
Exclusion 
Criteria
X
Demographic and 
Medical History 
X
ECOG 
(Performance 
status)
X
Oxygen 
saturation 
X
Height
X
Weightc
X
X
X
X
AE Assessment
X
X
X
X
X
X
X
X
X
Prior/
Concomitant 
Medication 
Review
X
X
X
X
X
X
X
X
X
12-lead ECG
X
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Study Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
EOT/ 
DC
Posttreatment Phase
Notes
Treatment 
Cycle/Title:
Visit 1
1
2
3
≥4
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Treatment Day 
per Cycle:
-28 to -1a
1b
8
15
1
8
15
1
8
15
1
8
30 days from 
last dose 
Every 12 
Weeks
Every 12 
Weeks
Window (days):
±1
±2
±3
±1
±2
±3
±1
±2
±3
±1
±21
+7
±7
±7
Study Drug Administration 
Infusion 
premedication (if 
needed)
X
X
X
X
X
X
X
VLS-101 
Administration 
X
X
X
X
X
X
X
IV Infusion
Laboratory Assessments
Urinalysis 
X
Serum virology 
(HIV, HBV, and
HCV)
X
Coagulation 
INR/aPTT
X
Serum pregnancy 
test
X
X
X
X
X
X
Serum chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
C2D15 serum
chemistry may be
collected at a non-
study center
laboratory.
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
C2D15 hematology
may be collected at a
non-study center
laboratory.
Plasma for VLS-
101 
pharmacokineticsd
X
X
X
X
X
X
X
X
X
X
X
Serum for ADAe
X
X
X
X
X
Disease-Related Assessments
Plasma for 
ctDNAf
X
X
X
X
X
Tumor for 
ROR1/other 
profiling
X
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Study Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
EOT/ 
DC
Posttreatment Phase
Notes
Treatment 
Cycle/Title:
Visit 1
1
2
3
≥4
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Treatment Day 
per Cycle:
-28 to -1a
1b
8
15
1
8
15
1
8
15
1
8
30 days from 
last dose 
Every 12 
Weeks
Every 12 
Weeks
Window (days):
±1
±2
±3
±1
±2
±3
±1
±2
±3
±1
±21
+7
±7
±7
Radiological 
examinationg
X
X
X
X
First on-study scan: 9 
weeks, ±7days.
See Section 8.10.4.2 
for Efficacy FU 
requirements.
Vital status
Survival information 
(vital status) may be 
requested at any time 
during the study.
Posttherapy follow-up
Posttherapy 
safety assessment
X
See Section 8.10.4.1.
Survival follow-
up
X
See Section 8.10.4.3.
Abbreviations: ADA=antidrug antibodies; AE=adverse event; aPTT=activated partial thromboplastin time; C=cycle; ctDNA=circulating tumor deoxyribonucleic acid; D=Day; 
DC=discontinuation; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOI=end of infusion; EOT=end of treatment; FU=follow-up; HBV=hepatitis B; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=international normalized ratio, IV=intravenous; PD=progressive disease; ROR1=receptor tyrosine kinase-
like orphan receptor-1.
a
Screening procedures may be performed over as many days as necessary provided that screening activities are completed within 28 days before C1D1 of the study.
b
If obtained within 3 days prior to the start of therapy, serum pregnancy, serum chemistry, and hematology studies collected during screening need not be repeated on 
C1D1.
c
The C1 weight measurement may be obtained up to 72 hours before C1D1. If ≥5% change in body weight occurs, weight-based dosing should be readjusted.
d
Plasma for VLS-101 pharmacokinetics will be collected on C1D1 and C1D8 (predose and EOI), C1D15, C2D1 and C2D8 (predose and EOI),C≥3D1 and C≥3D8 (predose 
and EOI), C3D15, and at EOT. The acceptable margins relative to EOI is +5 minutes. 
e
Serum for VLS-101-reactive antibodies will be collected once on C1D1 (predose), C2D1 (predose), C≥3D1 (predose), and EOT.
f
Plasma for ctDNA will be collected once on C1D1 (predose), C2D1 (predose), C≥3D1 (predose), and EOT.
g
The baseline evaluation should occur within 28 days before C1D1. Scan timing should follow calendar days and should not be adjusted for delays in cycle starts. An EOT 
radiology assessment should be performed unless the participant already has radiographic confirmation of PD ≤4 weeks before permanent study drug discontinuation.
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2
INTRODUCTION
According to the NCI SEER program, ~40% of American men and women will develop 
cancer during their lifetimes [National Cancer Institute 2017]. In 2020, an estimated 
1,806,590 people in the United States will be diagnosed with a new cancer and >15,000,000 
are living with cancer. Despite advances in cancer prevention, diagnosis, and treatment, 
~606,520 patients died of this disease in 2020. Thus, cancer remains a continuing public 
health concern of major proportions.
Among those patients who develop a fatal cancer, most will have a solid tumor malignancy 
derived from epithelial or mesenchymal tissues that has metastasized, resulting in life-
threatening organ dysfunction. While metastatic disease is largely incurable, patients can be 
offered systemic hormonal, chemotherapeutic, or immunotherapeutic agents to delay tumor 
progression, manage disease-related complications, and extend life. Patients typically receive 
sequential therapies in an attempt to control disease manifestations. However, due to the 
acquisition of drug resistance, progressively less activity is observed; the disease course is 
characterized by a continuous decrease in the quality and the duration of tumor response with 
each subsequent treatment. Novel mechanisms of action are needed to safely offer new 
treatment options for patients with metastatic cancers that have become resistant to existing 
therapies.
VLS-101/MK-2140 is an antibody-drug conjugate that is an antagonist of ROR1-positive
tumors. VLS-101/MK-2140 is under study for the treatment of metastatic solid tumors as 
monotherapy. This is a Phase 2, nonrandomized, single-arm, multisite, open-label, study
evaluating the efficacy, safety, PK, immunogenicity, and pharmacodynamics of VLS-
101/MK-2140 in participants with metastatic solid tumors that are likely to express ROR1. 
Refer to the MK-2140 IB for further information.
2.1
Study Rationale
The purpose of this study is to provide critical efficacy, safety, PK, immunogenicity, and 
pharmacodynamic data in support of continued clinical development of VLS-101 and is 
typical for Phase 2 studies intended to evaluate efficacy of an investigational therapy in 
patients with cancer.
2.2
Background
2.2.1
Receptor Tyrosine Kinase-like Orphan Receptor 1
ROR1 is a type 1 transmembrane protein that shares homology with other receptor tyrosine 
kinases and shows high evolutionary conservation [Masiakowski, P. 1992] [Forrester, W. C., 
et al 1999] [Yoda, A., et al 2003]. The extracellular portion contains immunoglobulin-like 
sequences, a cysteine-rich domain homologous to frizzled receptors for various Wnt ligands, 
and a Kringle domain. The cytoplasmic portion contains a tyrosine kinase-like domain 
followed by serine/threonine- and proline-rich motifs.
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Based on studies in rodents, ROR1 is an embryonic factor that is physiologically expressed
during early embryogenesis and plays a critical role in neural, skeletal, and vascular
organogenesis [Oishi, I., et al 1999] [Al-Shawi, R., et al 2011] [Matsuda, T., et al 2001] 
[Lyashenko, N., et al 2010]. Functional studies in primary embryonic cells suggest that 
binding of the secreted glycoprotein ligand, Wnt5a, results in heterodimerization of ROR1 
with ROR2 (the other member of the ROR family) and can stimulate neuronal synapse 
formation [Paganoni, S., et al 2010]. During fetal development, the expression of ROR1 
decreases [Masiakowski, P. 1992] [Al-Shawi, R., et al 2011] [Paganoni, S., et al 2010]. 
Normal adult tissues lack surface expression of the ROR1 protein [Fukuda, T., et al 2008] 
[Hudecek, M., et al 2010] [Zhang, S., et al 2012] [Liu, Y., et al 2015] except for rare B-
lymphocyte precursors known as hematogones (thenon-neoplastic counterpart to precursor-B
ALL) [Broome, H. E., et al 2011].
However, consistent with a role as an onco-embryonic factor, high levels of ROR1 protein
expression have been found in multiple cancers, including both solid tumors [Zhang, S., et al
2012] [Balakrishnan, A., et al 2017] and hematological malignancies [Daneshmanesh, A. H., 
et al 2013] ROR1 expression and activation appear to be correlated with features of tumor 
aggressiveness in models of breast cancer, lung cancer, gastric cancer, melanoma, and CLL
[Li, P., et al 2010] [Gentile, A., et al 2011] [Zhang, S., et al 2012] [Yamaguchi, T., et al 
2012] [Daneshmanesh, A. H., et al 2013] [Hojjat-Farsangi, M., et al 2013] [Hojjat-Farsangi, 
M., et al 2013] [O'Connell, M. P., et al 2013] [Hamilton, G., et al 2015] [Ida, L., et al 2016] 
[Janovska, P., et al 2016]. ROR1 expression is also associated with markers for CSCs, which 
appear relatively resistant to conventional therapy and repopulate tumors following standard 
treatment [Zhang, S., et al 2014] [Jung, E. H., et al 2016] [Hamilton, G., et al 2015] [Katoh, 
M. 2017] [Cao, J., et al 2018]. It is also expressed on cells that have developed greater 
invasiveness and metastatic potential because theyhave undergone EMT [Cui, B., et al 2013] 
[Hamilton, G., et al 2015] [Jung, E. H., et al 2016] [Cao, J., et al 2018]. In multiple cancers, 
ROR1 expression has been associated with poor clinical outcomes [Zhang, H., et al 2014] 
[Zhang, S., et al 2014] [Cui, B., et al 2016] [Zhou, J. K., et al 2017].
2.2.2
ROR1 in Solid Tumors
Consistent with a role as an onco-embryonic factor, high levels of ROR1 gene and protein
expression have been found in multiple solid tumors [Balakrishnan, A., et al 2017] [Zhang, S., 
et al 2012]. Breast, lung, ovarian, pancreatic and gastric carcinomas have some of the highest 
expression of ROR1.
A tissue microarray study of tumor specimens from 112 patients with breast cancer found 
that 72% expressed ROR1, including 40% with high ROR1 staining and 32% with moderate 
or low ROR1 staining [Zhang, S., et al 2012]. ROR1 expression appears to be more common 
in aggressive subtypes such as TNBC and basal-like breast cancer [Klemm, F., et al 2011] 
[Zhang, S., et al 2012] [Cui, B., et al 2013] [Bleckmann, A., et al 2016] [Chang, H., et al 
2015] [Balakrishnan, A., et al 2017] [Li, C., et al 2017] [Fultang, N., et al 2019] [Pandey, G., 
et al 2019] but appears to increase in expression in TNBC, ER/progesterone receptor–
positive, and/or HER2-positive breast cancers following treatment with chemotherapy, the 
antibody-drug conjugate trastuzumab emtansine, or corticosteroids (as are commonly 
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administered in support of chemotherapy) [Islam, S. S., et al 2019] [Fultang, N., et al 2020] 
[Obradovic, M. M. S., et al 2019] [Zhang, S., et al 2019] ROR1 expression has been 
repeatedly demonstrated to be associated with shorter disease-free survival, metastasis-free 
survival, and OS in patients with breast cancer [Cui, B., et al 2013] [Chien, H. P., et al 2016] 
[Cao, J., et al 2018] [Islam, S. S., et al 2019] [Obradovic, M. M. S., et al 2019] [Pandey, G., 
et al 2019].
High levels of ROR1 gene or protein expression have been found in lung cancers [Gentile, 
A., et al 2011] [Zhang, S., et al 2012] [Karachaliou, N., et al 2014] [Liu, Y., et al 2015] 
[Zheng, Y. Z., et al 2016] [Liu-Kreyche, P., et al 2019] [Balakrishnan, A., et al 2017]. A 
tissue microarray study of tumor specimens from 64 patients with lung cancers found that 
77% expressed ROR1, with a high level of ROR1 staining evident in most ROR1-positive 
samples [Zhang, S., et al 2012]. In an IHC analysis in 232 patients with lung
adenocarcinoma, tumors from 218 (94%) patients showed evidence of ROR1 expression 
characterized as weak (21%), moderate (41%), or strong (31%) [Zheng, Y. Z., et al 2016]. 
Among the types of NSCLC, ROR1 expression has appeared to be more common in lung 
adenocarcinomas than in squamous cell lung carcinomas [Zhang, S., et al 2012] [Liu, Y., et 
al 2015] [Balakrishnan, A., et al 2017]. Higher ROR1 expression has been significantly 
associated with advanced-stage disease and lymph node metastasis in patients with lung 
cancers [Zheng, Y. Z., et al 2016]. The association between ROR1 expression and adverse
OS is particularly strong in lung cancers [Zheng, Y. Z., et al 2016] [Saleh, R. R., et al 
2019].
High levels of ROR1 expression have been reported in ovarian cancer [Zhang, H., et al 2014] 
[Zhang, S., et al 2014] [Zhang, S., et al 2012] [Balakrishnan, A., et al 2017]. High expression 
of ROR1 was also associated with poor clinical outcome as measured by disease-free and OS
[Zhang, H., et al 2014]. Expression was also positively correlated with stage, grade, and 
lymph node involvement. High expression of ROR1 was associated with worse DFS (HR: 
2.9, 95% CI: 1.6-5.1) and OS (HR: 3.5, 95% CI: 2.0-6.3).
High levels of ROR1 expression have been reported in gastric cancer [Chang, H., et al 2015].
Compared with other solid tumors, gastric cancers have some of the greatest gene expression 
according to data from TCGA available in the public domain (cbioportal.org). Expression of 
ROR1 in gastric cancer was positively correlated with expression of pAKT, pCREB, and 
proliferation as measured by Ki-67 labeling index. ROR1 expression was also positively 
associated with tumor stage and the presence of perineural invasion. 
High levels of ROR1 expression have also been reported in pancreatic cancer [Zhang, S., et 
al 2012] [Xu, G. L., et al 2018]. However, one study found a more modest expression of
ROR1 in pancreatic cancers [Balakrishnan, A., et al 2017]. Compared with other solid 
tumors, pancreatic cancers have very high gene expression according to data from TCGA 
available in the public domain (cbioportal.org). 
2.2.3
Summary
The accumulating data regarding its role in cancer and lack of expression in normal tissues
indicate that ROR1 represents an attractive therapeutic target for cancer intervention. For
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patients with breast cancer, the data indicate that ROR1 expression may be particularly 
frequent among those with TNBC or basal-like breast cancer or among those whose cancer
has progressed following prior cytotoxic therapy. For patients with NSCLC, it appears that 
ROR1 expression is most evident in those with metastatic lung adenocarcinoma, especially 
among thosewith therapy-resistant disease. For ovarian, gastric, and pancreatic cancers, 
ROR1 is highly expressed and associated with poor prognostic features. Collectively, the 
data support the potential for therapeutic benefit in these groups of patients with a ROR1-
targeted treatment.
Refer to the IB/approved labeling for detailed background information on MK-2140.
2.2.4
Chemistry
2.2.4.1
MK-2140 (VLS-101) 
MK-2140 (VLS-101) is an ADC comprising: 
•
The humanized IgG1 monoclonal antibody, UC-961 (previously also known as 
cirmtuzumab) that recognizes an epitope on the extracellular domain of ROR1
•
A proteolytically cleavable mc-vc-PAB linker, and
•
The antimicrotubule agent, MMAE.
MK-2140 (VLS-101) has a target mean drug-to-antibody ratio of 4.0 ± 0.5 (distribution: 0 to 
8). The combination of mc-vc-PAB and MMAE, was selected for conjugation to UC 961 
given the well characterized pharmacology, toxicology, clinical efficacy, and clinical safety 
of this linker-toxin combination, as exemplified by the FDA- and EMA-approved anti-CD30 
ADC, brentuximab vedotin (Adcetris™) [U.S. Prescribing Information 2019]; the anti-
CD79b ADC, PV (Polivy™) [U.S. Prescribing Information 2020]; and the anti-nectin-4 
ADC, enfortumab vedotin-ejfv (Padcev™) [U.S. Prescribing Information 2021]. A schematic 
of MK-2140 (VLS-101) is provided in Figure 2.
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Figure 2
Schematic view of MK-2140 (VLS-101) Antibody, Linker, and Toxin 
Components
Abbreviations: mc-val-cit-PABC=maleimidocaproyl-valine-citrulline-para-aminobenzoate; MMAE=monomethyl 
auristatin E.
2.2.4.2
Mechanism of Action
MK-2140 (VLS-101) is a ROR1 targeting ADC as described above, comprising UC-961 
conjugated to vedotin (the combination of mc-vc-PAB and MMAE). The anticancer activity 
of MK-2140 (VLS-101) is due to the binding of the ADC to ROR1-expressing cells, 
internalization of the ADC-ROR1 complex with trafficking to tumor cell lysosomes, and 
release of MMAE via lysosomal proteolytic cleavage. Binding of MMAE to tubulin disrupts 
the microtubule network within the tumor cell, subsequently inducing cell-cycle arrest and 
apoptotic tumor cell death.
The cell surface protein, ROR1, mediates signals from its ligand, the secreted glycoprotein, 
Wnt5a. Consistent with its role in influencing the fate of stem cells during embryogenesis, 
ROR1 expression is observed on invasive malignancies that revert to an embryonic 
transcriptional program. Expression of ROR1 is frequently expressed on the malignant cells 
of patients with hematological cancers but is not on normal adult tissues; thus, ROR1 has a 
favorable selectivity profile as a therapeutic target.
2.2.4.3
Pharmacology 
ROR1 is a type 1 transmembrane protein that shares homology to other receptor tyrosine 
kinases and shows high evolutionary conservation [Masiakowski, P. 1992] [Forrester, W. C., 
et al 1999] [Yoda, A., et al 2003] [Katoh, M. 2017]. The extracellular portion contains 
immunoglobulin-like sequences, a cysteine-rich domain homologous to frizzled receptors for 
various Wnt ligands, and a Kringle domain. The cytoplasmic portion contains a tyrosine 
kinase-like domain followed by serine/threonine- and proline-rich motifs.
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Based on studies in rodents, ROR1 is an embryonic factor that is physiologically expressed 
during early embryogenesis and plays a critical role in neural, auditory, skeletal, and vascular 
organogenesis [Matsuda, T., et al 2001] [Al-Shawi, R., et al 2011] [Lyashenko, N., et al 
2010]. Functional studies in primary embryonic cells suggest that binding of the secreted 
glycoprotein ligand, Wnt5a, results in heterodimerization of ROR1 with ROR2 (the other 
member of the ROR family) and can stimulate neuronal synapse formation [Paganoni, S., et 
al 2010]. During fetal development, the expression of ROR1 decreases [Al-Shawi, R., et al
2011] [Paganoni, S., et al 2010]. Normal adult tissues lack surface expression of the ROR1 
protein [Hudecek, M., et al 2010] [Zhang, S., et al 2012] [Liu, Y., et al 2015] except for rare 
B-lymphocyte precursors known as hematogones, the non-neoplastic counterpart to 
precursor-B ALL [Broome, H. E., et al 2011].
However, consistent with a role as an onco-embryonic factor, high levels of ROR1 protein 
expression have been found in multiple cancers, including both hematological malignancies 
[Daneshmanesh, A. H., et al 2013] and solid tumors [Zhang, S., et al 2012] [Zhang, S., et al 
2012] [Liu, Y., et al 2015]. Among hematological cancers, these studies indicate near 
universal expression of ROR1 expression in CLL/SLL and MCL and document evidence of 
ROR1 expression in many patients with MZL, FL, DLBCL, ALL, T-cell cancers, and AML 
[Barna, G., et al 2011] [Shabani, M., et al 2011] [Bicocca, V. T., et al 2012] [Daneshmanesh, 
A. H., et al 2013] [Hogfeldt, T., et al 2013] [Karvonen, H., et al 2017] [Yu, J., et al 2018] 
[Diamanti, P., et al 2019] [Karvonen, H., et al 2019].
The accumulating data regarding its role in cancer and lack of expression in normal tissues 
indicate that ROR1 represents an attractive, tumor-specific therapeutic target for cancer 
intervention. Collectively, these data support the potential for therapeutic benefit from a 
ROR1 targeted treatment in patients with relapsed refractory DLBCL. 
2.2.4.3.1
MMAE Pharmacology and Toxicology
The IC50 for MMAE in the hERG tail current assay has been estimated to be >100 µM. These 
data suggest a low risk of QT prolongation with MMAE as predicted by the hERG assay, 
because this in vitro concentration is several orders of magnitude higher than the expected 
mean plasma Cmax of MMAE in patients who are treated with a clinical dose of MK-2140 
(VLS-101). Such expectations are supported by lack of QT prolongation in participants 
receiving brentuximab vedotin.
In cell-free systems evaluating its effects on tubulin, MMAE was shown to inhibit 
microtubule polymerization, disrupting the intracellular microtubule network. Such effects 
result in cell-cycle arrest leading to apoptosis, especially in rapidly dividing tissues.
Binding of MMAE to plasma proteins is low to moderate, suggesting that variation in the 
binding capacity of plasma proteins does not have a major impact on the concentration of 
free drug in the plasma. MMAE rapidly distributes to erythrocytes, resulting in a blood-to-
plasma ratio of 2.
Refer to the IB for more information on MMAE pharmacology and toxicology for MK-2140.
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2.2.5
Preclinical and Clinical Studies
In studies evaluating its binding kinetics [Choi, M. Y., et al 2018], UC-961 showed high-
affinity binding against the ROR1 epitope with an equilibrium dissociation constant (Kd) of 
2 nM. Cellular binding to ROR1 in ROR1-positive JeKo-1 MCL cells showed highly 
reproducible binding in the linear range of the assay with a EC50 of ~9.5 ng/mL [Choi, M. Y., 
et al 2018].
In vitro incubation of Wnt5a-treated CLL cells with UC-961 was shown to disrupt the 
ROR1/ROR2 heterooligomer [Yu J, Chen L, Cui B, Widhopf GF 2nd, Shen Z, Wu R 2016]. 
UC-961 also inhibited the capacity of Wnt5a to recruit GEFs to either ROR1 or ROR2, thus 
blocking downstream activation of the oncogenic GTPases, Rac1 and RhoA, and inhibiting 
phosphorylation of HS1 [Hasan, M. K., et al 2017].
Similarly, in primary lymphoma cells from patients with MCL, UC-961 could inhibit the 
capacity of Wnt5a to induce Rac1 activation and could impair cycling of the malignant cells 
[Yu, J., et al 2018].
In vivo, UC-961 significantly inhibited the growth of human CLL-derived MEC1-ROR1 
cells in mice and attenuated tumor expression of ROR1 (consistent with internalization of the 
receptor in the presence of the antibody) [Yu J, Chen L, Cui B, Widhopf GF 2nd, Shen Z, 
Wu R 2016]. In the ROR1 × TCL1 immune-competent human transgenic mouse model that 
had been used to evaluate the precursor antibody, D10 [Widhopf, G. F. 2nd, et al 2014], UC-
961 treatment caused reductions in leukemic B cells in the spleens of the animals [Yu J, 
Chen L, Cui B, Widhopf GF 2nd, Shen Z, Wu R 2016].
In support of clinical testing of UC-961, University of California San Diego, performed a 
GLP safety pharmacology, toxicology, and toxicokinetic study of UC-961 in Wistar rats 
[Choi, M. Y., et al 2018] [Choi MY, Widhopf GF, Wu, CCN, Cui B, Lao, F, Sadarangani A 
2015]. The study evaluated UC-961 at doses of 40, 120, and 400 mg/kg given weekly for 5 
doses over 28 days with a 28-day recovery. In all dosing cohorts, UC-961 was well tolerated 
and showed no adverse clinical signs, clinical pathology findings, or histopathological 
effects. Toxicokinetic data indicated that UC-961 accumulated in the serum with successive 
weekly administrations of the drug, reaching trough concentrations by Day 28 of ~800, 
~3100, and 4700 μg/mL at doses of 40, 120, and 400 mg/kg, respectively. Based on the 
results of this study, UC-961 showed no drug-related adverse effects despite the achievement 
of substantial drug exposures; accordingly, the NOAEL in rats was the highest dose tested 
(400 mg/kg).
University of California San Diego also performed a single-dose safety and PK study of UC-
961 in 3 cynomolgus monkeys at a dose of 40 mg/kg [Choi, M. Y., et al 2018] [Choi MY, 
Widhopf GF, Wu, CCN, Cui B, Lao, F, Sadarangani A 2015]. The results indicated no 
adverse clinical, hematology, clinical chemistry, or circulating immunocyte perturbations 
despite achieving a mean Cmax of 2,023 μg/L and a mean t1/2 of 14.8 days. Clinical evaluation 
of UC-961 has comprised a Phase 1a, sequential, 3+3 dose-escalation study that enrolled 26 
adult men and women with relapsed or refractory CLL/SLL [Choi MY, Widhopf GF 2nd, 
Ghia EM, Kidwell RL, Hasan MK, Yu J, et al. 2018]. Study participants received a total of 4 
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IV infusions of UC-961 monotherapy given over infusion times of 1.5 to 4 hours at dose 
levels ranging from 0.15 to 20 mg/kg (the highest planned dose).
UC-961 was very well tolerated. AEs were primarily Grade 1 or 2 in intensity and comprised 
events that were most commonly related to the underlying CLL/SLL, intercurrent illness, 
comorbidity, or concomitant medications. There was no evidence of dose-dependent 
increases in the incidence or severity of AEs. No DLTs were observed, no Grade ≥4 events 
were reported, no drug-related SAEs occurred, and no MTD was established within the tested 
dose range. Infusion reactions were not evident. TLS was not seen.
UC-961 PK parameters of Cmax and AUC increased in a generally dose-proportional manner 
with mean Cmax values ranging from ~20 µg/mL to >360 µg/mL. Following the last (fourth) 
dose in participants across the dose range of 1 to 20 mg/kg, mean t1/2 values for the UC-961 
antibody ranged from 22.9 to 32.7 days.
Pharmacodynamic assessments showed dose- and exposure-dependent reductions in ROR1 
expression on CLL/SLL cells across the range of UC-961 doses. UC-961 also decreased 
downstream markers of ROR1 signaling in circulating CLL cells.
In summary, UC-961 therapy showed no overt drug-related adverse effects despite attaining 
high sustained systemic drug exposures and inhibition of ROR1-mediated signaling in CLL 
cells, thus documenting the safety and specificity of ROR1 targeting. However, the naked 
UC-961 antibody lacked clinical antitumor activity, suggesting that inhibition of ROR1 
signaling might not be sufficient for clinical efficacy and supporting the development of a 
UC-961-based ADC, specifically VLS-101.
There are no completed clinical studies of VLS-101/MK-2140. 
2.2.6
Ongoing Clinical Studies
Zilovertamab vedotin in various hematological malignancies is being evaluated in Study 
MK-2140-001. Zilovertamab vedotin has been administered IV Q3W, Q2/3W, or Q3/4W, 
with doses ranging from 0.5 mg/kg to 2.5 mg/kg.
The preliminary results from MK-2140-001 suggest that zilovertamab vedotin has a 
predictable PK profile consistent with those observed with other MMAE-containing ADCs 
approved for other indications, ie, brentuximab vedotin (Adcetris™) [U.S. Prescribing 
Information 2019]; PV (Polivy™) [U.S. Prescribing Information 2020]; and the anti-nectin-4 
ADC, enfortumab vedotin-ejfv (Padcev™) [U.S. Prescribing Information 2021]. For 
zilovertamab vedotin, the ADC, and MMAE, have a terminal t1/2 of approximately 4 days. 
Maximum MMAE concentrations are reached 4 days after dosing, reflecting the time scale of 
systemic release of MMAE. 
Available safety data (27-NOV-2020) suggest the safety profile of zilovertamab vedotin at 
the doses tested is tolerable and manageable. There were no DLTs observed among 
7 participants who received the lower doses of zilovertamab vedotin at 1.5 mg/kg (n=3), 
1 mg/kg (n=3), and 0.5 mg/kg (n=1) out of the 32 participants administered zilovertamab 
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vedotin at Q3W of the dose-escalation portion of the study. At 2.25 mg/kg, a DLT was 
observed in 1 of 10 (10%) participants who completed Cycle 1, comprising asymptomatic 
neutropenia (Grade 4); the event was managed successfully by dose reduction and 
pegfilgrastim support. At 2.5 mg/kg, DLTs were observed in 3 of 14 (21.4%) participants, 
comprising asymptomatic neutropenia (Grade 4), febrile neutropenia (Grade 3), and diarrhea 
(Grade 3); these events were managed by dose reduction and supportive care. TLS has not 
been observed in any of the patients as of the 27-NOV-2020 safety data cutoff date.
Preliminary efficacy results from participants with DLBCL in Study MK-2140-001 (data 
extract February 2021) resulted in an ORR of 42.9% (6 of 14) for participants treated with 
zilovertamab vedotin Q3W compared with 33.3% (3 of 9) for participants treated with 
zilovertamab vedotin Q2/3W or Q3/4W; thus, there was no evident difference in ORR 
between dosing schedules. These efficacy results provide clinical proof of concept for 
targeting ROR1 with zilovertamab vedotin and show durable objective responses in patients 
with advanced heavily pretreated cancers.
Refer to the respective IB for ongoing clinical study data for MK-2140.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
The design and conduct of this Phase 2 study of VLS-101 considers patient medical need, the
importance of the drug target in the planned treatment setting, nonclinical efficacy and safety
information, and clinical findings with VLS-101 and related drugs. The collective data 
supportthe following conclusions:
•
Metastatic cancers are serious, disabling, and life-threatening disorders. Existing 
therapies can induce prolonged regressions but typically lose effectiveness over time. 
New therapies with new mechanisms of action are needed to overcome disease resistance
and improve outcomes.
•
ROR1 expression offers a cancer-specific marker in several cancers. Through selective
targeting of ROR1-positive tumor cells, VLS-101 may safely improve clinical outcomes 
for patients with previously treated cancers.
•
The potential for beneficial clinical efficacy of VLS-101 against ROR1-positive cancers 
is well founded on evaluation of its therapeutic effects in relevant in vitro and in vivo 
efficacy models.
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•
The safety of advancing the development of VLS-101 in this study is well supported by
nonclinical evaluations of UC-961 and VLS-101 pharmacology, PK, and toxicology; by 
Phase 1 clinical assessment of the safety, PK, and pharmacodynamics of UC-961; and by 
Phase 1 clinical assessment of the safety, PK, pharmacodynamics, immunogenicity, and 
efficacy of VLS-101. These data are supplemented by nonclinical information regarding 
MMAE, and prior clinical experience with the commercially available ADCs 
brentuximab vedotin (anti-CD30), polatuzumab vedotin (anti-CD79b), and enfortumab 
vedotin (anti-nectin-4).
•
This collective information provides a basis for participant enrollment criteria; dose 
selection; administration of appropriate dosing regimens and supportive care; and safety,
PK, and efficacy monitoring within this study.
•
Given the seriousness of previously treated, progressive cancers and the aggregate 
potential benefits considered in the context of potential risks, clinical development of 
VLS-101 in patients with relapsed or refractory solid tumors is justified.
The rationale for specific design features of the study is provided in relevant sections of the
protocol, including Section 2.1 (Study Rationale), Section 3 (Hypotheses, Objectives, and 
Endpoints), Section 4 (Study Design), Section 5 (Study Population), and Section 6 (Study 
intervention)
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In male and female participants with advanced/metastatic solid tumors:
Objectives
Endpoints
Primary
•
To document the proportion of study 
participants who achieve an objective 
tumor response per RECIST 1.1 as 
assessed by blinded independent central 
review (BICR)
•
ORR, defined as the proportion of 
participants who achieve a confirmed 
CR or PR per RECIST 1.1 as assessed 
by BICR
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Objectives
Endpoints
Secondary
•
To document the proportion of study 
participants who achieve an objective 
tumor response per RECIST 1.1 as 
assessed by investigator
•
To characterize the duration of 
antitumor efficacy and to assess survival 
in participants receiving VLS-101
•
To document the safety of VLS-101
•
To evaluate the pharmacokinetic profile 
of VLS-101
•
ORR, defined as the proportion of 
participants who achieve a confirmed 
CR or PR per RECIST 1.1 as assessed 
by investigator
•
Time to response (TTR), defined as the 
interval from the start of study therapy 
to the first documentation of objective 
tumor response
•
Duration of response (DOR), defined as 
the interval from the first 
documentation of objective tumor 
response to the earlier of the first 
documentation of disease progression or 
death from any cause
•
Progression-free survival (PFS), defined 
as the interval from the start of study 
therapy to the  earlier of the first
documentation of disease progression or 
death from any cause
•
Time to treatment failure (TTF), defined 
as the interval from the start of study 
therapy to the earliest of the first 
documentation of disease progression, 
the permanent cessation of study drug
due to an AE, or death from any cause
•
Overall survival (OS), defined as the 
interval from the start of study therapy 
to death from any cause
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Objectives
Endpoints
•
Type, frequency, severity, timing of 
onset, duration, and relationship to 
study drug of any treatment-emergent 
adverse events (TEAEs); laboratory 
abnormalities; serious adverse events 
(SAEs); or adverse events (AEs)
leading to interruption, modification, or 
discontinuation of study treatment 
(referencing the NCI Common 
Terminology Criteria for Adverse 
Events [CTCAE], Version 5.0, for 
grading of the severity of AEs and 
laboratory abnormalities)
•
Derived total VLS-101, total antibody, 
and MMAE pharmacokinetic 
parameters (including, as appropriate 
for the analyte: Cmax and AUC, as 
determined using noncompartmental 
methods)
Tertiary/Exploratory
•
To explore the effects of VLS-101 on 
pharmacodynamic markers relating to
disease manifestations
•
To correlate baseline tumor 
characteristics with outcomes in 
participants administered VLS-101
•
To document the supportive care 
profiles of VLS-101
•
To assess the immunogenicity of 
VLS-101
•
Percent change in tumor dimensions, 
defined as the percent change from 
baseline in the sum of the longest 
diameters of non-nodal target lesions 
and the shortest diameters of nodal 
target lesions
•
Type, frequency, and timing of use of 
supportive care and other concomitant 
medications
•
Changes in concentrations of circulating
tumor-associated protein and DNA
markers (as measured using appropriate 
immunoassay and sequencing methods)
•
Baseline tumor protein expression of 
ROR1 and markers relating to tumor 
proliferation, apoptosis, and 
immunosurveillance (as assessed by 
IHC and/or fluorescent-activated cell
sorter [FACS])
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Objectives
Endpoints
•
Baseline tumor mutation, gene 
expression, and protein expression 
status (as assessed by appropriate 
techniques)
•
The incidence of ADA will be 
summarized by regimen
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2, nonrandomized, single-arm, multisite open-label study evaluating the 
efficacy, safety, PK, immunogenicity, and pharmacodynamics of VLS-101/MK-2140 in 
patients with metastatic solid tumors that are likely to express ROR1. Evaluation of VLS-101 
in participants with specific tumor types will be determined by the Sponsor considering 
available data on the frequency of ROR1 expression, VLS-101 activity in relevant animal 
models, and medical need. Accrual of the following cohorts is planned:
•
Cohort A: Participants with previously treated TNBC (ie, with disease that is ER-
negative, progesterone receptor-negative, and HER2-negative)
•
Cohort B: Participants with previously treated non-TNBC (ie, with disease that is ER-
positive and/or progesterone receptor–positive, and HER2-negative)
•
Cohort C: Participants with previously treated nonsquamous NSCLC
•
Cohort D: Participants with platinum-resistant ovarian cancer
•
Cohort E: Participants with previously treated gastric cancer
•
Cohort F: Participants with previously treated pancreatic cancer
Because a validated ROR1 expression assay is not yet available and because it is still 
necessary to explore whether the extent and magnitude of ROR1 expression determine 
response to VLS-101, study participants will not be preselected for ROR1 expression, but 
archival or fresh tumor tissue will be collected for post hoc correlation with clinical 
outcomes.
VLS-101 will be administered IV using the RDR as derived from a previous Phase 1 
evaluation. Drug administration can continue until the occurrence of any of the events noted 
in Section 7.1 below.
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Enrollment of each cohort will be performed using a 2-stage Simon design, in which the 
enrollment of further participants with that tumor type to the second stage will be decided 
based on the tumor response rate in the first stage and the totality of data.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The study has been designed to provide critical efficacy, safety, PK, immunogenicity, 
pharmacodynamic, and biomarker data in support of continued clinical development of VLS-
101 and is typical for Phase 2 studies intended to evaluate efficacy of an investigational 
therapy in patients with cancer.
Centralized conduct of the study using experienced sites, investigators, laboratories, and 
CROs is intended to provide a consistent approach to assessments of VLS-101 efficacy, 
safety, and pharmacology. A central IRC review offer systematic expert interpretations of 
efficacy findings.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The proposed endpoints are relevant to the pathophysiology and clinical manifestations of 
solid tumors, the biology of ROR1, the known pharmacology of VLS-101, and the goals of 
the study in providing information regarding drug efficacy. These types of endpoints have 
been employed in prior studies evaluating other ADCs and anticancer agents and can be 
evaluated with acceptable accuracy and reliability.
Determinations of the magnitude and duration of changes in tumor size will be based on 
well-established response and progression criteria as applied to radiographic or laboratory 
measurements. Beyond assessing the ability of the study drug to control tumor growth, tumor 
assessments will also be considered in defining the proper duration of treatment for each 
study participant. The specific endpoints of overall tumor control evaluated in this trial are 
customarily assessed and reported in studies of new therapies in patients with cancer. ORRs
provide integrated assessments of the magnitude and extent of changes in tumor dimension 
that conveniently categorize and describe treatment effects. PFS offers a well-established 
outcome measure that directly measures treatment effect, conveys important longitudinal 
information regarding tumor control, can be characterized in all participants using intention-
to-treat principles, and is readily analyzed using statistical methods such as Kaplan-Meier 
techniques.
TTR and DOR are important in characterizing the rapidity of achieving tumor shrinkage and 
the duration of tumor control. TTF offers a further characterization of participant outcome 
that incorporates the added dimension of drug tolerability; the degree of correspondence 
between PFS and TTF provides an assessment of how commonly chronic or cumulative 
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adverse effects are compromising the ability to maintain therapy. The 9- to 12-week cadence 
of tumor assessments is consistent with the expected natural history of response and 
progression in relapsed/refractory solid tumors, current clinical practice, and the goals of the 
trial in documenting meaningful VLS-101-mediated tumor regression.
Evaluation of plasma VLS-101 and MMAE concentrations will be performed using 
bioanalytical methods that have been validated for use in animal toxicology studies and in 
this clinical study. Plasma samples will be retained for any necessary follow-up assays.
An exploration of VLS-101 immunogenicity is critical to determining the utility of the drug 
when administered chronically. Correlations between the presence/absence of positivity for 
ADAs, PK and pharmacodynamic markers, activity, and safety of VLS-101 may be explored.
4.2.1.2
Safety Endpoints
Type, frequency, severity, timing of onset, duration, and relationship to study drug of any 
TEAEs; laboratory abnormalities; SAEs; or AEs leading to interruption, modification, or 
discontinuation of study treatment (referencing the NCI CTCAE, Version 5.0, for grading of 
the severity of AEs and laboratory abnormalities).
In defining the therapeutic ratio of a new drug, it is imperative that its safety profile be fully 
characterized. Proper description of each AE or laboratory abnormality requires an 
understanding of the type, incidence, timing, severity, and relatedness to study drug. In this 
study, particular focus will be placed on monitoring for toxicities that were encountered in 
the nonclinical studies of VLS-101 and prior clinical studies with VLS-101 and other 
MMAE-containing ADCs [U.S. Prescribing Information 2019] [U.S. Prescribing Information 
2020] [U.S. Prescribing Information 2021] [Saber H, Leighton JK. 2015]. For consistency of 
interpretation, AEs will be coded using the standard MedDRA. The severity of AEs and 
laboratory abnormalities will be graded using the CTCAE, Version 5.0 [National Cancer 
Institute 2017]. Standard definitions for seriousness will be applied (see Appendix 3.3). In 
the evaluation of safety, particular scrutiny will be applied to Grade ≥3 AEs, SAEs, and AEs 
causing interruption, dose modification, or discontinuation of study drug.
4.2.1.3
Pharmacokinetic Endpoints
Derived total VLS-101, total antibody, and MMAE PK parameters (including, as appropriate 
for the analyte: Cmax and AUC, as determined using noncompartmental methods).
PK blood sampling will characterize VLS-101 exposure and disposition. These data may be 
used to evaluate PK parameters by weight, age, sex, race, hepatic impairment (evaluating 
participants with no, mild, or moderate hepatic impairment as categorized by the NCI 
ODWG criteria), and renal impairment (evaluating participants with no [eClCR ≥90 
mL/minute], mild [eClCR ≥60 to <90 mL/minute], or moderate [eClCR ≥30 to <60 
mL/minute] renal impairment). Sampling during Cycle 1 will generate VLS-101 plasma 
concentration-time curves; sampling predose and postdose during subsequent cycles will 
provide steady-state VLS-101 exposure data while minimizing inconvenience for study 
participants and study center staff (see Section 8.6).
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4.2.1.4
Pharmacodynamic Endpoints
Evaluations of circulating tumor markers may offer insights into tumor status during VLS-
101 therapy that may supplement radiographic data in evaluating participant benefit.
Baseline evaluations of tumor ROR1 expression, and tumor mutational, gene expression, and 
protein expression status are intended to generate participant selection hypotheses for future 
studies.
4.2.1.5
Antidrug Antibodies
Formation of ADA can potentially confound drug exposures at therapeutic doses and prime 
for subsequent infusion-related toxicity. ADA response at the beginning of each cycle will be 
determined to understand drug metabolism, exposure, and safety. The incidence of ADA and 
neutralizing ADA will be evaluated and summarized over time by dose. Correlations 
between the presence/absence of positivity for ADAs and PK and pharmacodynamic 
markers, activity, and safety of VLS-101 will be explored.
4.2.1.6
Planned Exploratory Biomarker Research
The mechanism of action of many antitumor agents is not completely understood and much 
remains to be learned regarding how best to leverage new drugs in treating patients. Thus, to 
aid future patients, it is important to investigate the determinants of response or resistance to 
cancer treatments administered, as well as determinants of AEs in the course of our clinical 
studies. These efforts may identify novel predictive/pharmacodynamic biomarkers and 
generate information that may better guide single-agent and combination therapy with 
antineoplastic drugs. To identify novel biomarkers, biospecimens (ie, blood components, 
tumor material) will be collected to support analyses of cellular components (eg, protein, 
DNA, RNA, metabolites) and other circulating molecules. Investigations may include, but 
are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome to interpret tumor-specific DNA mutations. Finally, MSI may be evaluated as this is 
an important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to oncology drug 
development include the mutational burden of tumors and the clonality of T-cells in the 
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tumor microenvironment. Increased mutational burden (sometimes called a ‘hyper-mutated’ 
state) may generate neoantigen presentation in the tumor microenvironment. To conduct this 
type of research, it is important to identify tumor-specific mutations that occur across all 
genes in the tumor genome. Thus, genome-wide approaches may be used for this effort. Note 
that to understand tumor-specific mutations, it is necessary to compare the tumor genome 
with the germline genome. Microsatellite instability may also be evaluated as this is an 
important biomarker for some cancers (ie, colorectal cancer). Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that correlate to clinical response 
to treatment with antitumor therapies. Specific gene sets (ie, those capturing interferon-
gamma transcriptional pathways) may be evaluated and new signatures may be identified. 
Individual genes may also be evaluated (eg, IL-10). MicroRNA profiling may also be 
pursued as well as exosomal profiling.
Proteomics and IHC using blood and/or tumor
Tumor and/or blood samples from this study may undergo proteomic analyses (eg, PD-L1 
IHC). Therefore, tumor tissue may be subjected to proteomic analyses using a variety of 
platforms that could include, but are not limited to, immunoassays and liquid 
chromatography/mass spectrometry. This approach could identify novel protein biomarkers 
that could aid in patient selection for antitumor therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as ELISA measure such proteins in 
serum. Correlation of expression with response to therapy may identify new approaches for 
predictive biomarkers in blood, representing a major advance from today’s reliance on 
assessing tumor biomarkers. This research would serve to develop such assays for future 
clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Biomarker research using the human microbiome
The human microbiome plays a critical role in maintaining tissue homeostasis. Abnormal 
composition of the microbiome has been observed in several disease states, including 
digestive cancers and other malignancies. Furthermore, the composition of different bacterial 
signatures may be predictive of the efficacy of chemotherapeutic agents, and participant
response. The microbiome may thus serve as a valuable diagnostic tool for properly assessing 
and managing disease states.
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4.2.1.7
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 5.
4.3
Justification for Dose
The initial starting dose for the current study was based on the efficacy, PK, and safety data 
in the Phase 1 FIH study, MK-2140-001 (VLS-101-0001). In this dose-escalation and cohort-
expansion study of VLS-101 in participants with hematological malignancies, a VLS-101 
starting dose of 2.5 mg/kg was recommended for further evaluation when administering the 
drug using the Q1/3W schedule since this was the identified MTD. 
A dose of 2.5 mg/kg using a Q1/3W schedule was also initially chosen for patients with solid 
tumors. However, emerging serum PK data in patients with heme malignancies showed that 
the ADC was eliminated quickly (t1/2 ~4 days) relative to the three-week dosing schedule. 
Limited receptor occupancy data collected in CLL and MCL patients also showed that high 
levels of occupancy could not be maintained for the duration of the 3-week cycle. 
Preliminary serum PK data in patients with solid tumors was found to be similar to that in 
patients with heme malignancies. Intratumoral concentrations within solid tumors are limited 
by ADC penetration and are likely significantly lower than in serum. To increase 
intratumoral exposures in solid tumors while maintaining drug tolerability, the dosing 
schedule is being altered to 2.0 mg/kg Q2/3W. The 2.0 mg/kg Q2/3W schedule has been 
tolerated in patients with hematologic malignancies and has been determined to be the MTD 
on this schedule. Since toxicities to VLS-101 are likely to be driven by systemic exposure, 
and systemic exposure was found to be similar between hematologic and solid tumors, the 
toxicity profile of this regimen is also expected to be similar to that already established in the 
ongoing study of hematologic malignancies. The switch to a more frequent schedule is 
expected to improve the possibility of detecting an efficacy signal in solid tumors.
4.3.1
Starting Dose for This Study
This study will have a single starting dose of VLS-101 for most patients, of 2.0 mg/kg, which
was recommended for Phase 2 evaluation in adults when administering VLS-101 Q2/3W.
Participants who require coadministration of a strong inducer of CYP3A4 should also initiate 
therapy at a VLS-101 starting dose of 2.0 mg/kg. Participants requiring coadministration of a 
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strong inhibitor of CYP3A4 and for whom use of an alternate therapy is not possible should 
initiate therapy at a VLS-101 starting dose of 1.5 mg/kg. Dose for participants who 
discontinue a CYP3A4 inhibitor (for example, participants who complete a prescribed 
antibiotic course) may be increased as per Table 5 guidelines to a maximum dose of 
2.0 mg/kg, if warranted by the benefit/risk evaluation for that participant at that time. Doses 
may be adjusted downward or upward to accommodate individual subject tolerance, as 
described in Section 6.6. If ≥5% change in body weight occurs, weight-based dosing should 
be readjusted. Active study participants enrolled prior to protocol amendment 4 will remain 
on their current dose.
4.3.2
Maximum Dose/Exposure for This Study
Participants may receive VLS-101 until any discontinuation criteria (Section 7.1) are met. 
The highest dose level reached in a Q2/3W dosing regimen was 2.25 mg/kg, and the MTD 
was 2.0 mg/kg.
4.3.2.1
Rationale for Dose Interval
In this study, VLS-101/MK-2140 will be administered Q2/3W based on the PK, safety, and 
efficacy results observed to date.
Preliminary zilovertamab vedotin PK data are available for 18 participants with solid tumors 
in MK-2140-002. PK was found to be similar in hematological malignancies and solid 
tumors. Based on PK studies at the dose used in this study, the mean Cycle 1 Tmax values for 
VLS-101, total antibody, and MMAE were 0.5, 0.5, and 48 hours, respectively. The mean t1/2
values for total antibody and VLS-101 were 5.1 and 3.1 days, respectively. 
For detailed information, refer to the IB for PK, safety, and efficacy data for MK-2140.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator). For purposes of analysis and 
reporting, the overall study ends when the Sponsor receives the last laboratory result or at the 
time of final contact with the last participant, whichever comes last.
For studies conducted in the European Economic Area (EEA), the local start of the study is 
defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study or at (a) particular study site(s) may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, 
procedure-related problems or the number of discontinuations for administrative reasons is 
too high.
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Early study termination will be the result of the criteria specified below:
Incidence or severity of adverse drug reactions in this or other studies suggest a potential 
health hazard to participants
Plans to modify or discontinue the development of the study drug
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-2140.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), our studies include 
people of varying age, race, ethnicity, and sex. The collection and use of these demographic 
data is to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant is  eligible for inclusion in the study if the participant meets all of the following 
criteria:
Type of Participant and Disease Characteristics
•
Performance status of 0 or 1 on the ECOG performance scale assessed within 7 days 
before the start of study treatment.
•
Histologically or cytologically confirmed diagnosis of solid tumor as documented in 
medical history.
•
Presence of metastatic disease that has progressed during or following previous treatment.
•
Presence of radiographically measurable disease as determined by investigator (defined 
as the presence of ≥1 non-osseous tumor lesion that measures ≥10 mm in longest 
dimension [≥15 mm in shortest dimension for lymph nodes]) and is outside of any prior
radiation field).
Note: Participants with skin only disease are excluded. Participants who have metastatic 
disease fulfilling the previous criteria in addition to skin disease can be enrolled.
•
Availability of pretreatment tumor tissue from at least one of the following sources:
-
Fresh tumor biopsy obtained by a core needle, excisional, or incisional biopsy; or
punchbiopsy (for cutaneous disease); or
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-
Archival sample from a previous biopsy (if obtained since last prior therapy and 
within 24 weeks prior to the start of study therapy).
Note: Bone specimens are not acceptable.
Details pertaining to tumor tissue submission can be found in the procedures manual.
•
Completion of all previous therapy (including surgery, radiotherapy, chemotherapy,
immunotherapy, or investigational therapy) for the treatment of cancer ≥2 weeks before 
the start of study therapy.
Have life expectancy at least 3 months from enrollment.
Meet the following cohort-specific inclusion criteria:

Cohort A: TNBC
-
Have pathologically confirmed TNBC, as defined by the most recent ASCO/CAP 
guidelines
Note: Participants initially diagnosed with hormone receptor–positive and/or ER2-
positive breast cancer must have confirmation of TNBC in a tumor biopsy obtained 
from a local recurrence or distant metastasis site.
-
At least 1 and no more than 3 prior lines of cytotoxic therapy for metastatic disease 
-
Have completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months 
elapsed between the completion of treatment with curative intent (eg, date of primary 
breast tumor surgery or date of last adjuvant chemotherapy administration, whichever 
occurred last) and first documented local or distant disease recurrence
Note: Participants presenting with de novo metastatic TNBC are eligible for the 
study.
Note: Adjuvant radiation therapy is not considered treatment with curative intent for 
the purpose of calculating the ≥6-month interval requirement described above.
Note: First documentation of local or distant disease recurrence must be in the form 
of a dated biopsy, pathology, or imaging study report. A laboratory report indicating 
tumor marker elevation cannot be used as documentation of local or distant disease 
recurrence, unless accompanied by dated biopsy, pathology, or imaging study report.
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
Cohort B: Non-TNBC
-
No more than 2 prior lines of cytotoxic chemotherapy for metastatic disease
-
HER2-negative disease only and prior treatment with at least hormonal therapy, 
CDK4/6 inhibitor, and cytotoxic chemotherapy
Note: HER2+ disease is excluded.
-
Participants with advanced/metastatic, symptomatic visceral spread at risk of rapidly 
evolving into life-threatening complications, such as lymphangitic lung metastases, 
bone marrow replacement, carcinomatous meningitis, significant symptomatic liver 
metastases, shortness of breath requiring supplemental oxygen, symptomatic pleural 
effusion requiring supplemental oxygen, symptomatic pericardial effusion, 
symptomatic peritoneal carcinomatosis, or the need to achieve rapid symptom control 
are excluded.
Note: 
◦
Participants with symptomatic pleural effusion who have dyspnea at rest requiring 
supplemental oxygen, but which is alleviated by drainage of the fluid can be 
enrolled.
◦
Participants with symptomatic ascitic effusion caused by peritoneal 
carcinomatosis, which is alleviated after drainage of the ascitic fluid can be 
enrolled.
◦
Participants with symptomatic liver metastases include participants with rapidly 
increasing bilirubin > 1.5 x ULN in the absence of biliary obstruction with 
involvement of over than 50% of liver parenchyma by the disease.

Cohort C: NSCLC
-
Adenocarcinoma (nonsquamous) histology
-
Progression of disease on no more than 2 prior lines of therapy for metastatic disease
-
Prior treatment with a checkpoint inhibitor and platinum-containing regimen, which 
may be given as combination therapy or separately, unless previously treated with a 
tyrosine kinase inhibitor for actionable molecular biomarker
-
At least one prior platinum-containing regimen
Note: Completion of treatment with a platinum-containing doublet as neoadjuvant or 
adjuvant therapy or as part of definitive chemoradiation treatment for early-stage
disease (Stage I-III) will satisfy the prior platinum treatment requirement
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-
Patients whose disease is positive for EGFR-sensitizing-mutation, ALK 
rearrangement, ROS1 rearrangement, BRAF-V600E mutation, NTRK gene fusion, 
MET exon 14 skipping  mutation, or RET rearrangement must have received at least 1
relevant tyrosine kinase inhibitor.

Cohort D: Ovarian Cancer (Including Fallopian Tube Cancer and Primary 
Peritoneal Cancer)
-
High-grade serous histology or carcinosarcomas with a high-grade serous component
-
Has radiographic evidence of disease progression within 6 months (180 days) after 
the last dose of platinum-based chemotherapy for ovarian cancer (ie, platinum-
resistant disease)
-
No more than 1 prior line of therapy for platinum-resistant disease
-
No limit on prior platinum-containing regimens for platinum sensitive disease
-
Primary platinum-resistant or refractory patients may be enrolled if they have had at 
least 1 TFI of at least 6 months after a nonplatinum agent
Note: Maintenance therapies do not count as prior lines of treatment.

Cohort E: Gastric Cancer
-
Adenocarcinoma histology
-
No more than 2 prior lines of therapy, except for patients whose disease 
overexpresses HER2 where an additional line of HER2-directed monotherapy is 
allowed
-
GEJ patients allowed, if adenocarcinoma
-
Patients with peritoneal metastases are excluded

Cohort F: Pancreatic Cancer
-
Has histologically confirmed diagnosis of metastatic or locally advanced PDAC
Note: Histologies other than adenocarcinoma including mixed histology are not 
allowed.
-
No more than 2 prior lines of therapy for unresectable or metastatic disease
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Note: Maintenance regimens administered with the purpose of maintaining response 
after treatment will not be considered as separate lines of therapy. For example, 
PARP inhibitor maintenance therapy after initial chemotherapy will be counted as 1 
line of systemic therapy (such as FOLFIRINOX followed by olaparib for BRCA 
mutated pancreatic cancer). Participants who have not received PARP maintenance 
after initial platinum-based chemotherapy for known BRCA mutated pancreatic 
cancer but initiate PARP therapy alone after first-line chemotherapy after documented 
disease progression after initial chemotherapy will be eligible.
Note: Adjuvant therapy will be counted as a line of therapy if a participant progressed 
during therapy or within 6 months of completion of last dose of therapy.
Note: Locoregional therapies will not be counted as a line of therapy.
Adequate organ function (post-nadir following any prior myelosuppressive therapy) as 
defined in the following (Table 2).
Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
>1500/mcL 
Platelets
>75,000/mcL 
Hemoglobina
>8 g/dL 
Renal
Creatinine OR
Measured or calculatedb CrCl
(GFR can also be used in place of CrCl)
≤1.5 x ULN or
≥30 mL/min for participants with creatinine levels 
>1.5 x ULN 
Hepatic
Total bilirubin
≤1.5 x ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 x ULN
AST (SGOT) and ALT (SGPT)
<3 X ULN or ≤5 × ULN for participants with liver 
metastases
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of 
normal.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
a.
Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be 
on stable dose of erythropoietin (≥ approximately 3 months).
b.
Creatinine clearance (CrCl) should be calculated per institutional standard.
Demographics
Is male or female, at least 18 years of age, at the time of providing informed consent. Note: 
Men with breast  cancer may participate in this study.
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Male Participants
If male, agrees to the following during the intervention period and for at least 110 days after 
the last dose of VLS-101/MK-2140:
•
Refrains from donating sperm
PLUS either:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to 
medical cause, documented from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview) as detailed below:
-
Uses a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile-
vaginal penetration.
-
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), with low user dependency, or be abstinent from heterosexual intercourse as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as 
described in Appendix 4 during the intervention period and for at least 50 days after 
the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to 
others or freeze/store for her own use for the purpose of reproduction during this 
period. The investigator should evaluate the potential for contraceptive method failure 
(ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
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-
Has a negative highly sensitive pregnancy test (urine or serum as required by local 
regulations) within 24 hours before the first dose of study intervention. If a urine test 
cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded from participation if the 
serum pregnancy result is positive. Additional requirements for pregnancy testing 
during and after study intervention are in Section 8.3.5. 
-
Abstains from breastfeeding during the study intervention period and for at least 20 
days after study intervention VLS-101/MK-2140.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
Willingness and ability of the participant to comply with scheduled visits, drug
administration plan, protocol-specified laboratory tests, other study procedures (including all 
tumor biopsy/aspirations and radiographic studies), and study restrictions.
Negative viral serology or adequate therapy for HIV, HBV, and HCV infection:
•
HIV: Absence of serum HIV antibodies; or absence of HIV virus in the blood by 
quantitative assay; or ongoing antiretroviral therapy for HIV for ≥4 weeks before the start 
of study therapy and blood HIV viral load <400 copies/mL; and
•
HBV: Absence of serum HbsAg and serum HBcAb; or absence of HBV in the blood by 
quantitative assay; or receiving suppressive anti-HBV therapy before the start of study 
therapy; and
•
HCV: Absence of serum HCV antibody; or absence of HCV in the blood by quantitative 
assay; or receiving anti-HCV therapy and blood HCV viral load below the limit of 
quantitation.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
Peripheral neuropathy of Grade >1.
•
Clinically active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain or meningeal metastases may participate and be eligible for 
treatment provided they are stable and asymptomatic (without evidence of progression by 
MRI scan of the brain separated by at least 4 weeks after treatment), have no evidence of 
new or enlarging brain metastases, are evaluated within 4 weeks before first study 
intervention administration, and are off immunosuppressive doses of systemic steroids at 
least 2 weeks before enrollment.
Note: Screening MRI of the brain is onlyrequired in participants with known or clinically 
suspected CNS malignancy.
•
Presence of another cancer with disease manifestations or therapy that could adversely 
affectparticipant safety or longevity, create the potential for drug-drug interactions, or 
compromise theinterpretation of study results. A history of a second malignancy, unless 
potentially curative treatment has been completed with no evidence of recurrence for at 
least 2 years. 
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma in situ, 
cervical cancer in situ).
•
Uncontrolled ongoing systemic bacterial, fungal, or viral infection (including upper
respiratory tract infection) at the time of start of study therapy or any active infection 
requiring systemic therapy. 
Note: Participants with localized fungal infections of skin or nails are not excluded. 
Participants may be receiving prophylactic or therapeutic antibiotics if there is no 
occurrence of fever within 48 hours before starting study therapy.
•
Significant cardiovascular event (eg, myocardial infarction, arterial thromboembolism,
cerebrovascular thromboembolism) within 4 weeks before the start of study therapy;
unstableangina; symptomatic peripheral vascular disease; Grade ≥2 congestive heart 
failure; uncontrolled Grade ≥3 hypertension (diastolic BP ≥100 mm Hg or systolic BP
≥160 mm Hg) despite antihypertensive therapy; or significant conduction system ECG 
abnormalities, including second degree AV block type II, third degree AV block, or 
Grade ≥2 bradycardia.
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Known diagnosis of liver cirrhosis.
•
Pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening Visit through 120 days after 
the last dose of study intervention. 
•
Prior treatment with a ROR1-directed therapy.
•
Known tumor resistance or participant intolerance to a prior MMAE-containing drug.
•
History or current evidence of any condition, therapy, laboratory abnormality, or other 
circumstance that might confound the results of the study or interfere with the 
participant’s participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
•
Known psychiatric or substance abuse disorders that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
•
Pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening Visit through 120 days after 
the last dose of study intervention.
•
Not fully recovered from any effects of major surgery without significant detectable 
infection. Surgeries that required general anesthesia must be completed at least 2 weeks 
before first study intervention administration. Surgery requiring regional/epidural 
anesthesia must be completed at least 72 hours before first study intervention 
administration and participants should be recovered.
Prior/Concomitant Therapy
•
Has received prior systemic anticancer therapy, definitive or palliative radiotherapy, 
including investigational agents within 2 weeks (2 weeks for palliative radiation) before 
the start of study treatment.
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 
1 or baseline.
Prior/Concurrent Clinical Study Experience
•
Currently participating and receiving study intervention in a study of an investigational 
agent or has participated and received study intervention in a study of an investigational 
agent or has used an investigational device within 28 days of administration of MK-2140.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent.
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Diagnostic Assessments
This is not applicable to this study. 
Other Exclusions
This is not applicable to this study. 
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Participant should maintain a normal diet unless modifications are required to manage an AE, 
such as diarrhea, nausea, or vomiting.
5.3.1.2
Fruit Juice Restrictions
Participants should be advised to avoid ingestion of grapefruit, grapefruit juice, Seville 
oranges, or starfruit (all of which contain CYP3A4 inhibitors).
No other specific dietary restrictions are required. 
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be rescreened for eligibility, as clinically indicated.
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies provided by the Sponsor will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
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6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 3.
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Table 3
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
VLS-101/
MK-2140
Experimental
zilovertamab 
vedotin
Biological/ 
Vaccine
Vial
10 mg/mL
2.0 mg/kg
IV Infusion
Q2/3W
Test 
Product
IMP
Central
VLS-101/
MK-2140
Experimental
zilovertamab 
vedotin
Biological/
Vaccine
Lyophilized 
Powder
60 mg
2.0 mg/kg
IV Infusion
Q2/3W
Test 
Product
IMP
Central
Abbreviations: EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP=noninvestigational/auxiliary medicinal product; 
Q2/3W=repeated 3-week cycles with a drug infusion on Day 1 and Day 8 of each cycle.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 3 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
VLS-101/MK-2140 will be prepared for dosing as described in the study pharmacy manual 
associated with this clinical protocol. Specific calculations or evaluations required to be 
performed to administer the proper dose to each participant are provided. The rationale for 
selection of doses to be used in this study is in Section 4.3. See pharmacy/procedures manual
for further details.
6.2.2
Dose Administration
Details on administration of VLS-101 are provided in the appropriate pharmacy/procedures 
manual.
6.2.3
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Interruptions from the protocol-specified  require consultation between the investigator and 
the Sponsor and written documentation of the collaborative decision on participant 
management.
When study intervention is administered to the participants, they will receive study 
intervention directly from the investigator or designee, under medical supervision. The date 
and time of each dose administered in the clinic will be recorded in the source documents and 
recorded in the CRF. The dose of study intervention and study participant identification will 
be confirmed at the time of dosing by a member of the study-site staff other than the person 
administering the study intervention.
6.5
Concomitant Therapy
Consistent with participant safety and comfort, administration of any prescription or OTC
drug products other than study medication will be minimized during the study period. 
Participants should be discouraged from use of herbal remedies, self-prescribed drugs, 
tobacco products, or street drugs during their participation in the clinical study and should be 
counseled to minimize use of alcohol or nonmedical marijuana.
If considered necessary for the participant’s well-being, drugs for concomitant medical 
conditions or for symptom management may be given at the discretion of the investigator. 
The investigator’s decision to authorize the use of any drug other than study drug will take 
into account participant safety, the medical need, the potential for drug interactions, the 
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possibility for masking symptoms of a more significant underlying event, and whether use of 
the drug will compromise the outcome or integrity of the study.
Participants will be instructed about the importance of the need to inform the clinic staff of 
the use of any drugs or remedies (whether prescribed, OTC, or illicit) before and during the 
course of the study.
Recommendations regarding specific types of concomitant therapies, supportive care, diet, 
and other interventions are provided below. To minimize variations in supportive care, the 
recommended supportive care agents should be considered unless there is a medical rationale 
in a specific participant for use of an alternative product.
6.5.1
Antibiotics, Antifungals, Antivirals
Care should be taken to avoid or minimize concomitant administration of prophylactic or 
therapeutic antibacterial, antifungal, or antiviral agents that are strong CYP3A4 inhibitors or 
inducers (see Appendix 7). Local practices or guidelines regarding infection prophylaxis may 
be followed.
Participants developing an intercurrent infection during study drug treatment may receive 
therapeutic antibacterial, antiviral, or antifungal drugs for intercurrent infections as needed. 
Continuation of study therapy during treatment for an intercurrent infection is at the 
discretion of the investigator.
6.5.2
Anticancer Therapies Other than the Study Drug
No systemic anticancer therapies (including chemotherapy, antibody therapy, hormonal 
therapy, immunotherapy, or other experimental therapies) for the participant’s cancer are 
permitted while the participant is receiving study treatment.
The use of palliative radiotherapy should be minimized given the potential of such treatment 
to confuse assessments of study drug safety and therapeutic effect. However, administration 
of limited-fraction radiotherapy is permitted after Cycle 1 to control local tumor-related
symptoms if irradiation is unlikely to induce major organ toxicity or affect target lesions 
being followed for tumor response and progression.
6.5.3
Anticoagulants
Use of local anticoagulation or antithrombotic agents to maintain a venous access catheter is 
permitted. In addition, participants who have preexisting conditions or develop conditions 
that require anticoagulant therapy may participate in the study.
6.5.4
Antidiarrheals
Participants experiencing diarrhea (and/or abdominal cramping) should have evaluation for 
causes related to the underlying malignancy, a comorbid condition, an intercurrent illness 
(eg, infection), or a concomitant medication.
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Participants may take loperamide at the earliest sign of a loose stool, an increase in bowel 
movements by 1 to 2 episodes compared with baseline, or an increase in stool volume or 
liquidity. The recommended regimen is 4 mg at the first onset of diarrhea, then 2 mg with 
each succeeding diarrheal stool until the participant is diarrhea-free for at least 12 hours.
Additional antidiarrheal measures may be implemented at the discretion of the investigator. 
Participants should also be instructed to maintain oral fluid intake to help sustain fluid and 
electrolyte balance during episodes of diarrhea. Participants with more severe diarrhea or 
comorbid medical conditions should receive IV hydration or hospitalization, as appropriate.
6.5.5
Antiemetics
If antiemetics are needed, investigators may prescribe serotonin antagonists (eg, granisetron, 
ondansetron, dolasetron), dopamine antagonists (eg, prochlorperazine, olanzapine), 
corticosteroids (eg, dexamethasone), or benzodiazepines (eg, alprazolam, diazepam, 
lorazepam). Based on currently available information regarding MMAE metabolism, the 
neurokinin 1 receptor antagonist, rolapitant, can be considered together with other antiemetic 
agents, but aprepitant or netupitant+palonosetron should be avoided because these drugs may 
inhibit CYP3A4 activity.
6.5.6
Antihistamine, Anti-inflammatory, and Antipyretic Drugs
Antihistamines (eg, cetirizine, diphenhydramine), and anti-inflammatory/antipyretic drugs 
(eg, acetaminophen [paracetamol], NSAIDs) may be used during the study, as medically 
warranted.
6.5.7
Corticosteroids
During study therapy, participants may use systemic, enteric, topical, inhaled, or 
intraarticular corticosteroids as required (eg, for intercurrent medical conditions or antiemetic 
prophylaxis).
6.5.8
Drugs Known to Inhibit or Induce Cytochrome P450 (CYP)3A4
In vitro data indicate that MMAE is a substrate of CYP3A4/5 and that MMAE is primarily 
metabolized by CYP3A4. Coadministration of brentuximab vedotin with ketoconazole, a 
potent CYP3A4 inhibitor, increased exposure to MMAE by ~34% while coadministration of 
brentuximab vedotin with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE 
by ~46% [U.S. Prescribing Information 2019].
Protocol candidates who require chronic therapy with a strong CYP3A4 inhibitor as listed in 
Appendix 7 should initiate protocol therapy at a VLS-101 starting dose of 1.5 mg/kg while 
those who chronically require a strong CYP3A4 inducer should initiate protocol therapy at a 
VLS-101 starting dose of 2.0 mg/kg (given that use of strong CYP3A4 inducers are likely to 
reduce toxicity associated with free MMAE). Dose adjustments may be made thereafter as 
recommended in Section 6.6.
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During study participation, coadministration of VLS-101 with any of the strong CYP3A4 
inhibitors listed in Appendix 7 should be avoided, if possible. However, a participant who 
develops a condition that may require use of such a drug is not required to permanently 
discontinue VLS-101 if the participant is experiencing clinical benefit and other options for 
treating the participant’s cancer are limited. If medically appropriate, investigators may wish 
to use a therapeutic alternative that would not be expected to inhibit this enzyme. For 
participants who require temporary use of a drug that does affect this enzyme (eg, treatment 
with a systemic antifungal agent), VLS-101 therapy can be temporarily interrupted and then 
resumed after completion of the other drug, if interruption would not delay drug treatment > 
4 weeks. For participants who require initiation of chronic therapy with a drug that strongly 
inhibits CYP3A4, investigators must consult with the medical monitor to consider the best 
course of action. If participants do receive a CYP3A4 inhibitor concomitantly with VLS-101, 
they should be monitored closely for signs of VLS-101 toxicity and a VLS-101 dose 
modification may be warranted.
6.5.9
Drugs Known to Prolong the QT Interval
Available nonclinical and clinical data obtained with VLS-101 or with other MMAE-
containing ADCs (e.g., brentuximab vedotin, polatuzumab vedotin, or enfortumab vedotin) 
do not suggest a high risk of cardiac interval QT prolongation [U.S. Prescribing Information 
2019] [U.S. Prescribing Information 2020] [U.S. Prescribing Information 2021]. 
Accordingly, there is no specific restriction on use of concomitant medications that might 
prolong the QT interval.
6.5.10
Extravasation Support
VLS-101 is neither a venous irritant nor a vesicant. Extravasation is not expected to induce 
ulcerative necrosis of dermal tissues. However, extravasation of VLS-101 can cause pain, 
erythema, cellulitis, and serous bulla formation that may require several days to resolve.
During each infusion, it is recommended that the participant be observed for local irritation, 
infiltration, or extravasation at the infusion site. If there is evidence of infiltration or 
extravasation, the infusion should be stopped, and the IV cannula should be removed. The 
infusion may be restarted at another site if clinically appropriate. If a participant has a central 
venous access device, VLS-101 may be infused through the device. Local toxicity at the site 
of the infusion should be recorded according to the injection site extravasation/reaction 
criteria in the General Disorders and Administration Site Conditions section of the NCI 
CTCAE, Version 5.0.
Participants may be provided with analgesia, drainage of bulla, debridement of exfoliating 
epidermis, and occlusive dressings. VLS-101 therapy may continue while the participant is 
recovering from the extravasation.
6.5.11
Hematopoietic Support
Prophylactic or reactive use of G-CSF (pegylated or non-pegylated forms) is encouraged to 
avoid neutropenic complications and promote neutrophil recovery in support of on-time 
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VLS-101 retreatment, as appropriate and consistent with current guidelines [Smith, T. J., et al 
2015] [National Comprehensive Cancer Network 2022].
Thrombopoietin receptor antagonists (eg, romiplostim or eltrombopag) may be administered 
to minimize thrombocytopenic complications. However, given lack of definitive evidence 
confirming their benefit in the management of chemotherapy-induced thrombocytopenia 
[Zhang, X., et al 2017], administration of such drugs is not specifically recommended.
Use of erythropoietic agents (eg, erythropoietin or darbepoetin) is not recommended based 
on current guidelines [Rizzo, J. D., et al 2008] [National Comprehensive Cancer Network 
2022].
Platelet or red blood cell transfusions may be administered as medically indicated.
6.5.12
Immunization
For participants who are at risk of an infection (eg, influenza, herpes zoster) that might be 
prevented by immunization, consideration should be given to providing the vaccine prior to 
initiation of study therapy.
Whether the study drug would increase the risk of live viral vaccines during study therapy is 
unknown. Pending the acquisition of additional information, live viral vaccination during 
study therapy should be avoided. 
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, or 
inactivated vaccines. These vaccines will be treated just as any other concomitant therapy. 
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
6.5.13
Infusion Reactions
Infusion reaction prophylaxis should be avoided on C1D1 unless infusion reactions become a 
safety concern during the study. Premedication administered thereafter may include 
acetaminophen, an antihistamine, and a corticosteroid (see Section 6.6). Participants who 
have experienced a prior infusion-related reaction should be premedicated for subsequent 
infusions and consideration should be given to extending the planned infusion time (eg, to 60 
minutes or longer).
The following guidelines for managing infusion reactions are provided in case such reactions 
occur:
•
If a Grade 1 infusion reaction occurs, the infusion rate should be slowed to half of the 
infusion rate at the time of the reaction. The infusion rate may be increased consistent 
with participant tolerance to a rate no higher than the initial rate.
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•
If an infusion reaction Grade ≥2 occurs, the infusion must be interrupted. Medical 
management (eg, oxygen, epinephrine, bronchodilators) should be instituted, as needed. 
Use of corticosteroids can be considered if medically necessary. After the severity of the 
reaction has decreased to Grade ≤1, VLS-101 may be restarted at a rate no higher than 
half of the infusion rate at the time the infusion was paused. For Grade 4 infusion 
reactions, VLS-101 should not be resumed.
6.5.14
Procedures/Surgery
Procedures or surgery may be offered to diagnose or treat the participant for intercurrent 
medical conditions. The extent to which the study drug may affect wound healing is 
unknown.
Considering ongoing need for control of the underlying cancer and the risk of 
myelosuppression due to VLS-101, investigators should use clinical discretion in deciding 
whether to interrupt study therapy before, during, and after surgery or other invasive 
procedures.
6.6
Dose Modification (Escalation/Titration/Other)
Guidelines for Dose Modification due to Adverse Events for VLS-101
If a participant experiences a TEAE that is suspected to be related to the study drug, 
appropriate monitoring and supportive care should be instituted consistent with the nature of 
the event. Inparticular, G-CSF (eg, filgrastim, pegfilgrastim) should be employed to prevent 
or mitigate drug-induced neutropenia and promote neutrophil recovery in support recovery in 
support of on-time study drug retreatment.
Table 4 provides recommendations for modifications of VLS-101 dosing considering the 
worst drug-related AEs or laboratory abnormalities in the current treatment cycle and the 
implications for drug administration in the next treatment cycle. The dose modification 
instructions focus on the types of events most often attributed to VLS-101. These 
recommendations comprise general guidelines; variations from these recommendations may 
be warranted based on an investigator’s individual judgment in considering potential risks, 
benefits, and therapeutic alternatives available to each participant. Investigators are 
encouraged to discuss modifications in the dosing regimen with the medical monitor. If ≥5% 
change in body weight occurs, weight-based dosing should be readjusted.
For participants undergoing a dose reduction, successive adjustments to progressively lower 
dose levels can be made. If the participant cannot tolerate VLS-101 after a decrease to 1.0
mg/kg, then the participant should be discontinued from study drug therapy. In general, after 
the VLS-101 dose is reduced, the dose should be maintained at that dose level, even if there 
is minimal or no toxicity with the reduced dose. However, if the participant tolerates a 
reduced dose of VLS-101 for ≥3 weeks with no toxicities of Grade ≥2, then the VLS-101 
dosing regimen may be reescalated to the next higher dose level, particularly if further 
evaluation reveals that the AE that led to the dose reduction was primarily related to the 
underlying malignancy, a comorbid condition, an intercurrent illness, or a concomitant 
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medication and a dose escalation is medical warranted (eg, for a participant with stable 
disease). Successive adjustments to progressively higher dose levels can be made with the 
caveat that the escalated dose cannot exceed 2.0 mg/kg (in the absence of a strong inhibitor 
of CYP3A4) or 1.5 mg/kg (for participants who require coadministration of a strong inhibitor 
of CYP3A4) and should not be attempted in a participant who should be removed from 
therapy for PD. Dose for participants who discontinue a CYP3A4 inhibitor (for example, 
participants who complete a prescribed antibiotic course) may be increased as per Table 5
guidelines to a maximum dose of 2.0 mg/kg, if warranted by the benefit/risk evaluation for 
that participant at that time.
If a participant experiences a TEAE precluding resumption of VLS-101 therapy by the 
planned Day 1 of the next cycle, the new cycle of treatment may begin when toxicities or 
laboratory abnormalities have resolved sufficiently and if the participant does not meet 
criteria for permanent discontinuation of study therapy (as indicated in Table 4). Upon 
initiation of a new cycle, the current cycle will be considered completed. If toxicity does not 
resolve to Grade 0 to 1 or to baseline within 28 days, study intervention should be 
discontinued after consultation with the Sponsor. Only hematologic toxicities are exceptions 
to this in which they need to resolve to ≤Grade 2. Drug administration may be interrupted or 
delayed due to any non-AE reason (medical procedure, etc.) for a maximum of 4 weeks
without consultation with the Sponsor. If AEs have not resolved in that time frame, the 
participant should be removed from study. If a participant experiences recurrent Grade 4 
nonhematological toxicity, then study intervention should be permanently discontinued, upon 
consultation with the Sponsor.
If ≥5% change in body weight occurs, weight-based dosing should be readjusted.
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Table 4
Dosing Modification Recommendations
Event(s)
Toxicity Grade 
(CTCAE v5.0)
Dose Delay or Modification
Neutropenia
≤Grade 1
•
Maintain current dose and schedule
Grade 2
•
Maintain current dose and schedule
Grade 3
•
Delay until resolved to ≤Grade 2 (ANC ≥1x109/L)
•
Administer growth factors (eg, G-CSF) as clinically 
indicated and for all subsequent cycles
•
Reduce dose by 1 dose level (see Table 5), if clinically 
indicated
≥Grade 3 febrile 
neutropenia or 
Grade 4
•
Delay until resolved to ≤Grade 2 (ANC ≥1x109/L)
•
Administer growth factors (eg, G-CSF) as clinically 
indicated and for all subsequent cycles
•
Reduce dose by 1 dose level (see Table 5), if clinically 
indicated
Thrombocytopenia
Grade 1, 2, or 3
•
Maintain current dose and schedule
≥Grade 3 with 
hemorrhage or 
Grade 4
•
Delay until resolved to ≤Grade 2 (platelet count ≥50x109/L)
•
Reduce dose by 1 dose level (see Table 5)
•
Administer transfusion, as appropriate
Diarrhea
Grade 1
•
Maintain current dose and schedule
•
Evaluate for infectious or other causes of diarrhea and treat, 
as appropriate. Provide antidiarrheal support
Grade 2 or 3
•
Delay until resolved to ≤Grade 1
•
Evaluate for infectious or other causes of diarrhea and treat, 
as appropriate. Provide antidiarrheal support
•
Reduce dose by 1 dose level (see Table 5)
Grade 4
•
Delay until resolved to ≤Grade 1
•
Evaluate for infectious or other causes of diarrhea and treat, 
as appropriate. Provide antidiarrheal support
•
Reduce dose by 1 dose level (see Table 5) or permanently 
discontinue
Neurological 
Toxicities
(including
peripheral 
neuropathy)
Grade 1
•
Maintain current dose and schedule
Grade 2 or 3
•
Delay until resolved to ≤Grade 1
•
Reduce dose by 1 dose level (see Table 5)
Grade 4
•
Permanently discontinue
Non-hematologic 
Toxicity Not 
Otherwise 
Specified
≤Grade 2
•
Maintain current dose and schedule
Grade 3 or 
nonrecurrent 
Grade 4
•
Delay until ≤Grade 1
•
Reduce dose by 1 dose level (see Table 5)
Recurrent Grade 
4
•
Permanently discontinue after consultation with the Sponsor
Abbreviations: ANC=absolute neutrophil count; CTCAE v5.0=Common Terminology Criteria for Adverse Events, 
Version 5.0; G-CSF=granulocyte colony-stimulating factor.
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Table 5
VLS-101 Dose Reduction Levels
Dose Level,
mg/kg
Dose Level Description
Dosing Schedule
1.0
Dose reduction levels
Q2/3W
1.25
1.5
Dose reduction level or starting dose in participants who require
coadministration of a strong inhibitor of CYP3A4a. See Section 
4.3.1
1.75
Dose reduction level 
2.0
Starting dose (in the absence of a strong inhibitor of CYP3A4a)
Abbreviations: CYP=cytochrome P450 (enzyme), Q2/3W=repeated 3-week cycles with a drug infusion on 
Day 1 and Day 8 of each cycle.
a
A listing of strong inhibitors and inducers of CYP3A4 is provided in Appendix 7.
Dose Modification and Toxicity Management of Infusion-related Reactions Related to 
Zilovertamab Vedotin
Although zilovertamab vedotin has not been associated with infusion reactions, other 
monoclonal antibodies have been known to cause severe or life-threatening infusion 
reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely within 
24 hours of completion of infusion. Dose modification and treatment guidelines on 
zilovertamab vedotin associated infusion reaction are provided in Table 6.
Table 6
Zilovertamab Vedotin Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Gradea
Treatmentb
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
•
Slow infusion rate to 50% of the 
infusion rate at the time of the 
reaction. The infusion rate may be 
increased consistent with 
participant tolerance to a rate no 
higher than the initial rate.
•
None
Grade 2 or 3
•
Stop infusion
•
Additional appropriate medical 
therapy may include but is not 
limited to:
•
IV fluids
•
Antihistamines
•
NSAIDs
•
Acetaminophen
•
Narcotics
Administer 30 to 60 minutes prior to 
infusion:
•
po or IV antipyretic
•
(acetaminophen [paracetamol]), 
650 to 1000 mg or equivalent
•
po or IV antihistamine
(cetirizine, 10 mg or equivalent)
•
An NSAID (ibuprofen, 400 to 
800 mg orally or equivalent)
may be added or substituted for 
acetaminophen. 
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NCI CTCAE Gradea
Treatmentb
Premedication at Subsequent 
Dosing
•
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
•
After the severity of the reaction 
has decreased to Grade ≤1, 
zilovertamab vedotin may be 
restarted at a rate no higher than 
50% of the infusion rate at the time 
the infusion rate was paused.
•
A corticosteroid (100 mg of 
prednisolone or equivalent) as a 
premedication can be 
considered.
Grade 4
Stop infusion
Additional appropriate medical therapy 
may include but is not limited to:
•
Epinephrine**
•
IV fluids
•
Antihistamines
•
NSAIDs
•
Acetaminophen
•
Narcotics
•
Oxygen
•
Pressors
•
Corticosteroids
•
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
•
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
•
Participant is permanently 
discontinued from further study 
drug intervention.
•
No subsequent dosing
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; NCI=National Cancer 
Institute; NSAID=nonsteroidal anti-inflammatory drug; po=orally.
a.
For further information, please refer to the Common Terminology Criteria for Adverse Events, Version 5.0 
(CTCAE v5.0) at http://ctep.cancer.gov
b.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
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6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Not applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.1.9, or if available, PCL.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Any prolonged interruption of study intervention beyond the permitted periods, as noted 
in Section 6.6. If treatment will not be restarted, the participant will continue to be 
monitored in the study and the reason for discontinuation of study intervention will be 
recorded in the medical record.
•
The participant has a medical condition or personal circumstance, which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Radiographic disease progression outlined in Section 8.2.1.4.
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•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in Section 
6.6.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in Section 
8.1.9. The procedures to be performed should a participant repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA. 
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed the amount specified in the laboratory manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
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The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout or run-in treatment including placebo run-in).
Demographic information will be recorded for all participants.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. 
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8.4.3.
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study intervention(s), 
the study intervention(s) should be discontinued and the participant will move into the 
Survival Follow-up Phase; if a participant initiates a new anticancer therapy within 30 days 
after the last dose of the study intervention, the 30-day Safety Follow-up Visit should occur 
before the first dose of the new therapy.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before intervention allocation. Each 
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participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. The assigned screening 
number will become the participants’ treatment number. Once a treatment/randomization 
number is assigned to a participant, it can never be reassigned to another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the pharmacy manual. The total volume of study intervention 
infused will be compared with the total volume prepared to determine compliance with each 
dose administered.
Refer to Section 6.1 for dose and treatment details.
8.1.8.1
Timing of Dose Administration
Study intervention will follow a 21-day cycle and will begin after all procedures/assessments 
have been completed as detailed in the SoA (Section 1.3).
Participants will be administered zilovertamab vedotin (VLS-101/MK-2140) administered IV 
over a planned infusion time of approximately 30 minutes.
8.1.8.2
Timing of Administration for VLS-101
VSL-101 will be administered as an IV infusion on Day 1 and Day 8 of a 21-day cycle. The 
reason for any variability in administration of VLS-101 outside the protocol-specified 
window should be documented in the participant’s medical chart and recorded on the eCRFs.
All subsequent cycles of study intervention may be administered up to 3 days before or 
3 days after the scheduled Day 1 of each cycle due to administrative reasons per the 
investigator’s judgment. All study interventions will begin on Day 1 of each cycle after all 
predose study procedures and assessments have been completed as detailed in the SoA 
(Section 1.3).
The pharmacy manual contains specific instructions for (dose calculation, reconstitution, 
preparation) of VLS-101, and administration.
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8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.10.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term 'scan' refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection, submission and/or retention can be found 
in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, contrast-
enhanced MRI may be used when CT with iodinated contrast is contraindicated or when 
mandated by local practice. The same scan technique should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the response assessment based on scans. 
Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility.
If brain scans are performed, MRI is preferred; however, CT imaging will be acceptable, if 
MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain x-rays acquired for 
correlation, should also be submitted and/or retained as specified in the SIM.
Other imaging modalities that may be collected, submitted and/or retained, and included in 
the response assessment include PET scans. Other types of medical imaging (such as 
ultrasound) should not be submitted and will not be included in response assessment.
8.2.1.1
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
treatment. Any scans obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment. The site must review screening scans to confirm the participant has measurable 
disease per RECIST 1.1.
8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at 9 weeks (7 days) from the date of treatment 
start. Subsequent tumor scans should be performed every 9 weeks (7 days) or more 
frequently if clinically indicated. After 36 weeks (7 days), participants who remain on 
treatment will have scans performed every 12 weeks (7 days). Scan timing should follow 
calendar days and should not be adjusted for delays in cycle starts.
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Scans are to be performed until disease progression is identified by the investigator, or until 
the start of new anticancer treatment, withdrawal of consent, or death, whichever occurs first.
Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular scan 
schedule, starting with the next scheduled time point. Participants who receive additional 
scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 
weeks later; scans may resume at the subsequent scheduled time point.
On-study brain or bone scans should be performed if clinically indicated or to confirm CR (if 
other lesions indicate CR and brain or bone lesions existed at baseline).
8.2.1.3
End-of-Treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4 week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of treatment start, refer to Section 8.2.1.2.
Scans are to be continued until one of the following conditions are met:
•
Disease progression as defined by RECIST 1.1
•
The start of a new anticancer treatment
•
Pregnancy
•
Death
•
Withdrawal of consent
•
The end of the study
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study intervention). Imaging scans are to be submitted/retained according 
to the SIM guidance.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
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(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the laboratory 
manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at screening, before the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA. Vital signs include temperature, pulse, respiratory rate, weight, and BP. 
Height will be measured at Visit 1 only.
Oxygen saturation will also be measured at time points specified in the SoA.
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8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA. Clinically significant abnormal findings should be recorded as 
medical history. Additional ECGs may be performed as clinically necessary.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Laboratory tests for screening should be performed within 3 days before to the first dose of 
study intervention. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days before the first dose. After Cycle 1, predose laboratory safety tests can be 
conducted up to 72 hours before dosing unless otherwise noted on the flow charts.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable before administration of each dose of study intervention. Unresolved
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests do not need to be repeated after the end of treatment if laboratory results are 
within normal range.
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8.3.5
Pregnancy Testing
•
Pregnancy testing: Pregnancy testing requirements for study inclusion are described in 
Section 5.1. Pregnancy testing (as required by local regulations) should be conducted at 
monthly intervals during intervention.
-
Pregnancy testing (as required by local regulations) should be conducted for the time 
required to eliminate systemic exposure after the last dose of each study 
intervention(s) as noted in Section 5.1. The length of time required to continue 
pregnancy testing for each study intervention is as follows:
-
MK-2140 (50 days)
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participant’s participation in the study.
8.3.6
Eastern Cooperative Oncology Group Performance Status
The ECOG performance status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc.) with Grades 0 to 5.
The investigator or qualified designee will assess ECOG performance status (Appendix 8) at 
screening, prior to the administration of each dose of study intervention, and during the 
follow-up period as specified in the SoA.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an AE and/or SAE was associated with a medication error, 
misuse, or abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
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will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation, must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation through 30 days after cessation of study 
intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation through 30 days 
after cessation of study intervention or 30 days after cessation of study intervention if the 
participant initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention
allocation through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.5, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 7.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours of 
learning of event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in)
Exception: A positive 
pregnancy test at the 
time of initial screening 
is not a reportable 
event.
Report all
Previously reported –
Follow to 
completion/termination
; report outcome
Within 24 hours of 
learning of event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in treated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
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must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that aggregated efficacy endpoint events and safety data are 
monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include: 
•
An overdose of Sponsor's product, as defined in Section 8.5.
•
An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
In addition, the following events are considered ECIs for MK-2140/VLS-101 (MK-2140 IB):
•
Grade ≥3 infusion reactions 
•
TLS of any grade
•
Grade ≥3 neuropathy
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-2140 by ≥20% of the indicated dose. No specific information is available on the 
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treatment of overdose of MK-2140. In the event of overdose, MK-2140 may be discontinued
and the participant should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
To further evaluate MK-2140 immunogenicity and exposure in these indications, and also to 
evaluate exposure of the proposed dosing regimen, sample collections for analysis of ADA 
and PK are currently planned as shown in Section 1.3. Blood samples will be obtained to 
measure PK of serum MK-2140. The MK-2140 serum Cmax and minimum concentration 
(Ctrough) at planned visits and times will be summarized. Blood samples collected may be 
stored and further analysis may be performed, if required.
8.6.1
Blood Collection for Plasma MK-2140 (VLS-101)
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the laboratory manual.
PK samples should be drawn according to the PK collection schedule for all participants. 
Every effort should be taken to collect samples at 30 days after end of study intervention.
8.6.2
Blood Collection for Antidrug Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the laboratory manual. Anti-MK-2140 samples should be drawn according to the ADA 
collection schedule for all participants (Section 1.3). Every effort should be taken to collect 
samples at 30 days after end of study intervention for ADA. Simultaneous PK sampling is 
required for interpretation of ADA analysis.
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples will be 
in the laboratory manual.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Tumor tissue
•
Plasma for ctDNA
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be in the procedure manual.
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8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover samples listed in Section 8.8.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 28 days before treatment allocation, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated as clinically indicated.
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame. Screening procedures are to be completed within 28 days before the 
first dose of study intervention.
8.10.2
Treatment Period/Vaccination Visit
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided above in Section 8.
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in the SoA (Section 1.3). Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7.
8.10.4
Posttreatment Visit
Participants will be required to return to the clinic approximately 14 days after the last dose 
of study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days 
after the last dose of study intervention, a subsequent follow-up telephone call should be 
made at 14 days post the last dose of study intervention to determine if any AEs have 
occurred since the poststudy clinic visit.
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8.10.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
All AEs that occur before the Safety Follow-up Visit should be recorded (up to 30 days after 
the end of treatment).
8.10.4.2
Efficacy Follow-up Visits
Participants who discontinue study intervention for reasons other than verified PD should 
continue with imaging assessments Q12W as defined in Section 1.3 until: (1) PD is verified 
or further confirmed by the investigator, (2) initiation of a new anticancer treatment, (3) 
death, (4) withdrawal of consent, or (5) study conclusion or early termination, whichever 
occurs first.
8.10.4.3
Survival Follow-up Contacts
Participants who experience confirmed disease progression or start a new anticancer therapy 
will move into the Survival Follow-up Phase. Participants should be contacted by telephone 
Q12W beginning from the last point of contact to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first.
The Sponsor may request survival status be assessed at additional time points during the 
course of the study. For example, these additional time points may be requested before an 
efficacy IA, and/or final analysis. All participants who are not known to have died before the 
request for these additional survival status time points will be contacted at that time.
8.10.5
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined time period will be 
contacted for their vital status.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other nonconfirmatory analyses will be 
outlined in a separate sSAP.
If, after the study has begun, changes are made to primary and/or secondary objectives or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
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after the protocol have been finalized but before the conduct of any analyses will be 
documented in the sSAP as needed and referenced in the CSR for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below. The comprehensive plan is provided in 
Section 9.2 through Section 9.12.
Study Design Overview
A Phase 2, nonrandomized, single-arm, multisite open-label study 
evaluating the efficacy, safety, PK, immunogenicity, and 
pharmacodynamics of VLS-101/MK-2140 in patients with metastatic 
solid tumors that are likely to express ROR1.
Intervention Assignment
Participants will be allocated by nonrandom assignment. This is an 
open-label study.
Analysis Populations
Efficacy and Safety: (FAS) 
Primary Endpoint
ORR per RECIST 1.1 by BICR
Secondary Endpoints
PK parameters including AUC, Cmin, and Cmax
Statistical Methods for 
Efficacy Analyses
The point estimate of ORR will be provided for each tumor type and 
dosing schedule, together with 95% CI using exact binomial method.
Statistical Methods for 
Safety Analyses
Summary statistics (eg, counts and percentages) will be provided for the 
safety endpoints per tumor cohort and dosing schedule.
Interim Analyses
For each disease cohort and dosing schedule, a futility IA is planned for 
approximately the first 13 participants using Simon’s mini-max, 2-stage 
procedure.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power
It is anticipated that up to ~30 participants per disease cohort will be 
accrued if enrollment proceeds through both stages of the Simon 2-stage 
enrollment paradigm for that cohort. To allow for the possibility that 
some participants may not be fully evaluable for efficacy, up to 5 
additional participants (~35 total per cohort) may be enrolled. With 
Simon’s mini-max 2-stage design, this study has a power of >0.8 with a 
significance level of <0.05 when the ORR of a null hypothesis is 5% 
and the true ORR is 20% for each disease cohort.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The study is open-label (ie, participants, investigators, and Sponsor personnel will be aware 
of participant intervention assignment after each participant is enrolled and treatment is 
assigned). Participants will be allocated by nonrandom assignment.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3.
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9.4
Analysis Endpoints
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Primary Endpoint
•
ORR, defined as the proportion of participants who achieve a confirmed CR or PR per 
RECIST 1.1 as assessed by BICR
Secondary Endpoints
•
ORR, defined as the proportion of participants who achieve a confirmed CR or PR per 
RECIST 1.1 as assessed by investigator
•
TTR, defined as the interval from the start of study therapy to the first documentation of 
objective tumor response
•
DOR, defined as the interval from the first documentation of objective tumor response to 
the earlier of the first documentation of disease progression or death from any cause
•
PFS, defined as the interval from the start of study therapy to the earlier of the first 
documentation of disease progression or death from any cause
•
TTF, defined as the interval from the start of study therapy to the earliest of the first 
documentation of disease progression, the permanent cessation of study drug due to an 
AE, or death from any cause
•
OS, defined as the interval from the start of study therapy to death from any cause
9.4.2
Safety Endpoints
The primary safety endpoint is the assessment of AEs: type, frequency, severity, timing of 
onset, duration, and relationship to study drug of any TEAEs; laboratory abnormalities; 
SAEs; or AEs leading to interruption, modification, or discontinuation of study treatment. 
The NCI CTCAE, Version 5.0, will be used for grading of the severity of AEs and laboratory 
abnormalities.
In addition, safety and tolerability will be assessed by clinical review of all relevant 
parameters including AEs, laboratory tests, and vital signs.
A description of safety measures is provided in Section 8.3.
9.4.3
Pharmacokinetics Endpoints
The PK endpoints will be derived total VLS-101, total antibody, and MMAE PK parameters, 
including as appropriate for the analyte: Cmax and AUC, as determined using 
noncompartmental methods.
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Details of the analysis plan for exploratory endpoints will be documented in the sSAP.
9.5
Analysis Populations
9.5.1
Full Analysis Set
The FAS population will be used for the analyses of efficacy and safety data in this study. 
The FAS includes data from all participants who receive ≥1 dose of study drug and will be 
used in the analyses of participant characteristics, ORR, CR rate, PR rate, PFS, TTF, OS, 
study drug administration, and safety.
9.5.2
Responding Analysis Set
The responding analysis set will include data from participants in the FAS who have 
measurable disease, who can be evaluated for tumor response with both baseline and on-
study tumor evaluations, and who achieve an objective response. This analysis set will be 
used in the analyses of TTR and DOR.
9.5.3
Evaluable Analysis Set
Evaluable analysis sets include participants in the FAS who have the necessary baseline and 
on-study measurements to provide interpretable results for specific parameters of interest. 
These analysis sets will be used in the analyses of PK, immunogenicity, pharmacodynamic, 
and biomarker parameters.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and key secondary 
objectives. Methods related to exploratory endpoints will be described in the sSAP.
9.6.1
Statistical Methods for Efficacy Analysis
Categorical Endpoints
ORR, CR, and PR rates will be described. In analyses of response rates in the FAS, 
participants who do not have sufficient baseline and on-study tumor assessments to 
characterize response (ie, have a best overall response of NE) will be counted as failures. For 
all analyses, the corresponding 95% CIs will be presented.
Continuous Endpoints
The percent change in tumor dimensions will be described. 
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Time-to-Event Tumor Control and Survival Endpoints
For time-to-event endpoints, the following definitions and censoring conventions will be 
applied:
•
TTR will be defined as the interval from the start of study therapy to the first 
documentation of objective tumor response. TTR data will not be censored.
•
DOR will be defined as the interval from the first documentation of objective tumor 
response to the earlier of the first documentation of PD or death from any cause. Data 
from surviving, non-progressing participants will be censored at the earliest of the time of 
initiation of antitumor treatment other than the study treatment or the last time that lack 
of PD was objectively documented. Data from participants who have PD or die after ≥2 
consecutive missing tumor assessments will be censored at the last time prior to the 
missing assessments that lack of PD was objectively documented.
•
PFS will be defined as the interval from the start of study therapy to the earlier of the first 
documentation of PD or death from any cause. Data from surviving, non-progressing 
participants will be censored at the earliest of the time of initiation of antitumor treatment 
other than the study treatment or the last time that lack of PD was objectively 
documented. Data from participants who have PD or die after ≥2 consecutive missing 
tumor assessments will be censored at the last time prior to the missing assessments that 
lack of PD was objectively documented.
•
TTF will be defined as the interval from start of study therapy to the earliest of the first 
documentation of PD, the permanent cessation of study drug due to an AE, or death from 
any cause. Data from surviving participants who do not have treatment failure will be 
censored at the earliest of the time of initiation of antitumor treatment other than the 
study treatment or the last on-therapy time that lack of treatment failure was objectively 
documented. Data from participants who have treatment failure due to PD or die after ≥2 
consecutive missing tumor assessments will be censored at the last time prior to the 
missing assessments that lack of treatment failure was objectively documented.
•
OS will be defined as the interval from the start of study therapy to death from any cause. 
Data from surviving participants will be censored at the last time that the participant was 
known to be alive.
Time-to-event endpoints will be described in the appropriate analysis sets using Kaplan-
Meier methods with appropriate censoring. Medians, ranges, and relevant corresponding CIs 
will be presented.
9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements. 
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All AEs will be listed. AEs will be summarized by counts and frequencies for each dose 
level. Laboratory tests, vital signs, and other safety endpoints will be summarized as
appropriate.
The focus of AE summarization will be on TEAEs, which is defined as an AE that occurs or 
worsens in the period from the first dose of studydrug administration to 30 days after the
final dose of study drug administration. AEs that occur before the first dose of study drug 
administration or >30 days afterthe final study drug administration will be included in data 
listings.
AEs will be classified using MedDRA with descriptions by System Organ Class and 
Preferred Term. The severity of AEs will be graded by the investigator according to the
CTCAE, Version 5.0 [National Cancer Institute 2017], whenever possible. If a CTCAE 
criterion does not exist for a specific type of AE, the grade corresponding to the appropriate 
adjective will be used by the investigator to describe the maximum intensity of the AE: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 
(fatal). The relationship of the AE to the study drug will be described based on the categories 
as outlined in Appendix 3.5. As necessary, attributions of “definitely,” “probably,” or
“possibly” related may be aggregated as “related” and attributions of “unlikely” or 
“unrelated” may be aggregated as “unrelated” to provide a dichotomous description of causal 
relationships.
Summary tables will be presented to show the number of participants reporting TEAEs by 
severity grade and corresponding percentages. A participant who reports multiple TEAEs 
within the same Preferred Term (or System Organ Class) is counted only once for that 
Preferred Term (or SystemOrgan Class) using the worst severity grade. AE descriptions will 
be presented in order of decreasing frequency for System Organ Class, and by decreasing
frequency in the overall or totalcolumn for a given Preferred Term.
Separate listings and summaries will be prepared for the following types of AEs:
•
Study-drug-related AEs
•
AEs that are Grade 3, 4, or 5 in severity
•
AEs leading to study drug interruption and/or dose modification
•
AEs leading to study drug discontinuation
•
SAEs (with categorization of the primary outcome that results in the AE being considered
serious, eg, life-threatening, requiring hospitalization)
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9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be listed and summarized for the FAS.
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
PK parameters of study interventions will be summarized by planned visit and time for each 
dose separately.
PK and pharmacodynamics modeling analyses will be documented in the sSAP.
9.7
Interim Analyses
An IA may be conducted to enable future study planning at the Sponsor’s discretion, and data 
will be examined on a continuous basis to allow for dose-finding decisions.
For each disease cohort and dosing schedule, a futility IA is planned using Simon’s mini-
max, 2-stage procedure. That is, after the first 13 participants (Stage 1) of a given disease 
cohort under a specific dosing schedule had the opportunity to have their end-of-Cycle 6 
radiographic evaluation, if 0 of 13 participants have an objective response based on the 
investigator assessment, that specific disease cohort and dosing schedule may be stopped for 
futility. Otherwise, 14 additional participants (Stage 2) will be accrued for a total of 27 
participants. The futility bar is not binding, and the totality of the data will be evaluated for 
decision-making.
The IA constitutes a futility analysis; it will not be used to stop the trial early for positive 
efficacy. Enrollment may not pause during the IAs. If Stage 1 is considered nonfutile for both 
breast cancer cohorts, the Sponsor may elect to proceed with Stage 2 independently for each 
or may combine them in Stage 2.
Final study reporting is expected to occur after all participants have discontinued study
treatment or ≥24 weeks after accrual of the final participant (whichever occurs earlier). The 
exact binomial test will be used in the final analyses because of the practical consideration 
that accrual cannot be limited to exactly 27 participants and because participants included in 
the Stage 1 analysis as nonresponding may be included in the final analysis as responding if
they experience a late response.
After the final analyses, additional supplemental analyses may be performed to assess long-
term PFS and OS and to satisfy regulatory requirements.
9.8
Multiplicity
There will be no multiplicity control in this study.
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9.9
Sample Size and Power Calculations
The study will use the Simon 2 stage mini-max approach to test a null hypothesis vs an 
alternative hypothesis regarding drug activity. For each specific disease cohort and dosing 
schedule, the study will evaluate a null hypothesis that the ORR is ≤5% against the 
alternative hypothesis that it is ≥20%. In this instance, 13 participants will be accrued in the 
first stage. If 0 of 13 participants have an objective tumor response, then enrollment to that 
cohort may be stopped. Otherwise, 14 additional participants will be accrued for a total of 27 
participants. The null hypothesis will be rejected if ≥4 objective responses are observed in 
the total of 27 participants (15% ORR). This design yields a significance level of <0.05 and a 
power of >0.80 when the true ORR is 20%. At the end of Stage 1, the probability of 
erroneously proceeding with the study is 0.49 under the null hypothesis and the probability of 
erroneously discontinuing the study is 0.05 under the alternative hypothesis.
9.10
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Descriptive information will be provided regarding the number of VLS-101 infusions 
prescribed,the number of VLS-101 infusions administered, the VLS-101 body-weight-
adjusted and total doses administered, the duration of infusions, the number and timing of 
prescribed VLS-101 infusion delays or interruptions, dose modifications and therapy 
interruptions, and the reasons forVLS-101 infusion delays or interruptions, dose
modifications, and therapy interruptions.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
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regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 8 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 8
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive 
Chemistry Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or urine)b
Hemoglobin
Alkaline phosphatase
Glucose
PT/INR
Platelet count
ALT
Protein
aPTT or PTT
WBC (total and 
differential)a
AST
Specific gravity 
Total T3 (or FT3), Total T4 (or 
FT4), and TSHc,d
RBC
Bicarbonate
Microscopic examination, 
if abnormal results are 
noted
Anti-HCV
Absolute 
lymphocyte counta
Calcium
HCV viral loadd
Absolute 
neutrophil counta
Chloride
HCV genotyped
Creatinine
Anti-HBsd
Glucose
HBsAg 
Phosphorus
Anti-HBc (total and IgM)d
Potassium
HBeAgd
Sodium
Anti-HBed
Total bilirubin  
HBV viral loadd
Direct bilirubin
Anti-HDVd
Total protein
AFP
Blood urea nitrogen
CRP
GGT
Abbreviations: AFP=α fetoprotein; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; 
AST=aspartate aminotransferase; CRP=c-reactive protein; FT3=free T3; FT4=free T4; GGT=gamma-glutamyl 
transpeptidase; HBe=hepatitis B e-antigen; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis 
C virus; HDV=hepatitis delta virus; IgM=immunoglobulin M; INR=international normalized ratio; PT=prothrombin 
time; PTT=partial thromboplastin time; RBC=red blood cell; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-
stimulating hormone; WBC=white blood cell.
a.
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
b.
Perform on women of childbearing potential only 72 hours before Day 1 of Cycle 1. Pregnancy tests must be 
repeated before every cycle if required or as specified per local regulatory guidance.
c.
T3 is preferred; if not available, Free T3 may be tested.
d.
If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory 
for testing. Details are provided in the procedure manual.
Investigators must document their review of each laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol-specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the 
Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
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•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
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•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.￼
Assessment of intensity /toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE. Any AE that changes CTCAE 
grade over the course of a given episode will have each change of grade recorded on the 
AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
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-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
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-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
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•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
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•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
   
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10.4
Appendix 4: Contraceptive Guidance
10.4.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.4.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. A spermatogenesis 
cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or medical 
history interview.
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 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a) Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for participants of clinical studies.
b) If locally required, in accordance with CTFG guidelines, acceptable contraceptive 
implants are limited to those which inhibit ovulation.
c) IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and LAM.
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•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom should not be used together (due to risk of failure with 
friction).
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10.5
Appendix 5: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a) Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b) Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c) Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d) DNA: Deoxyribonucleic acid.
e) RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways with which drugs/vaccines may interact
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a) Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b) Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c) eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d) Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
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to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.6
Appendix 6: Country-specific Requirements
There are no country-specific requirements. 
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10.7
Appendix 7: Strong Inhibitors and Inducers of Cytochrome P450 (CYP)3A4
Effect on CYP3A4
Drug
Strong CYP3A4 Inhibitors
boceprevir, clarithromycin, cobicistat, danoprevir and ritonavir, 
elvitegravir and ritonavir, grapefruit juice, idelalisib, indinavir and 
ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, 
nelfinavir, paritaprevir and ritonavir (and ombitasvir and/or dasabuvir),
posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and 
ritonavir), telithromycin, troleandomycin,voriconazole
Strong CYP3A4 Inducers
apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, 
rifampin,St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme.
Source [Food and Drug Administration 2022].
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10.8
Appendix 8: Eastern Cooperative Oncology Group
Grade
Performance Status
0
Normal activity. Fully active, able to carry on all predisease performance without 
restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.
5
Dead
Source [ECOG-ACRIN Cancer Research Group 2016].
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADC
antibody-drug conjugate
ADL
activities of daily living  
AE
adverse event 
ALK
anaplastic lymphoma kinase
ALL
acute lymphoblastic leukemia
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ASCO/CAP
American Society of Clinical Oncology/College of American 
Pathologists
AST
aspartate aminotransferase
AUC
area under the curve
AV
atrioventricular
BICR
blinded independent central review
BP
blood pressure
BRCA
breast cancer gene
CD
cluster of differentiation
CI
confidence interval
CLL
chronic lymphocytic leukemia
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRF
case report form 
CRO
contract research organization
CSC
cancer stem cells
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
Ctrough
concentration reached by a drug immediately before the next dose is 
administered
CYP
cytochrome P450
DFS
disease-free survival
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid 
DOR
duration of response
EC50
half maximal effective concentration
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Abbreviation
Expanded Term
ECG
electrocardiogram 
ECI
event of clinical interest
eClCr
estimated creatinine clearance
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EEA
European Economic Area
EGFR
endothelial growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EMT
epithelial-mesenchymal transition
ER
estrogen receptor
FACS
fluorescent-activated cellsorter
FAS
Full Analysis Set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FIH
first in human
FL
follicular lymphoma
FOLFIRINOX
folinic acid (leucovorin), fluorouracil (5-FU), irinotecan 
(Camptosar), oxaliplatin (Eloxatin)
FSR
First Site Ready
GCP
Good Clinical Practice 
G-CSF
granulocyte colony-stimulating factor
GEF
guanine exchange factors
GEJ
gastroesophageal junction adenocarcinoma
GLP
Good Laboratory Practice
GTP
guanosine triphosphate
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
hERG
human ether-à-go-go-related gene
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
HS1
hematopoietic-lineage-specific protein 1
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure 
IC50
half maximal inhibitory concentration
ICF
informed consent form
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Abbreviation
Expanded Term
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ID 
identification
IEC
Independent Ethics Committee
IgG1
immunoglobulin G1
IHC
immunohistochemistry
IL-10
interleukin-10
IMP
investigational medicinal product
IND
Investigational New Drug 
IRB
Institutional Review Board
IRC
Imaging Review Committee
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
kd
equilibrium dissociation constant
Ki-67
proliferation marker for human tumor cells
LAM
lactational amenorrhea method
MCL
mantle cell lymphoma
mc-vc-PAB
maleimidocaproyl-valine-citrulline-para-aminobenzoate
MEC
mouse embryonic epicardial cell line
MedDRA
Medical Dictionary for Regulatory Activities
MMAE
monomethyl auristatin E
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
MZL
marginal zone lymphoma
n
number
N/A
not applicable
NCI
National Cancer Institute
NE
not evaluable
NOAEL
no observed adverse effect level 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non–small cell lung cancer
NTRK
neurotrophic tyrosine receptor kinase
ODWG
Organ Dysfunction Working Group
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PAB
para-aminobenzoate
pAKT
phosphorylated AKT (protein kinase B)
PARP
poly-ADP ribose polymerase
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Abbreviation
Expanded Term
PCL
protocol clarification letter
pCREB
phosphorylated cAMP response element binding protein
PD
progressive disease
PDAC
pancreatic ductal adenocarcinoma
PD-L1
programmed cell death ligand 1
PET
positron emission tomography 
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PV
Polivy™
Q1/2W
every 1 out of 2 weeks
Q2/3W
Repeated 3-week cycles with a drug infusion on Day 1 and Day 8 
of each cycle
Q3W
every 3 weeks
Q3/4W
every 3 out of 4 weeks
Q12W
every 12 weeks
Rac1
Ras-related C3 botulinum toxin substrate 1
RDR
recommended dosing regimen
RECIST 1.1
Response Evaluation Criteria in Solid Tumors 1.1
RhoA
Ras homolog gene family member A
RNA
ribonucleic acid
ROR
receptor tyrosine kinase-like orphan receptor
ROR1
receptor tyrosine kinase-like orphan receptor-1
ROR2
receptor tyrosine kinase-like orphan receptor-2
RP2D
recommended Phase 2 dose
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SEER
Surveillance, Epidemiology, and End Results
SIM
Site Imaging Manual
SLAB
supplemental laboratory test(s)
SLL
small lymphocytic lymphoma
SNP
single nucleotide polymorphism
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
t1/2
elimination half-life
TCGA
The Cancer Genome Atlas
TCL
T-cell leukemia/lymphoma protein
TEAE
treatment-emergent adverse event
TFI
treatment-free interval
TLS
tumor lysis syndrome
Tmax
time to maximum plasma concentration
TNBC
triple-negative breast cancer
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Abbreviation
Expanded Term
TTF
time to treatment failure
TTR
time to response
ULN
upper limit of normal
Wnt
secreted glycoproteins important during embryogenesis and tissue 
homeostasis (orchestrate cell proliferation and polarization)
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
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11
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