Open-Label Phase 2 Study of Ladiratuzumab Vedotin (LV) for Unresectable Locally Advanced or Metastatic Solid Tumors
Phase: PHASE2
Conditions: Small Cell Lung Cancer, Non-small Cell Lung Cancer, Squamous, Non-small Cell Lung Cancer, Non-squamous, Head and Neck Squamous Cell Carcinoma, Esophageal Squamous Cell Carcinoma, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Prostate Cancer, Melanoma
Sponsor: Seagen Inc.

This document contains information proprietary to Seagen Inc. The information is being provided to you for the 
purpose of conducting a clinical trial for Seagen Inc. You may disclose the contents of this document to study 
personnel under your supervision and to your Institutional Review Board (IRB) or Ethics Committee (EC) for the 
same purpose. You may not disclose the contents of this document to any other party, unless government regulations 
or laws require such disclosure, without prior written permission from Seagen Inc. Any supplemental information 
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procedure described above.
Protocol Number:
SGNLVA-005
Version:
Amendment 04; 02-Nov-2022
Protocol Title:
Open-Label Phase 2 Study of Ladiratuzumab Vedotin (LV) for 
Unresectable Locally Advanced or Metastatic Solid Tumors
Investigational Product:
Ladiratuzumab vedotin
Brief Title:
A Study of Ladiratuzumab Vedotin in Advanced Solid Tumors
Phase:
2
IND Number:
117532
EudraCT Number
2019-001946-17
Sponsor:
Seagen Inc.
21823 30th Drive SE
Bothell, WA 98021, USA
Medical Monitor:
 MD, PhD
Seagen, Inc
Tel:
E-mail:
Study Director: 
 PharmD
Seagen, Inc
Tel:
E-mail:
SAE Email or Fax:
See email or fax number specified on the SAE report form.
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PPD
PPD
PPD
PPD
PPD
PPD

 
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PROTOCOL SYNOPSIS 
Protocol Number  
SGNLVA-005 
Version 
Amendment 04; 02-Nov-2022 
Phase 
2 
Product Name  
Ladiratuzumab vedotin 
Sponsor 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Protocol Title 
Open-Label Phase 2 Study of Ladiratuzumab Vedotin (LV) for Unresectable Locally Advanced or Metastatic Solid 
Tumors 
Study Objectives 
Primary 
● Evaluate antitumor activity of LV as monotherapy (Part A, Part B, and Part C Arm 1 [Cohort 8 only]) and 
LV + pembrolizumab (Part C Arms 2 and 3, Cohort 8 only) as measured by investigator-determined 
confirmed objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1) for all tumor types 
● For prostate cancer, evaluate antitumor activity of LV as measured by investigator-determined 
prostate-specific antigen (PSA) response by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) 
criteria in addition to ORR 
Secondary 
● Evaluate the safety and tolerability of LV as monotherapy (Part A, Part B, and Part C Arm 1 [Cohort 8 
only]) and LV + pembrolizumab (Part C Arms 2 and 3, Cohort 8 only) as measured by type, incidence, 
severity, seriousness, and relatedness of adverse events (AEs) 
● Evaluate stability and control of disease as measured by investigator-determined disease control rate (DCR) 
as measured by RECIST v1.1 
● Evaluate durability of response as measured by duration of response (DOR) in subjects who respond to LV 
as monotherapy (Part A, Part B, and Part C Arm 1 [Cohort 8 only]) and LV + pembrolizumab (Part C 
Arms 2 and 3, Cohort 8 only) as measured by RECIST v1.1 for all tumors, and investigator-determined 
PSA for prostate cancer 
● Assess progression-free survival (PFS) in subjects who respond to LV as monotherapy (Part A, Part B, and 
Part C Arm 1 [Cohort 8 only]) and LV + pembrolizumab (Part C Arms 2 and 3, Cohort 8 only) as measured 
by RECIST v1.1 for all tumors, and by investigator-determined PSA for prostate cancer 
● Assess survival as measured by overall survival (OS) in subjects who respond to LV as monotherapy 
(Part A, Part B, and Part C Arm 1 [Cohort 8 only]) and LV + pembrolizumab (Part C Arms 2 and 3, 
Cohort 8 only) 
● Assess pharmacokinetics (PK) and immunogenicity of LV (Parts A-C) 
Additional 
● Assess biomarkers of biological activity, resistance, and predictive biomarkers of response 
Study Population 
Adult subjects with the following advanced solid tumors (Parts A, B, and C): 
● Cohort 1: small cell lung cancer (SCLC) (Parts A and B) 
● Cohort 2: non-small cell lung cancer-squamous (NSCLC-squamous) (Parts A and B) 
● Cohort 3: non-small cell lung cancer–nonsquamous (NSCLC-nonsquamous) (Parts A and B) 
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● Cohort 4: head and neck squamous cell carcinoma (HNSCC) (Parts A and B) 
● Cohort 5: esophageal squamous cell carcinoma (esophageal-squamous) (Parts A and B) 
● Cohort 6: gastric and gastroesophageal junction (GEJ) adenocarcinoma (Parts A and B) 
● Cohort 7: castration-resistant prostate cancer (CRPC) (Part B only) 
● Cohort 8: melanoma (Parts B and C) 
Number of Planned Subjects 
Up to approximately 414 subjects will be enrolled in the entire study, including up to 72 subjects in Part A (LV 
2.5 mg/kg on Day 1 of every 21-day cycle [q3wk] dosing), up to 252 subjects in Part B (LV Day 1, Day 8, and 
Day 15 every 21-day cycle [q1wk] dosing), and approximately 90 subjects in Part C ([Cohort 8 melanoma only] LV 
1.5 mg/kg Day 1 and Day 8 but not Day 15 every 21-day cycle [2q3wk], LV 1.5 mg/kg 2q3wk + 200 mg 
pembrolizumab q3wk, LV 1.25 mg/kg q1wk + 200 mg pembrolizumab q3wk). 
Study Design 
This global, open-label, multicenter trial is designed to assess the activity, safety, and tolerability of LV 
monotherapy for the treatment of solid tumors. The study consists of 3 Parts evaluating subjects in 8 tumor cohorts, 
summarized in the table below. 
● Part A: LV administered by intravenous (IV) infusion at a dose of 2.5 mg/kg on Day 1 of each 21-day 
cycle (q3wk). 
● Part B: LV administered by IV infusion at a dose of 1.0 mg/kg (Cohort 1 through Cohort 6) or 1.25 mg/kg 
(Cohort 1 through Cohort 8) on Day 1, Day 8, and Day 15 of each 21-day cycle (q1wk).  
● Part C: LV administered by IV infusion at a dose of 1.5 mg/kg on Day 1 and Day 8 of each 21-day cycle 
(2q3wk) as monotherapy (Arm 1) or in combination with 200 mg pembrolizumab administered by IV 
infusion on Day 1 of each 21-day cycle (Arm 2) or LV administered by IV infusion at a dose of 1.25 mg/kg 
on Day 1, Day 8, and Day 15 of each 21-day cycle (q1wk) in combination with 200 mg pembrolizumab 
administered by IV infusion on Day 1 of each 21-day cycle (Arm 3).  
 
Cohort 1: 
SCLC 
Cohort 2: 
NSCLC- 
squamous 
Cohort 3: 
NSCLC- 
nonsquamous 
Cohort 4: 
HNSCC 
Cohort 5: 
esophageal-
squamous 
Cohort 6: 
gastric & GEJ 
adenocarcinoma 
Cohort 7: 
CRPC 
Cohort 8: 
melanoma 
Part A 
X 
X 
X 
X 
X 
X 
 
 
Part B 
X 
X 
X 
X 
X 
X 
X 
X 
Part C 
 
 
 
 
 
 
 
X 
 
Subjects will be enrolled in Part A until the individual tumor cohorts have 12 subjects or activation of Protocol 
Amendment 1 at each respective investigative site, whichever comes first. Upon activation of Protocol 
Amendment 1 at each investigative site, all subsequent subjects enrolled at that site will be in Part B. Subjects in 
Part A may cross over to Part B with sponsor’s approval based on emerging safety and efficacy data. 
Part B will assess LV q1wk in the tumor cohorts. The planned dose levels in Part B are 1.0 mg/kg (Dose Level 0) 
and 1.25 mg/kg (Dose Level +1). Initially, approximately 12 subjects across the tumor cohorts will be enrolled and 
receive LV 1.0 mg/kg q1wk. Based on collective safety data from the initial 12 subjects and from the concurrently 
ongoing phase 1 study SGNLVA-001 evaluating LV q1wk in breast cancer, subsequent enrollment in Part B will 
either: 
● Continue enrolling up to 12 subjects in each tumor cohort at LV 1.0 mg/kg q1wk for interim analysis for 
futility, or 
● Enroll an additional 12 subjects across the tumor cohorts to receive LV 1.25 mg/kg q1wk (Dose Level +1) 
for safety analysis. If tolerability is demonstrated, enrollment will continue to 12 subjects in each tumor 
cohort at LV 1.25 mg/kg q1wk for interim analysis for futility. 
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Interim analysis for futility will be performed separately for each cohort after approximately 12 efficacy-evaluable 
subjects of a given cohort have been treated at a specific LV dose and schedule. Cohorts that successfully pass the 
interim analysis for futility may, at the sponsor’s decision, continue to enroll up to an additional 18 subjects, totaling 
up to 30 subjects for each tumor cohort at a specific dose and schedule.  
Part C will assess LV 1.5 mg/kg 2q3wk dosing as monotherapy (Arm 1), LV 1.5 mg/kg 2q3wk in combination with 
pembrolizumab (Arm 2), or LV 1.25 mg/kg q1wk in combination with pembrolizumab (Arm 3) dosing in subjects 
with melanoma (Cohort 8) only. Enrollment for Part C will begin following completion of enrollment for Part B 
Cohort 8 (melanoma). Each arm will enroll 30 subjects. Eligible subjects will be randomized in a 2:1:1 ratio to 
Arms 1, 2, and 3, respectively. Thus, of the first 60 subjects, 30 subjects will be enrolled in Arm 1, 15 subjects will 
be enrolled in Arm 2 and 15 subjects will be enrolled in Arm 3. This will ensure that Arm 1 reaches the target 
enrollment sooner. Arm 1 will be closed to further enrollment once it reaches 30 subjects, and the randomization 
will continue between Arm 2 and Arm 3 in a 1:1 ratio until their enrollment targets are reached. 
Additional tumor types may be included in this study in future protocol amendments. Alternative dosing regimens, 
biopsy/biomarkers, and LV-based combinations may be tested in future amendments. 
Investigational Product, Dose, and Mode of Administration 
Part A (q3wk dosing): LV will be administered at a dose of 2.5 mg/kg as a 30-minute IV infusion on Day 1 of each 
21-day cycle. For subjects weighing more than 100 kg, dosing will be capped at 250 mg per infusion. Any subject 
receiving >200 mg LV per infusion (weight >80 kg) is required to receive prophylactic granulocyte 
colony-stimulating factor (G-CSF).  
Part B (q1wk dosing): LV will be administered at a dose of 1.0 or 1.25 mg/kg as a 30-minute IV infusion on Day 1, 
Day 8, and Day 15 of each 21-day cycle. The maximum dose will be 200 mg per infusion. 
Part C (LV monotherapy or LV plus pembrolizumab combination):  
● Arm 1: LV will be administered at a dose of 1.5 mg/kg as a 30-minute IV infusion 2q3wk on Day 1 and 
Day 8 of each 21-day cycle. The maximum dose will be 200 mg per infusion.  
● Arm 2: LV will be administered at a dose of 1.5 mg/kg as a 30-minute IV infusion 2q3wk on Day 1 and 
Day 8 of each 21-day cycle. The maximum LV dose will be 200 mg per infusion. Pembrolizumab will be 
administered at a dose of 200 mg, approximately 60–90 minutes after administration of LV, q3wk on 
Day 1 of each 21-day cycle. 
● Arm 3: LV will be administered at a dose of 1.25 mg/kg as a 30-minute IV infusion q1wk on Day 1, 
Day 8, and Day 15 of each 21-day cycle. The maximum LV dose will be 200 mg per infusion. 
Pembrolizumab will be administered at a dose of 200 mg, approximately 60–90 minutes after 
administration of LV, q3wk on Day 1 of each 21-day cycle.  
Duration of Treatment 
Subjects will continue to receive study treatment until disease progression, unacceptable toxicity, investigator 
decision, consent withdrawal, study termination by the sponsor, pregnancy, or death, whichever comes first. 
Efficacy Assessments 
For non-prostate cancer subjects, tumor assessment according to RECIST v1.1 will be performed every 6 weeks 
(±3 days) for the first 12 months after the first dose of LV and then every 12 weeks (±7 days) thereafter. Objective 
responses (complete response [CR] or partial response [PR]) will be confirmed with repeat scans 4 to 6 weeks after 
the first documentation of response. For subjects receiving pembrolizumab in Part C, investigators will make 
treatment decisions based on site assessments of scans using iRECIST. 
For prostate cancer subjects (Part B, Cohort 7), PSA will be assessed every 3 weeks (±3 days). Soft tissue tumor 
assessment by computed tomography or magnetic resonance imaging scan (CT/MRI) and bone scans according to 
PCWG3 criteria will be assessed every 8 weeks (±7 days) for the first 24 weeks, then every 12 weeks (±7 days) 
thereafter.  
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Pharmacokinetic and Immunogenicity Assessments 
Subject serum and plasma samples will be obtained for LV PK and antitherapeutic antibody (ATA) evaluation at 
protocol-specified time points. Concentrations of LV (antibody-drug conjugate [ADC]), total antibody, and 
monomethyl auristatin E (MMAE) will be measured in plasma and ATA in serum. 
Biomarker Assessments 
Tumor samples and blood will be collected at protocol-specified time points. Target expression by 
immunohistochemistry (IHC) and RNA will be performed retrospectively and there will be no subject preselection. 
Biomarker assessments from tumor tissue may include protein expression, gene expression, disease subtype 
classification, tumor microenvironment, and mutational profile. Assessments in blood samples may include cytokine 
measurements, immunoassays, and circulating nucleic acids. Methods of analysis may include IHC, polymerase 
chain reaction (PCR), next-generation sequencing, multiplex immunofluorescence, flow cytometry, immunoassays, 
and proteomic methodologies such as enzyme-linked immunosorbent assay (ELISA) and microvesicle assessment. 
Safety Assessments 
Safety assessments will include the surveillance and recording of AEs, physical examination findings, vital signs, 
concomitant medications, pregnancy testing, and laboratory tests. An ongoing, real-time review of subject safety and 
serious adverse events (SAEs) will be conducted by the sponsor’s Drug Safety Department. Adverse event (AE) 
severity will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 5. 
Statistical Methods 
The primary analysis of the study will be performed separately for each cohort in Parts A, B, and C when all treated 
subjects in the cohort have been followed for at least 6 months or come off study, whichever comes first. The 
primary efficacy endpoint of confirmed ORR per RECIST v1.1 will be estimated for each cohort based on the full 
analysis set (FAS), comprising all subjects who received any amount of study treatment. The point estimate of ORR 
and 90% exact confidence intervals (CIs) using the Clopper-Pearson method will be provided for each cohort.  
For the prostate cancer cohort, the confirmed PSA response rate and 90% exact CI will also be presented. The 
confirmed PSA response is defined as a reduction from baseline PSA level of at least 50%, measured twice 
≥3 weeks apart. 
Interim futility analyses will be performed separately for each cohort in Part A and Part B after approximately 
12 subjects of a given cohort have been treated with a specific LV dose and schedule (LV q3wk at 2.5 mg/kg, LV 
q1wk at 1.0 mg/kg, or LV q1wk at 1.25 mg/kg) and are efficacy evaluable post-baseline. Enrollment to each cohort 
may be held after approximately 12 subjects for interim futility analysis of the respective cohorts. The Bayesian 
predictive probability of success (PPoS) approach will be used to determine the futility criteria. At the time of each 
interim analysis, the PPoS will be calculated. A PPoS <10% (i.e., ≤1 response among the first 12 subjects, or 
≤3 responses among the first 12 prostate cancer subjects) indicates that it is unlikely the ORR will be better than the 
response rate of current standard of care at the end of the cohort given the interim result. Based on efficacy and 
safety data, together with the PPoS, a cohort may be stopped early by the sponsor. A cohort may also be 
discontinued at any point at the discretion of the sponsor. 
Safety measurements will be summarized by descriptive statistics based on the safety analysis set. The safety 
analysis set will include all subjects who received any amount of study treatment. 
For all the parts, the sample size is not based on power calculation for a formal hypothesis testing but is selected to 
provide a degree of characterization of commonly occurring AEs in the safety profile and/or a reasonable estimation 
precision of ORR.  
For a sample size of 30 subjects per cohort/arm, assuming confirmed ORR and confirmed PSA response rate for 
CRPC is between 10% and 50%, the 2-sided 90% exact CI are summarized below: 
 
 
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Confirmed ORR* 
90% Exact CI (N=30) 
10% 
(3%, 24%) 
20% 
(9%, 36%) 
30% 
(17%, 47%) 
40% 
(25%, 57%) 
50% 
(34%, 66%) 
*Including confirmed PSA response rate for CRPC cohort 
 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .............................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................................................. 13 
1. 
INTRODUCTION ................................................................................................................................ 18 
1.1. 
LIV-1 .................................................................................................................................................... 18 
1.2. 
Ladiratuzumab vedotin ......................................................................................................................... 18 
1.2.1. 
Mechanism of Action .......................................................................................................... 18 
1.2.2. 
Summary of Preclinical Activity ......................................................................................... 19 
1.2.3. 
Summary of Nonclinical Toxicology .................................................................................. 19 
1.2.4. 
Summary of Clinical Study SGNLVA-001: A Phase 1 Trial of LV in Subjects 
With Locally Advanced/Metastatic Breast Cancer .............................................................. 20 
1.2.4.1. 
Study Design of SGNLVA-001 ............................................................................... 20 
1.2.4.2. 
DLTs and Maximum Administered Dose ................................................................ 20 
1.2.4.3. 
Safety in SGNLVA-001 ........................................................................................... 20 
1.2.4.4. 
Preliminary Efficacy Data for SGNLV-001 ............................................................. 22 
1.3. 
Pembrolizumab Background ................................................................................................................. 25 
1.3.1. 
Pharmaceutical and Therapeutic Background ..................................................................... 25 
1.3.2. 
Summary of Pre-Clinical Studies ........................................................................................ 26 
1.3.3. 
Summary of Study SGNLVA-002: A Phase 1b/2 Trial of LV Combined with 
Pembrolizumab in Subjects with LA/mTNBC .................................................................... 26 
1.3.3.1. 
Study Design of SGNLVA-002 ............................................................................... 26 
1.3.3.2. 
Safety in SGNLVA-002 ........................................................................................... 27 
1.3.3.3. 
Preliminary Efficacy Data for SGNLVA-002 .......................................................... 29 
1.4. 
Rationale for Study ............................................................................................................................... 29 
2. 
OBJECTIVES ....................................................................................................................................... 31 
3. 
INVESTIGATIONAL PLAN ............................................................................................................... 32 
3.1. 
Summary of Study Design .................................................................................................................... 32 
3.1.1. 
Retreatment .......................................................................................................................... 36 
3.2. 
Discussion and Rationale for Study Design .......................................................................................... 36 
3.2.1. 
Rationale for Not Selecting Subjects Based Upon Detectable LIV-1 Protein 
Expression ........................................................................................................................... 36 
3.2.2. 
Rationale for Selection of q3wk LV Dose ........................................................................... 36 
3.2.3. 
Rationale for Mandatory G-CSF for Subjects Receiving More than 200 mg LV 
per Infusion in Part A .......................................................................................................... 37 
3.2.4. 
Rationale for Selection of q1wk LV Doses ......................................................................... 37 
3.2.5. 
Rationale for Selection of 2q3wk LV Dose (Part C) ........................................................... 38 
3.2.6. 
Rationale for Combining LV with Pembrolizumab in Part C .............................................. 39 
3.2.7. 
Rationale for Pembrolizumab Dose ..................................................................................... 40 
3.2.8. 
Blinding and Unblinding ..................................................................................................... 41 
4. 
STUDY POPULATION ....................................................................................................................... 42 
4.1. 
Inclusion Criteria .................................................................................................................................. 42 
4.2. 
Exclusion Criteria ................................................................................................................................. 48 
4.3. 
Childbearing Potential .......................................................................................................................... 50 
4.4. 
Removal of Subjects From Therapy or Assessment ............................................................................. 50 
4.4.1. 
Discontinuation of Study Treatment .................................................................................... 50 
4.4.2. 
Subject Withdrawal From Study ......................................................................................... 51 
5. 
TREATMENTS .................................................................................................................................... 52 
5.1. 
Treatments Administered ...................................................................................................................... 52 
5.2. 
Investigational Study Drug: LV ............................................................................................................ 52 
5.2.1. 
Description .......................................................................................................................... 52 
5.2.2. 
Method of Procurement ....................................................................................................... 52 
5.2.3. 
Dose and Administration ..................................................................................................... 52 
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5.2.3.1. 
Dosing Criteria ......................................................................................................... 53 
5.2.4. 
Dose Modifications.............................................................................................................. 54 
5.2.4.1. 
Part A (q3wk dosing) ............................................................................................... 54 
5.2.4.2. 
Part B (q1wk dosing) and Part C (Arm 3; q1wk dosing) ......................................... 56 
5.2.4.3. 
Part C (Arm 1 and Arm 2; 2q3wk dosing) ............................................................... 59 
5.2.5. 
Storage and Handling .......................................................................................................... 62 
5.2.6. 
Packaging and Labeling ....................................................................................................... 62 
5.2.7. 
Preparation ........................................................................................................................... 62 
5.3. 
Pembrolizumab ..................................................................................................................................... 62 
5.3.1. 
Description .......................................................................................................................... 62 
5.3.2. 
Method of Procurement ....................................................................................................... 63 
5.3.3. 
Dose and Administration ..................................................................................................... 63 
5.3.4. 
Dose Modifications.............................................................................................................. 63 
5.3.4.1. 
Dose Modification and Toxicity Management for Immune-Related AEs Associated 
with Pembrolizumab ................................................................................................ 63 
5.3.4.2. 
Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab ........................................................................................................ 67 
5.3.4.3. 
Other Allowed Dose Interruption for Pembrolizumab ............................................. 68 
5.3.5. 
Storage and Handling .......................................................................................................... 68 
5.3.6. 
Packaging and Labeling ....................................................................................................... 68 
5.3.7. 
Preparation ........................................................................................................................... 68 
5.4. 
Concomitant Therapy ........................................................................................................................... 68 
5.4.1. 
Required Concomitant Therapy ........................................................................................... 69 
5.4.2. 
Allowed Concomitant Therapy ............................................................................................ 69 
5.4.2.1. 
Blood Product Transfusions ..................................................................................... 70 
5.4.2.2. 
Premedication ........................................................................................................... 70 
5.4.2.3. 
Radiotherapy ............................................................................................................ 70 
5.4.2.4. 
Supportive Care Medications ................................................................................... 70 
5.4.3. 
Myeloid Growth Factors ...................................................................................................... 70 
5.4.4. 
Prohibited Concomitant Therapy ......................................................................................... 70 
5.4.4.1. 
Prohibited Concomitant Therapy for Pembrolizumab (Part C) ................................ 71 
5.5. 
Management of Adverse Reactions ...................................................................................................... 71 
5.5.1. 
Management of Infusion Reactions ..................................................................................... 71 
5.5.1.1. 
LV ............................................................................................................................ 71 
5.5.1.2. 
Pembrolizumab ........................................................................................................ 72 
5.5.1.3. 
Infusion-Related Reaction of Uncertain Cause ........................................................ 72 
5.5.2. 
Management of Overdose .................................................................................................... 72 
5.5.2.1. 
LV Overdose ............................................................................................................ 72 
5.5.2.2. 
Pembrolizumab Overdose ........................................................................................ 72 
5.5.3. 
Management of Overlapping Toxicities .............................................................................. 72 
5.5.4. 
Supportive Care Guidelines for Pembrolizumab ................................................................. 72 
5.6. 
Management of Hyperglycemia ............................................................................................................ 73 
5.7. 
Treatment Compliance .......................................................................................................................... 74 
6. 
STUDY ACTIVITIES .......................................................................................................................... 75 
6.1. 
Schedule of Events ............................................................................................................................... 75 
6.2. 
Part A (q3wk dosing) ............................................................................................................................ 75 
6.2.1. 
Screening Visit (Days –28 to 1) ........................................................................................... 75 
6.2.2. 
Baseline Visit (Days –7 to Day 1) ....................................................................................... 75 
6.2.3. 
Treatment Cycle (Day 1 to Day 21)..................................................................................... 76 
6.2.3.1. 
Day 1 ........................................................................................................................ 76 
6.2.3.2. 
Day 3 ........................................................................................................................ 77 
6.2.3.3. 
Day 8 (± 2 days) ....................................................................................................... 77 
6.2.3.4. 
Day 15 (± 2 days) ..................................................................................................... 77 
6.3. 
Part B (q1wk dosing) ............................................................................................................................ 78 
6.3.1. 
Screening Visit (Days –28 to 1) ........................................................................................... 78 
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6.3.2. 
Baseline Visit (Days –7 to Day 1) ....................................................................................... 78 
6.3.3. 
Treatment Cycle (Day 1 to Day 21)..................................................................................... 79 
6.3.3.1. 
Day 1 ........................................................................................................................ 79 
6.3.3.2. 
Day 3 ........................................................................................................................ 80 
6.3.3.3. 
Day 8 (± 2 days) ....................................................................................................... 80 
6.3.3.4. 
Day 15 (± 2 days) ..................................................................................................... 81 
6.4. 
Part C (monotherapy and pembrolizumab combination) ...................................................................... 81 
6.4.1. 
Screening Visit (Days –28 to 1) ........................................................................................... 81 
6.4.2. 
Baseline Visit (Days –7 to Day 1) ....................................................................................... 82 
6.4.3. 
Treatment Cycle (Day 1 to Day 21)..................................................................................... 82 
6.4.3.1. 
Day 1 ........................................................................................................................ 82 
6.4.3.2. 
Day 3 ........................................................................................................................ 83 
6.4.3.3. 
Day 8 (± 2 days) ....................................................................................................... 84 
6.4.3.4. 
Day 15 (± 2 days) ..................................................................................................... 84 
6.5. 
On treatment Response Assessments .................................................................................................... 85 
6.5.1. 
For non-prostate cancer subjects (Cohorts 1–6, and 8): ....................................................... 85 
6.5.2. 
For prostate cancer subjects (Cohort 7): .............................................................................. 86 
6.6. 
End of Treatment Visit (30 to 37 days after last dose of study drug) ................................................... 86 
6.7. 
Follow-up .............................................................................................................................................. 87 
6.8. 
End of Study/End of Follow-up ............................................................................................................ 87 
7. 
STUDY ASSESSMENTS .................................................................................................................... 88 
7.1. 
Screening/Baseline Assessments .......................................................................................................... 88 
7.1.1. 
Tumor Tissue After Treatment ............................................................................................ 88 
7.1.2. 
Tumor Sample Requirements and Collection ...................................................................... 88 
7.2. 
Response/Efficacy Assessments ........................................................................................................... 88 
7.2.1. 
Tumor Cohort-Specific Imaging Requirements ................................................................... 90 
7.3. 
Pharmacokinetic and Immunogenicity Assessments ............................................................................ 90 
7.4. 
Biomarker Studies ................................................................................................................................ 96 
7.4.1. 
Biomarkers in Blood ............................................................................................................ 96 
7.4.2. 
Biomarkers in Tumor Tissue ............................................................................................... 96 
7.5. 
Biospecimen Repository ....................................................................................................................... 96 
7.6. 
Safety Assessments ............................................................................................................................... 97 
7.6.1. 
Adverse Events .................................................................................................................... 97 
7.6.1.1. 
Definitions ................................................................................................................ 97 
7.6.1.2. 
Procedures for Eliciting and Recording Adverse Events ......................................... 99 
7.6.1.3. 
Reporting Periods for Adverse Events and Serious Adverse Events ..................... 102 
7.6.1.4. 
Serious Adverse Events Require Immediate Reporting ......................................... 102 
7.6.1.5. 
Sponsor Safety Reporting to Regulatory Authorities ............................................. 102 
7.6.1.6. 
Events of Clinical Interest ...................................................................................... 103 
7.6.2. 
Vital Signs ......................................................................................................................... 103 
7.6.3. 
Clinical Laboratory Tests .................................................................................................. 104 
7.6.4. 
Physical Examination ........................................................................................................ 104 
7.6.5. 
Pregnancy Testing ............................................................................................................. 105 
7.7. 
Appropriateness of Measurements ...................................................................................................... 105 
8. 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 106 
8.1. 
Site Training and Monitoring Procedures ........................................................................................... 106 
8.2. 
Data Management Procedures ............................................................................................................ 106 
8.3. 
Access to Source Data ........................................................................................................................ 107 
8.4. 
Accuracy and Reliability of Data ........................................................................................................ 107 
8.5. 
Quality Assurance Procedures ............................................................................................................ 107 
8.6. 
Data Handling and Record Keeping ................................................................................................... 107 
8.6.1. 
Data Handling .................................................................................................................... 107 
8.6.2. 
Investigator Record Retention ........................................................................................... 108 
9. 
DATA ANALYSIS METHODS ........................................................................................................ 109 
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9.1. 
Determination of Sample Size ............................................................................................................ 109 
9.2. 
Study Endpoint Definitions ................................................................................................................ 110 
9.2.1. 
Confirmed ORR ................................................................................................................. 110 
9.2.2. 
Confirmed PSA Response Rate ......................................................................................... 110 
9.2.3. 
Disease Control Rate ......................................................................................................... 110 
9.2.4. 
Duration of Response ........................................................................................................ 110 
9.2.5. 
Progression-Free Survival ................................................................................................. 111 
9.2.6. 
Overall Survival ................................................................................................................. 111 
9.2.7. 
Prostate-Specific Antigen Progression-Free Survival........................................................ 111 
9.3. 
Statistical and Analytical Plans ........................................................................................................... 111 
9.3.1. 
General Considerations ...................................................................................................... 111 
9.3.1.1. 
Randomization and Blinding .................................................................................. 111 
9.3.1.2. 
Adjustments for Covariates .................................................................................... 112 
9.3.1.3. 
Handling of Dropouts and Missing Data ................................................................ 112 
9.3.1.4. 
Multicenter Studies ................................................................................................ 112 
9.3.1.5. 
Multiple Comparisons and Multiplicity ................................................................. 112 
9.3.1.6. 
Data Transformations and Derivations ................................................................... 112 
9.3.1.7. 
Analysis Sets .......................................................................................................... 112 
9.3.1.8. 
Examination of Subgroups ..................................................................................... 113 
9.3.1.9. 
Timing of Analyses ................................................................................................ 113 
9.3.2. 
Subject Disposition ............................................................................................................ 113 
9.3.3. 
Subject Characteristics ...................................................................................................... 113 
9.3.4. 
Treatment Administration .................................................................................................. 113 
9.3.5. 
Efficacy Analyses .............................................................................................................. 113 
9.3.5.1. 
Primary Efficacy Analyses ..................................................................................... 113 
9.3.5.2. 
Secondary Efficacy Analyses ................................................................................. 114 
9.3.6. 
Pharmacokinetic and Immunogenicity Analyses ............................................................... 114 
9.3.7. 
Biomarker Analyses .......................................................................................................... 114 
9.3.8. 
Safety Analyses ................................................................................................................. 114 
9.3.8.1. 
Extent of Exposure ................................................................................................. 114 
9.3.8.2. 
Adverse Events....................................................................................................... 114 
9.3.8.3. 
Deaths and Serious Adverse Events ....................................................................... 115 
9.3.8.4. 
Clinical Laboratory Results .................................................................................... 115 
9.3.8.5. 
Other Safety Analyses ............................................................................................ 115 
9.3.9. 
Interim Analyses ................................................................................................................ 115 
10. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS .......................................................................................................................... 118 
10.1. 
Informed Consent ............................................................................................................................... 118 
10.2. 
Ethical Review .................................................................................................................................... 118 
10.3. 
Regulatory Considerations .................................................................................................................. 119 
10.3.1. 
Investigator Information .................................................................................................... 119 
10.3.2. 
Protocol Amendments and Study Termination .................................................................. 119 
10.4. 
Study Documentation, Privacy and Records Retention ...................................................................... 119 
10.5. 
Clinical Trial Agreement .................................................................................................................... 119 
11. 
REFERENCES ................................................................................................................................... 120 
APPENDIX A. 
SCHEDULE OF EVENTS FOR SCREENING/BASELINE (PARTS A, B, AND 
C) 
 ........................................................................................................................................... 125 
APPENDIX B. 
SCHEDULE OF EVENTS FOR TREATMENT (Q3WK DOSING; PART A) ............... 127 
APPENDIX C. 
SCHEDULE OF EVENTS FOR TREATMENT (Q1WK DOSING; PART B) ............... 129 
APPENDIX D. 
SCHEDULE OF EVENTS FOR TREATMENT (PART C) ............................................. 131 
APPENDIX E. 
NEW YORK HEART ASSOCIATION CLASSIFICATION ........................................... 136 
APPENDIX F. 
P-GP AND CYP3A INDUCERS/INHIBITORS ............................................................... 137 
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APPENDIX G. 
PROPHYLACTIC GRANULOCYTE-COLONY STIMULATING FACTOR (G-
CSF) THROUGHOUT SUPPORT RECOMMENDATIONS ........................................................... 139 
APPENDIX H. 
RECIST VERSION 1.1 ..................................................................................................... 142 
APPENDIX I. 
IRECIST: GUIDELINES FOR RESPONSE CRITERIA FOR USE IN TRIALS 
TESTING IMMUNOTHERAPEUTICS ............................................................................................ 143 
APPENDIX J. 
PERFORMANCE STATUS SCALES CONVERSION ................................................... 145 
APPENDIX K. 
GUIDANCE ON CONTRACEPTION ............................................................................. 146 
APPENDIX L. 
PCWG3 SUGGESTED OUTCOME MEASURES FOR CLINICAL TRIALS IN 
METASTATIC PROSTATE CANCER ............................................................................................. 147 
APPENDIX M. 
INVESTIGATOR SIGNATURE PAGE ........................................................................... 150 
APPENDIX N. 
DOCUMENT HISTORY .................................................................................................. 151 
SUMMARY OF CHANGES IN AMENDMENT 01 ................................................................................................ 152 
SUMMARY OF CHANGES IN AMENDMENT 02 ................................................................................................ 156 
SUMMARY OF SUBSTANTIVE CHANGES IN AMENDMENT 03 .................................................................... 160 
SUMMARY OF CHANGES IN AMENDMENT 04 ................................................................................................ 161 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Treatment-emergent adverse events occurring in ≥20% of subjects treated in 
Study SGNLVA-001 by preferred term – LV monotherapy q3wk ....................................................... 21 
Table 2: 
Treatment-emergent adverse events occurring in ≥20% subjects treated in 
Study SGNLVA-001 – LV monotherapy q1wk ................................................................................... 22 
Table 3: 
Best response by LV q3wk dose level – TNBC subjects ...................................................................... 23 
Table 4: 
Best response by LV q1wk dose level – 2L TNBC subjects ................................................................ 25 
Table 5: 
Treatment-emergent adverse events occurring in ≥20% subjects treated with LV q3wk or 
q1wk + pembrolizumab in Study SGNLVA-002 by preferred term ..................................................... 28 
Table 6: 
Preliminary Efficacy for SGNLVA-002: Objective response rate ........................................................ 29 
Table 7: 
Objectives and corresponding endpoints .............................................................................................. 31 
Table 8: 
Planned dose levels for Part B (LV q1wk dosing) ................................................................................ 35 
Table 9: 
Q3wk LV dose levels ............................................................................................................................ 54 
Table 10: 
Dose modifications for LV-associated toxicity (Part A; q3wk dosing) ................................................ 55 
Table 11: 
Q1wk LV dose reductions .................................................................................................................... 56 
Table 12: 
Dose modifications for LV treatment-associated toxicity (Part B and Part C [Arm 3] q1wk 
dosing) .................................................................................................................................................. 57 
Table 13: 
2q3wk LV dose levels .......................................................................................................................... 59 
Table 14: 
Dose modifications for LV-associated toxicity (Part C [Arms 1 and 2]; 2q3wk dosing) ..................... 60 
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Table 15 
Dose modification and toxicity management guidelines for immune-related AEs associated 
with pembrolizumab ............................................................................................................................. 64 
Table 16 
Pembrolizumab infusion reaction dose modification and treatment guidelines .................................... 67 
Table 17: 
Pharmacokinetic, immunogenicity, and biomarker sample collection time points – 21 day 
cycles (Part A; q3wk dosing) ................................................................................................................ 91 
Table 18: 
Pharmacokinetic, immunogenicity, and biomarker sample collection time points – 21 day 
cycles (Part B; q1wk dosing) ................................................................................................................ 92 
Table 19: 
Pharmacokinetic, immunogenicity, and biomarker sample collection time points – 21 day 
cycles (Part C; 2q3wk, q1wk) ............................................................................................................... 94 
Table 20: 
PPoS based on response among the first 12 subjects .......................................................................... 116 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Percent change in sum of tumor diameters by breast cancer subtype and dose for 
Study SGNLVA-001 ............................................................................................................................ 24 
Figure 2: 
Study Design and Cohorts – Parts A, B, and C ..................................................................................... 33 
Figure 3: 
Study Schema Overview ....................................................................................................................... 34 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
1L 
first line 
2L 
second line 
2q3wk 
Day 1 and Day 8 but not Day 15 every 21-day cycle 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ART 
anti-retroviral therapy 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibody 
AUC 
area-under-the-curve 
BRAF 
B-Raf proto-oncogene serine/threonine kinase gene 
C1 
Cycle 1 
C2 
Cycle 2 
C4 
Cycle 4 
C5 
Cycle 5 
CBC 
complete blood count 
CBR 
clinical benefit ratio 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CR 
complete response 
CRF 
case report form 
CRPC 
castration-resistant prostate cancer 
CSPC 
castration-sensitive prostate cancer 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
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CYP3A 
cytochrome P450 3A 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
ELISA 
enzyme-linked immunosorbent assay 
EOT 
end of treatment 
esophageal-squamous 
esophageal squamous cell carcinoma 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
G-CSF 
granulocyte-colony stimulating factor 
GEJ 
gastroesophageal junction 
GFR 
glomerular filtration rate 
Hb1Ac 
hemoglobin A1c 
HER2 
human epidermal growth factor receptor 2 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma 
HNSTD 
highest non-severely toxic dose 
HR+ 
hormone receptor positive 
IB 
Investigator’s Brochure 
ICD 
immunogenic cell death 
ICH 
International Council for Harmonisation  
iCPD 
confirmed disease progression by iRECIST guidelines 
IEC 
independent ethics committee 
IgG1 
immunoglobulin G1 
IgG4 
immunoglobulin G4 
IHC 
immunohistochemistry 
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IND 
investigational new drug 
irAE 
immune-related adverse event 
IRB 
institutional review board 
iRECIST 
immune Response Evaluation Criteria in Solid Tumors 
iRIS 
ICON Results Integration Services 
IRR 
infusion-related reaction 
iUPD 
unconfirmed progression by iRECIST guidelines 
IV 
intravenous 
LA/mTNBC 
locally advanced and/or metastatic triple-negative breast cancer 
LC/MS/MS 
liquid chromatography with tandem mass spectrometry 
LV 
ladiratuzumab vedotin 
mAb 
monoclonal antibody 
mBC 
metastatic breast cancer 
MDRD 
Modification of Diet in Renal Disease [study] 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen-activated protein kinase kinase 
MMAE 
monomethyl auristatin E 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK cells 
natural killer cells 
NLT 
new lesions-target 
NLNT 
new lesions-non-target 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PBPK 
physiologically-based pharmacokinetics 
PCR 
polymerase chain reaction 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PD-1 
programmed cell death 1 receptor 
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PD-L1 
programmed cell death ligand 1  
PD-L2 
programmed cell death ligand 2 
PD(L)1 
programmed cell death 1 receptor or programmed cell death ligand 1, collectively 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PPoS 
predictive probability of success 
PR 
partial response 
PSA 
prostate-specific antigen 
q1wk 
Day 1, Day 8, and Day 15 of every 21-day cycle 
q3wk 
Day 1 of every 21-day cycle 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RNA 
ribonucleic acid 
ROS 
reactive oxygen species 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
Scr 
serum creatinine 
SD 
stable disease 
SJS 
Stevens-Johnson Syndrome 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TME 
tumor microenvironment 
TNBC 
triple-negative breast cancer 
TRK 
tropomyosin receptor kinase 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
vc 
valine-citrulline 
WFI 
water for injection 
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β-hCG 
beta human chorionic gonadotropin  
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1. 
INTRODUCTION 
1.1. 
LIV-1 
LIV-1 is a member of the solute carrier family 39 and is a multispan transmembrane protein with 
putative zinc transporter and metalloproteinase activity (Taylor 2003). It was first identified as an 
estrogen-induced gene in the breast cancer cell line ZR-75-1 (Manning 1988). Subsequently, 
normal tissue expression has been demonstrated in hormonally regulated tissues with the highest 
expression in breast and prostate samples (Seagen Inc., data on file). 
LIV-1 expression has been linked with malignant progression to metastasis and is associated 
with lymph node involvement in breast cancer (Manning 1994). It has been detected in a number 
of cancer types including breast, prostate, melanoma, ovarian, cervical, uterine, and pancreatic 
cancer (Manning 1988; Manning 1994; Dressman 2001; Tozlu 2006; Unno 2009; Sussman 2011) 
(Seagen Inc., data on file). In an immunohistochemistry (IHC) analysis conducted by Seagen 
Inc., the highest prevalence and level of expression is seen in breast ductal carcinoma (93% of 
relapsed post-treatment subject samples). Of the 631 fresh or archival metastatic breast cancer 
(mBC) tumor samples evaluated by IHC analysis in a phase 1 study conducted by Seagen Inc., 
>90% were positive for LIV-1 expression and 75% had moderate to high expression. In subjects 
with triple-negative breast cancer (TNBC), approximately 70% of samples had moderate to high 
expression of LIV-1 (Modi 2018). 
1.2. 
Ladiratuzumab vedotin 
Ladiratuzumab vedotin (LV) is an antibody-drug conjugate (ADC), also known as SGN-LIV1A, 
directed against the LIV-1 antigen that is being developed to treat subjects with solid tumor 
malignancies. The antibody backbone of LV is a humanized immunoglobulin G1 (IgG1) 
monoclonal antibody (mAb) called hLIV22. This antibody is chemically conjugated to a 
synthetic analog of dolastatin 10 (monomethyl auristatin E [MMAE]), which is a naturally 
occurring tubulin-disrupting molecule. The protease-cleavable valine-citrulline (vc) 
maleimidocaproyl linker covalently attaches MMAE to hLIV22. An average of 4 MMAE 
molecules are present on each antibody molecule. 
1.2.1. 
Mechanism of Action 
The mechanism of action of LV is as follows (Sussman 2014): 
• After binding to cell-surface LIV-1, LV is internalized and trafficked through the 
endocytic pathway to the lysosomes, 
• Proteolytic degradation of the drug linker in lysosomes releases MMAE, 
• MMAE binds to tubulin and disrupts the cellular microtubule network, arrests cells at 
the G2/M phase of the cell cycle, prevents cell division, and eventually leads to the 
death of tumor cells. 
Preclinical data also point to important additional mechanisms of action for MMAE-linked 
ADCs like LV, including drug-induced endoplasmic reticulum stress and subsequent 
engagement of the immune system, proinflammatory cytokine release, and the recruitment of 
antigen-presenting cells (eg, macrophages and dendritic cells) into the tumor, which is consistent 
with immunogenic cell death (ICD) (Cao 2018). 
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1.2.2. 
Summary of Preclinical Activity 
The pharmacologic effects of LV in vitro, such as cell binding and cytotoxicity in LIV-1-positive 
cell lines, have been characterized in multiple studies (Sussman 2014). The affinity of LV to the 
LIV-1 protein is 0.58 nM, while the half maximal inhibitory concentration (IC50) of LV on 
MCF-7 cells is 6.3 ng/mL.  
The antitumor activity of LV has been evaluated in xenograft models of breast, prostate, and 
cervical cancer (Sussman 2014). Treatment with LV at 3 mg/kg every 4 days for 4 doses resulted 
in significant tumor shrinkage in a patient-derived breast cancer model (BR0555) compared to a 
non-binding control ADC (hIg vcMMAE). The antitumor activity of LV observed in the BR0555 
model was dose-dependent. LV also demonstrated antitumor activity at similar doses against 
other LIV-1-positive breast cancer (MCF-7), prostate cancer (PC3) and cervical (HeLa) 
xenograft models, while the unconjugated parental antibody alone showed no effect. 
1.2.3. 
Summary of Nonclinical Toxicology 
The toxicity of LV following intravenous (IV) administration has been evaluated in single- and 
repeat-dose studies in rats and monkeys. The dose-limiting toxicity (DLT) was bone marrow 
suppression observed in both animal models, with concomitant reductions in hematology 
endpoints (predominantly anemia and neutropenia). Dose-dependent toxicities included testes 
(atrophy and degeneration of seminiferous tubules and lack of spermatozoa), liver (mild biliary 
hyperplasia, mild portal inflammation, minimal hepatocellular single cell necrosis, and arrested 
mitotic figures), small intestine (minimal to mild crypt epithelium necrosis), mammary gland 
(minimal to mild glandular hyperplasia), thymus (moderate to severe lymphoid depletion), 
kidney (minimal arrested mitotic figures), spleen (mild arrested mitotic figures and moderate 
hemosiderosis in the red pulp), ovary (arrested follicular development), mesenteric lymph node 
(lymphocyte depletion), skin, and rectum (inflammation with bacterial colonies likely due to 
bone marrow suppression). 
Similar hematopoietic cell depletion and target organs of toxicity have been observed for MMAE 
(the cytotoxic component of LV) administered at molar equivalents of ADC highest non-severely 
toxic dose (HNSTD) levels. An additional MMAE-related toxicity, not observed to date in LV 
studies in monkeys, is decreased number/absent secondary and tertiary ovarian follicles 
following repeated administration of MMAE-based ADCs. This change is considered to be due 
to the antiproliferative effect of MMAE and is considered reversible due to the evidence of 
recovery upon treatment cessation and the lack of effects on primordial follicles. Treatment with 
MMAE during pregnancy in rats also led to embryo-fetal development toxicity characterized by 
significant increases in total resorptions, post-implantation loss, early delivery, and loss of viable 
fetuses. 
A complete summary of the nonclinical data relevant to the investigational product and its study 
in human subjects is provided in the Investigator’s Brochure (IB). 
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1.2.4. 
Summary of Clinical Study SGNLVA-001: A Phase 1 Trial of LV in 
Subjects With Locally Advanced/Metastatic Breast Cancer 
1.2.4.1. 
Study Design of SGNLVA-001 
This is an ongoing phase 1 dose-escalation and expansion study to define the safety and 
tolerability of LV in subjects with unresectable locally advanced/metastatic breast cancer. The 
study is being conducted in 6 parts, each studying different subject populations. Part A is 
monotherapy including the dose escalation and first expansion cohort. Part B is combination 
therapy with trastuzumab. Parts C and D are monotherapy at the recommended dose. Part E is 
monotherapy evaluating LV administered on Day 1, Day 8, and Day 15 every 21-day cycle 
(q1wk). Part F is monotherapy evaluating LV intermittent dosing given on Day 1 and Day 8 but 
not Day 15 of every 21-day cycle (2q3wk). 
Please see the LV IB for complete information on SGNLVA-001. 
1.2.4.2. 
DLTs and Maximum Administered Dose 
Part A of Study SGNLVA-001 assessed dose escalation of LV from 0.5–2.8 mg/kg. A total of 
22 subjects were treated in the dose escalation phase. No DLTs were observed during dose 
escalation up to doses of 2.8 mg/kg. The maximum tolerated dose (MTD) was not reached. 
Based on safety and activity data observed in the dose escalation and initial expansion cohorts, 
the recommended monotherapy dose was determined to be 2.5 mg/kg on Day 1 of every 21-day 
cycle (q3wk) intravenously. 
Subjects in Parts A, B, C, and D will receive LV on Day 1 q3wk. Subjects in Part E 
(monotherapy with q1wk dosing) will receive LV 0.75–1.75 mg/kg on Day 1, Day 8, and Day 15 
of every 21-day cycle. Subjects in Part F (intermittent dosing) will receive LV 1.5 mg/kg 2q3wk. 
1.2.4.3. 
Safety in SGNLVA-001 
Safety Data of LV Monotherapy q3wk 
As of 26 July 2021, LV monotherapy has been evaluated in 191 subjects with mBC with the 
majority of subjects receiving LV 2.0 mg/kg (n=36) and LV 2.5 mg/kg (n=141) q3wk. The most 
common treatment-emergent adverse events (TEAEs) occurring in ≥20% of subjects with mBC 
treated with LV monotherapy using the q3wk schedule (n=191) are shown in Table 1. This 
includes all patients who received LV monotherapy q3wk from 0.5 mg/kg to 2.8 mg/kg dose.  
The most common Grade 3 or higher events were neutropenia (25.7%), anemia (9.9%), 
fatigue (8.9%), nausea (6.8%), abdominal pain, dehydration, and dyspnea (5.2% each). Serious 
adverse events (SAEs) were reported in 71 subjects (37.2%) with 36 subjects (18.8%) 
experiencing SAEs that were considered at least possibly related to LV. The most commonly 
reported SAEs included abdominal pain (3.7%), dehydration, nausea (3.1% each), neutropenia, 
vomiting (2.6% each), constipation, and febrile neutropenia (2.1% each) (Seagen Inc., data on 
file). 
 
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Table 1: 
Treatment-emergent adverse events occurring in ≥20% of subjects treated in 
Study SGNLVA-001 by preferred term – LV monotherapy q3wk  
Preferred Term a,  
n (%) 
Total 
(N=191) 
Fatigue 
112 (58.6) 
Nausea 
88 (46.1) 
Constipation 
78 (40.8) 
Decreased appetite 
72 (37.7) 
Peripheral sensory neuropathy 
69 (36.1) 
Alopecia 
68 (35.6) 
Diarrhoea 
59 (30.9) 
Neutropenia 
57 (29.8) 
Abdominal pain 
48 (25.1) 
Arthralgia 
47 (24.6) 
Vomiting 
41 (21.5) 
a MedDRA Version 24.0 
Note: For each preferred term, subjects are included only once, even if they experienced multiple events in that 
preferred term 
LV=ladiratuzumab vedotin; MedDRA=Medical Dictionary for Regulatory Activities; q3wk=Day 1 every 21-day 
cycle. 
Source: Seagen Inc., data on file. 
Safety Data of LV Monotherapy q1wk  
As of 26 July 2021, 81 subjects have been dosed with LV q1wk in SGNLVA-001 (20 subjects 
with 1.0 mg/kg, 52 subjects with 1.25 mg/kg, and 9 subjects with 1.5 mg/kg). LV monotherapy 
q1wk doses of 1.0 mg/kg, 1.25 mg/kg, and 1.5 mg/kg were safely delivered without DLTs. 
The adverse event (AE) profile occurring in >20% subjects (Seagen Inc., data on file) in subjects 
dosed with LV monotherapy using the q1wk schedule is shown in Table 2. The most common 
Grade 3 or higher events for all subjects that received LV q1wk were neutropenia (21.0%), 
fatigue (14.8%), hyperglycemia, neutrophil count decrease (11.1% each), hypokalemia, 
hypophosphatemia (9.9% each), and nausea (8.6%). SAEs were reported in 35 subjects (43.2%). 
Of those, SAEs in 17 subjects (21.0%) were considered at least possibly related to LV. The most 
commonly reported SAEs included fatigue, febrile neutropenia, nausea (3.7% each), abdominal 
pain, dehydration, hyponatremia, and neutrophil count decrease (2.5% each) (Seagen Inc., data 
on file). 
 
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Table 2: 
Treatment-emergent adverse events occurring in ≥20% subjects treated in 
Study SGNLVA-001 – LV monotherapy q1wk 
Preferred Term a,  
n (%) 
1 mg/kg 
(N=20) 
1.25 mg/kg 
(N=52) 
1.5 mg/kg 
(N=9) 
Total 
(N=81) 
Fatigue 
12 (60.0) 
31 (59.6) 
7 (77.8) 
50 (61.7) 
Nausea 
10 (50.0) 
31 (59.6) 
4 (44.4) 
45 (55.6) 
Peripheral sensory neuropathy 
3 (15.0) 
28 (53.8) 
5 (55.6) 
36 (44.4) 
Constipation 
8 (40.0) 
20 (38.5) 
6 (66.7) 
34 (42.0) 
Decreased appetite 
6 (30.0) 
23 (44.2) 
2 (22.2) 
31 (38.3) 
Diarrhoea 
9 (45.0) 
16 (30.8) 
4 (44.4) 
29 (35.8) 
Vomiting 
10 (50.0) 
16 (30.8) 
2 (22.2) 
28 (34.6) 
Myalgia 
4 (20.0) 
16 (30.8) 
4 (44.4) 
24 (29.6) 
Neutropenia 
4 (20.0) 
14 (26.9) 
6 (66.7) 
24 (29.6) 
Abdominal pain 
5 (25.0) 
17 (32.7) 
1 (11.1) 
23 (28.4) 
Alopecia 
5 (25.0) 
14 (26.9) 
3 (33.3) 
22 (27.2) 
Hypokalaemia 
5 (25.0) 
14 (26.9) 
3 (33.3) 
22 (27.2) 
Arthralgia 
4 (20.0) 
16 (30.8) 
1 (11.1) 
21 (25.9) 
Dyspnoea 
4 (20.0) 
13 (25.0) 
4 (44.4) 
21 (25.9) 
Weight decreased 
3 (15.0) 
12 (23.1) 
4 (44.4) 
19 (23.5) 
Muscular weakness 
1 (5.0) 
13 (25.0) 
4 (44.4) 
18 (22.2) 
Dizziness 
4 (20.0) 
11 (21.2) 
2 (22.2) 
17 (21.0) 
Insomnia 
1 (5.0) 
14 (26.9) 
2 (22.2) 
17 (21.0) 
a MedDRA Version 24.0 
Note: For each preferred term, subjects are included only once, even if they experienced multiple events in that 
preferred term. The 20% cutoff is based on percentages in the “Total” column.  
LV=ladiratuzumab vedotin; MedDRA=Medical Dictionary for Regulatory Activities; q1wk= Days 1, 8, and 15 
every 21-day cycle. 
Source: Seagen Inc., data on file 
1.2.4.4. 
Preliminary Efficacy Data for SGNLV-001 
LV q3wk Responses in TNBC Subjects 
As of 29 September 2017, 35 of the 60 subjects (58%) treated with LV q3wk in the TNBC 
monotherapy cohorts achieved a PR (15 [25%] subjects) or stable disease (SD) (20 subjects 
[33%]) (Modi 2018). The overall response rate was 25% (objective response rate [ORR]) and 
28% clinical benefit rate (CBR) (see Table 3). 
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Table 3: 
Best response by LV q3wk dose level – TNBC subjects 
 
Dose level (mg/kg) 
Total 
(N=60) a 
 
2.0 
(N=31) 
2.5 
(N=26) 
2.8 
(N=1) 
Best clinical response, n (%) 
 
 
 
 
CR 
0 (0) 
0 (0) 
0 (0.0) 
0 (0.0) 
PR 
4 (12.9) 
9 (34.6) 
1 (100) 
15 (25.0) 
SD 
12 (38.7) 
7 (26.9) 
0 (0.0) 
20 (33.3) 
PD 
15 (48.4) 
10 (38.5) 
0 (0.0) 
25 (41.7) 
ORR, % (95% CI) 
13 (4, 30) 
35 (17, 56) 
100 (3, 100) 
25 (15, 38) 
DCR, n (%) 
16 (51.6) 
16 (61.5) 
1 (100) 
35 (58.3) 
CBR, % (95% CI) 
13 (4, 30) 
39 (20, 59) 
100 (3, 100) 
28 (18, 41) 
CBR=clinical benefit rate (CR + PR + SD ≥24 weeks); CI=confidence interval; CR=complete response; 
DCR=disease control rate (CR + PR + SD); ORR=objective response rate (CR + PR); PD=progressive 
disease; PR=partial response; SD=stable disease; TNBC=triple-negative breast cancer 
Source: San Antonio Breast Cancer Symposium Poster, December 2017 (Modi 2018). 
a Response data is shown for efficacy evaluable subjects 2.0 mg/kg and higher doses 
LV q1wk Responses in TNBC and HR+ mBC Subjects 
Preliminary efficacy results from the LV q1wk dose schedule (Part E) of the SGNLVA-001 
study are shown in Figure 1, which demonstrates best percentage change in the sum of tumor 
diameters from baseline for both subjects with second line (2L) TNBC and subjects with first 
line (1L) or 2L hormone-refractory hormone receptor positive (HR+) mBC (data cutoff 
06-Jan-2021). 
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Figure 1:
Percent change in sum of tumor diameters by breast cancer subtype and dose for 
Study SGNLVA-001
Source: Seagen, data on file (data cutoff 06-Jan-2021)
Efficacy results for subjects with 2L metastatic TNBC treated with LV q1wk were available as 
of 19 March 2021. Twenty-four of the 39 total subjects treated with LV q1wk achieved a PR 
(8 subjects [21%]) or SD (16 subjects [41%]) (Tsai 2021). Table 4 summarizes the responses 
according to the dose levels explored in this part of the study. 
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Table 4: 
Best response by LV q1wk dose level – 2L TNBC subjects 
 
Dose level (mg/kg) a 
 
1.0 
(N=10) 
1.25 
(N=29) 
Best clinical response, n (%) 
 
 
CR 
0 (0) 
0 (0) 
PR 
0 (0) 
8 (28) 
SD 
3 (30) 
13 (45) 
PD 
6 (60) 
7 (24) 
NE 
1 (10) 
1 (3) 
ORR, % (95% CI) 
0 (0, 31) 
28 (13, 47) 
Duration of response, months (95% CI) 
0 
2.9 (2.2, 7.0) 
a LV 1.5 mg/kg q1wk, only 1 LA/mTNBC subject accrued and had PD as best response 
CI=confidence interval; CR=complete response; NE=not evaluable; ORR=objective response rate (CR + PR); 
PD=progressive disease; PR=partial response; q1wk= Day 1, 8, and 15 every 21-day cycle; SD=stable disease; 
LA/mTNBC= locally advanced and/or metastatic triple-negative breast cancer 
Note: unconfirmed PRs are categorized as SD 
Source: European Society of Medical Oncology Poster (September 2021)  
1.3. 
Pembrolizumab Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal mAb with high 
specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an IV immunotherapy for advanced malignancies. Keytruda® 
(pembrolizumab) is indicated for the treatment of patients across a number of indications. For 
more details on specific indications refer to the IB. 
Refer to the IB/approved labeling for detailed background information on MK-3475. 
Justification for the planned dose of pembrolizumab for this study is detailed in Section 3.2.7.  
1.3.1. 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis 2010). Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T cells correlates with improved prognosis and long-term survival in 
solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; 
malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded 
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ex vivo and reinfused, inducing durable objective tumor responses in cancers such as melanoma 
(Dudley 2005; Hunder 2008). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2) (Okazaki 2001; Greenwald 2005). 
The structure of murine PD-1 has been resolved (Zhang 2004). PD-1 and its family members are 
type I transmembrane glycoproteins containing an Ig-Variable-type domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules, such as CD3 zeta, protein kinase C-theta, and 
zeta-chain-associated protein kinase, which are involved in the CD3 T cell signaling cascade 
(Okazaki 2001; Chemnitz 2004; Sheppard 2004; Riley 2009). The mechanism by which PD-1 
down-modulates T-cell responses is similar to, but distinct from that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins (Parry 2005; Francisco 2010). 
Consequently, the PD-1/PD-L1 (collectively PD[L]1) pathway is an attractive target for 
therapeutic intervention in solid tumor malignancies like melanoma. 
1.3.2. 
Summary of Pre-Clinical Studies 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD(L)1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to 
tumor rejection, either as a monotherapy or in combination with other treatment modalities 
(Strome 2003; Blank 2004; Hirano 2005; Curran 2010; Pilon-Thomas 2010; Weber 2010; 
Spranger 2014). Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor 
responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, acute 
myeloid leukemia, and colorectal carcinoma (Strome 2003; Zhang 2004; Nomi 2007; Curran 
2010; Pilon-Thomas 2010). In such studies, tumor infiltration by CD8+ T cells and increased 
IFN-γ, granzyme B, and perforin expression were observed, indicating that the mechanism 
underlying the antitumor activity of PD-1 checkpoint inhibition involved local infiltration and 
activation of effector T cell function in vivo (Curran 2010). Experiments have confirmed the in 
vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in combination with 
chemotherapy, in syngeneic mouse tumor models (see the IB). 
1.3.3. 
Summary of Study SGNLVA-002: A Phase 1b/2 Trial of LV Combined 
with Pembrolizumab in Subjects with LA/mTNBC 
1.3.3.1. 
Study Design of SGNLVA-002 
This is an ongoing phase 1b/2, open-label, combination-treatment study and is intended to 
determine the safety, tolerability, and antitumor activity of LV when used in combination with 
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pembrolizumab in 1L treatment of subjects with locally advanced and/or metastatic 
triple-negative breast cancer (LA/mTNBC). 
There are 3 treatment schedules in this study: a 2.0 or 2.5 mg/kg q3wk LV plus 200 mg q3wk 
pembrolizumab schedule, a 1.0–1.25 mg/kg q1wk LV plus 200 mg q3wk pembrolizumab 
schedule, and a 1.5 mg/kg 2q3wk plus 200 mg q3wk pembrolizumab schedule. 
1.3.3.2. 
Safety in SGNLVA-002 
At the time of the data cutoff (26 July 2021), 136 subjects have received LV plus pembrolizumab 
treatment. Ninety-one subjects have been treated with LV q3wk and 45 subjects with LV q1wk 
in combination with pembrolizumab. 
The most common TEAEs reported in ≥20% of subjects receiving LV q3wk plus pembrolizumab 
or LV q1wk plus pembrolizumab are shown in Table 5. 
 
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Table 5: 
Treatment-emergent adverse events occurring in ≥20% subjects treated with LV 
q3wk or q1wk + pembrolizumab in Study SGNLVA-002 by preferred term 
Preferred Term, a 
n (%)  
LV q3wk+ 
Pembrolizumab 
(N=91) 
LV q1wk + 
Pembrolizumab 
(N=45) 
Total 
(N=136) 
Nausea 
60 (66) 
22 (49) 
82 (60) 
Fatigue 
57 (63) 
24 (53) 
81 (60) 
Diarrhoea 
45 (49) 
18 (40) 
63 (46) 
Constipation 
41 (45) 
15 (33) 
56 (41) 
Alopecia 
45 (49) 
10 (22) 
55 (40) 
Decreased appetite 
36 (40) 
11 (24) 
47 (35) 
Peripheral sensory neuropathy 
37 (41) 
7 (16) 
44 (32) 
Vomiting 
27 (30) 
9 (20) 
36 (26) 
Abdominal pain 
26 (29) 
9 (20) 
35 (26) 
Arthralgia 
27 (30) 
8 (18) 
35 (26) 
Weight decreased 
26 (29) 
8 (18) 
34 (25) 
Hypokalaemia 
26 (29) 
6 (13) 
32 (24) 
Cough 
25 (27) 
4 (9) 
29 (21) 
Pyrexia 
22 (24) 
7 (16) 
29 (21) 
Headache 
25 (27) 
3 (7) 
28 (21) 
Alanine aminotransferase increased 
18 (20) 
9 (20) 
27 (20) 
Aspartate aminotransferase increased 
16 (18) 
11 (24) 
27 (20) 
Pruritus 
21 (23) 
6 (13) 
27 (20) 
a MedDRA Version 24.0 
Please note: Treatment-emergent adverse events are presented and defined as newly occurring (not present at 
baseline) or worsening after first dose of investigational product. 
The 20% cutoff is based on percentages in the “Total” column. 
LV=ladiratuzumab vedotin; MedDRA=Medical Dictionary for Regulatory Activities; q1wk=Days 1, 8, and 15 every 
21-day cycle; q3wk=Day 1 every 21-day cycle. 
Seventy-one of 91 subjects (78%) treated with LV q3wk plus pembrolizumab and 29 of 
45 subjects (64%) treated with LV q1wk plus pembrolizumab experienced National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3 or higher 
TEAEs. The most common of these events in all subjects were neutropenia (13%), hypokalemia 
(12%), fatigue (10%), hyperglycemia, and peripheral sensory neuropathy (9%), (Seagen Inc., 
data on file). 
SAEs were reported in 52 subjects (57%) treated with LV q3wk plus pembrolizumab and of 
these, 26 subjects (29%) had events assessed by the investigator to be related to either LV or 
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pembrolizumab. Twenty subjects (44%) treated with LV q1wk plus pembrolizumab reported 
SAEs and of these, 12 subjects (27%) had events assessed to be related to either LV or 
pembrolizumab (Seagen Inc., data on file). Out of total subjects in SGNLVA-002, the most 
common SAEs deemed to be related to either LV or pembrolizumab were abdominal pain (4%), 
colitis, pyrexia (3% each), acute kidney injury, and diarrhea (2% each).  
Please see the LV IB for further details on safety of combination therapy. 
1.3.3.3. 
Preliminary Efficacy Data for SGNLVA-002 
As of 07 October 2019, LV q3wk in combination with pembrolizumab achieved a confirmed 
ORR of 35% (Han 2020). SD was observed in 32 subjects (48%), see Table 6. 
Table 6: 
Preliminary Efficacy for SGNLVA-002: Objective response rate 
 
Total 
(N=66)a 
Confirmed ORR, % (95% CI) 
35% (23.5, 47.6) 
CR confirmed, n (%) 
2 (3%) 
PR confirmed, n (%) 
21 (32%) 
SD, n (%) 
32 (48%) 
PD, n (%) 
8 (12%) 
Not evaluable/not done, n (%) 
3 (5%) 
a All subjects whose C1D1 date was at least 3 months before the data extract 
CI=confidence interval; CR=complete response; ORR=objective response rate; PD=progressive disease; PR=partial 
response; SD=stable disease. 
Source: San Antonio Breast Cancer Symposium Poster, December 2019 (Han 2020) 
1.4. 
Rationale for Study 
LIV-1 expression has been linked with malignant progression to metastasis and is associated 
with lymph node involvement in breast cancer (Manning 1994). Based on the activity observed 
in TNBC (Section 1.2.4), LV may also have activity in other solid tumors expressing LIV-1. In 
order to identify those indications most likely to be successfully treated with LV, we evaluated 
multiple internal and external sources of data on LIV-1 expression. LIV-1 expression has been 
detected in a number of cancer types including breast, prostate, melanoma, ovarian, bladder, 
small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), head and neck squamous 
cell carcinoma (HNSCC), esophageal, and gastric adenocarcinoma. Among the 8 primary 
indications chosen for this trial, prevalence of LIV-1 expression was as high as 99% (SCLC) and 
largely above 50%. Prevalence of LIV-1-expressing tumors across cancer subtypes based on 
RNA is similar to that estimated by protein expression (both IHC and mass spectrometry) 
(Manning 1988; Manning 1994; Dressman 2001; Tozlu 2006; Unno 2009; Sussman 2011; Zhu 
2014; George 2015); (Seagen Inc., data on file).  
Patients with advanced solid tumors generally have poor outcomes. Some advances have been 
made with the introduction of anti-PD(L)1 therapies; however, there remains a high unmet need 
in patients who progress on anti-PD(L)1 therapies, or patients who are not eligible for 
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anti-PD(L)1 therapies. Chemotherapy often remains the chosen treatment option for these 
patients but is associated with poor responses and often high toxicity. LV, with its targeted 
delivery of a cytotoxic payload, may have enhanced efficacy and safety.  
Additionally, there may be benefit in combining LV with pembrolizumab, an anti-PD-1 mAb 
(Section 3.2.6). Preclinical studies combining other vedotin-conjugated ADC therapies with 
anti-PD(L)1 agents reported improved efficacy over either drug individually (Cao 2017; Huang 
2022). A preliminary report using protein and gene expression data from SGNLV-001 and 
SGNLV-002 found LV combined with pembrolizumab in subjects with LA/mTNBC had 
improved infiltration of immune cells to the tumor microenvironment (TME) (Pusztai 2020).  
Preliminary clinical findings from the phase 3 Keynote-006 study suggest that rechallenging with 
pembrolizumab upon disease progression after previous immune checkpoint inhibitor treatment 
can provide additional disease control in patients with advanced melanoma (Robert 2019). A 
recent phase 2 study also demonstrated significant antitumor activity and tolerability of 
pembrolizumab in combination with ipilimumab in patients with unresectable or metastatic 
melanoma who experienced progressive disease after anti-PD(L)1 immunotherapy (Olson 2021). 
Furthermore, results from the recent phase 2 LEAP-004 study of lenvatinib plus pembrolizumab 
demonstrated clinically meaningful and durable responses in patients with advanced melanoma 
who had progressive disease following previous treatment with anti-PD(L)1 immunotherapy 
(Arance 2022). 
This study is designed to assess the activity of LV in subjects with advanced solid tumors as a 
monotherapy (Part A, Part B, Part C Arm 1) and in combination with pembrolizumab (Part C 
Arm 2 and Arm 3). 
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2. 
OBJECTIVES 
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of LV in subjects with 
solid tumors. Specific objectives and corresponding endpoints for the study are summarized in 
Table 7. 
Table 7: 
Objectives and corresponding endpoints 
Primary Objective 
Corresponding Primary Endpoint 
● Evaluate antitumor activity of LV as 
monotherapy (Part A, Part B, and Part C 
Arm 1 [Cohort 8 only]) and in combination 
with pembrolizumab (Part C Arm 2 and 
Arm 3, Cohort 8 only) 
● Investigator-determined confirmed ORR as 
measured by RECIST v1.1 for all tumor types 
● For prostate cancer, investigator-determined PSA 
response by Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3) criteria in addition to ORR 
Secondary Objectives 
Corresponding Secondary Endpoints 
● Evaluate the safety and tolerability of LV 
as monotherapy (Part A, Part B, and Part C 
Arm 1 [Cohort 8 only]) and in combination 
with pembrolizumab (Part C Arm 2 and 
Arm 3, Cohort 8 only) 
● Type, incidence, severity, seriousness, and 
relatedness of AEs 
● Evaluate stability and control of disease 
● Investigator-determined DCR as measured by  
RECIST v1.1 
● Evaluate durability of response in subjects 
who respond to LV as monotherapy 
(Part A, Part B, and Part C Arm 1 
[Cohort 8 only]) and in combination with 
pembrolizumab (Part C Arm 2 and Arm 3, 
Cohort 8 only) 
● Investigator-determined DOR as measured by  
RECIST v1.1 for all tumors 
● For prostate cancer, investigator-determined 
PSA-DOR 
● Evaluate PFS of subjects treated with LV 
as monotherapy (Part A, Part B, and Part C 
Arm 1 [Cohort 8 only]) and in combination 
with pembrolizumab (Part C Arm 2 and 
Arm 3, Cohort 8 only) 
● Investigator-determined PFS as measured by  
RECIST v1.1 for all tumors 
● For prostate cancer, investigator-determined 
PSA-PFS 
● Evaluate survival of subjects treated with 
LV as monotherapy (Part A, Part B, and 
Part C Arm 1 [Cohort 8 only]) and in 
combination with pembrolizumab (Part C 
Arm 2 and Arm 3, Cohort 8 only) 
● OS 
● Assess PK of LV (Parts A-C) 
● Selected PK parameters for LV, total antibody, and 
MMAE 
● Assess immunogenicity of LV (Parts A-C)  
● Incidence of ATAs to LV 
Additional Objectives 
Corresponding Additional Endpoints 
● Assess biomarkers of biological activity 
and resistance and predictive biomarkers 
of response 
● Relationship between biomarkers in blood and tumor 
tissue to efficacy, safety, or other biomarker 
endpoints following treatment with LV monotherapy 
and in combination with pembrolizumab 
 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This global, open-label, multicenter trial is designed to assess the activity, safety, and tolerability 
of LV monotherapy for the treatment of solid tumors.  
Subjects with the following advanced solid tumors will be enrolled: 
 
Cohort 1: SCLC (Parts A and B) 
 
Cohort 2: NSCLC-squamous (Parts A and B) 
 
Cohort 3: NSCLC-nonsquamous (Parts A and B) 
 
Cohort 4: HNSCC (Parts A and B) 
 
Cohort 5: esophageal squamous cell carcinoma (esophageal-squamous) (Parts A and B) 
 
Cohort 6: gastric and gastroesophageal junction (GEJ) adenocarcinoma (Parts A and B)  
 
Cohort 7: castration-resistant prostate cancer (CRPC) (Part B only) 
 
Cohort 8: melanoma (Parts B and C) 
The study consists of: 
• Part A (LV q3wk; Cohorts 1 through 6): LV administered by IV infusion at a dose of 
2.5 mg/kg on Day 1 of each 21-day cycle (see Section 5.1).  
• Part B (LV q1wk; Cohorts 1 through 6 will receive 1.0 mg/kg or Cohorts 1 through 8 
will receive 1.25 mg/kg; starting with Protocol Amendment 1): LV administered by 
IV infusion at a dose of 1.0 mg/kg or 1.25 mg/kg on Day 1, Day 8, and Day 15 of 
each 21-day cycle (see Section 5.1).  
• Part C (LV 1.5 mg/kg 2q3wk, LV 1.5 mg/kg 2q3wk plus 200 mg pembrolizumab 
q3wk, LV 1.25 mg/kg q1wk plus 200 mg pembrolizumab q3wk; Cohort 8 only):  
o Arm 1: LV administered by IV infusion at a dose of 1.5 mg/kg on Day 1 and 
Day 8 but not Day 15 of each 21-day cycle as monotherapy.  
o Arm 2: LV administered by IV infusion at a dose of 1.5 mg/kg on Day 1 and 
Day 8 but not Day 15 of each 21-day cycle in combination with 200 mg 
pembrolizumab administered by IV infusion on Day 1 of each 21-day cycle. 
o Arm 3: LV administered by IV infusion at a dose of 1.25 mg/kg on Day 1, 
Day 8, and Day 15 of each 21-day cycle in combination with 200 mg 
pembrolizumab administered by IV infusion on Day 1 of each 21-day cycle. 
The study design and cohorts for Parts A, B, and C are depicted in Figure 2 and the study schema 
is depicted in Figure 3. 
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Figure 2: 
Study Design and Cohorts – Parts A, B, and C 
 
a Part A will include Cohorts 1 through 6 only. 
b In Part B, Cohorts 1 through 6 will receive 1.0 mg/kg LV or Cohorts 1 through 8 will receive 1.25 mg/kg LV (see 
Section 5.1). The planned LV q1wk doses are 1.0 mg/kg in an initial cohort, to be escalated to 1.25 mg/kg based 
on safety assessments (details in Section 3.1). 
c Includes subjects enrolled prior to and after the safety analysis at a selected LV dose. 
d Includes subjects enrolled prior to and after the interim analysis for futility at a selected LV dose and schedule. 
e Part C for Cohort 8 will start enrollment upon completion of enrollment for Cohort 8 Part B. 
Interim analysis for futility will be performed separately for each cohort of Part A and Part B after approximately 
12 efficacy-evaluable subjects of a given cohort have been treated at a specific LV dose and schedule (details in 
Section 9.3.9).  
For Part C, randomization will be stratified according to BRAF mutational status (wild-type vs mutated). 
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Figure 3:
Study Schema Overview
Subjects will be enrolled in Part A until the individual tumor cohorts have 12 subjects or 
activation of Protocol Amendment 1 at each respective investigative site, whichever comes first. 
Upon activation of Protocol Amendment 1 at each investigative site, all subsequent subjects 
enrolled at that site will be in Part B. Subjects in Part A may cross over to Part B with sponsor’s
approval based on emerging safety and efficacy data.
Part B will assess LV q1wk in the tumor cohorts. The planned dose levels in Part B are shown in 
Table 8. Initially, approximately 12 subjects across the tumor cohorts will be enrolled and 
receive LV 1.0 mg/kg q1wk. Based on collective safety data from the initial 12 subjects and from
the concurrently ongoing phase 1 study SGNLVA-001 evaluating LV q1wk in breast cancer, 
subsequent enrollment in Part B will either:
•
Continue enrolling up to 12 subjects in each tumor cohort at LV 1.0 mg/kg q1wk for
interim analysis for futility, or
•
Enroll an additional 12 subjects across the tumor cohorts to receive LV 1.25 mg/kg 
q1wk (Dose Level +1) for safety analysis. If tolerability is demonstrated, enrollment 
will continue to 12 subjects in each tumor cohort at LV 1.25 mg/kg q1wk for interim 
analysis for futility.
•
Intrapatient dose escalation to a dose level shown to be safe is permitted with sponsor 
approval if a subject tolerates study treatment.
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Table 8: 
Planned dose levels for Part B (LV q1wk dosing) 
Dose Level 
Weekly LV Dose (mg/kg/wk) 
Maximum LV Dose in a 21-Day Cycle (mg/kg/cycle) 
0 
1.0 
3.0 
+1 
1.25 
3.75 
Interim analysis for futility will be performed separately for each cohort after approximately 
12 efficacy-evaluable subjects of a given cohort have been treated at a specific LV dose and 
schedule (Section 9.3.9). Cohorts that successfully pass the interim analysis for futility may, at 
the sponsor’s decision, continue to enroll up to an additional 18 subjects, totaling up to 
30 subjects for each tumor cohort at a specific dose and schedule.  
Part C will assess LV as monotherapy and in combination with pembrolizumab in subjects with 
melanoma (Cohort 8). Enrollment in Part C will begin after Cohort 8 Part B enrollment has been 
completed. Subjects will be randomized to 1 of 3 arms with 30 subjects per arm. The 
randomization ratio will be 2:1:1 until Arm 1 reaches 30 subjects. Thus, of the first 60 subjects, 
30 subjects will be enrolled in Arm 1, 15 subjects will be enrolled in Arm 2 and 15 subjects will 
be enrolled in Arm 3. This will ensure that Arm 1 reaches the target enrollment sooner. 
Afterwards, the remaining subjects will be randomized in a 1:1 ratio to either Arm 2 or Arm 3. 
Randomization will be stratified according to B-Raf proto-oncogene serine/threonine kinase gene 
(BRAF) mutational status (wild-type versus mutated). 
• Arm 1 (LV monotherapy 2q3wk): subjects will receive 1.5 mg/kg LV on Day 1 and 
Day 8 but not Day 15 of each 21-day cycle. 
• Arm 2 (LV 2q3wk+pembrolizumab q3wk): subjects will receive 1.5 mg/kg LV on 
Day 1 and Day 8 but not Day 15 of each 21-day cycle and 200 mg pembrolizumab on 
Day 1 of each 21-day cycle. 
• Arm 3 (LV q1wk+pembrolizumab q3wk): subjects will receive 1.25 mg/kg LV on 
Day 1, Day 8, and Day 15 of each 21-day cycle and 200 mg pembrolizumab on Day 1 
of each 21-day cycle. 
Pembrolizumab administration will be capped at 35 cycles (approximately 2 years).  
Disease progression for determining eligibility of treatment continuation will be based on 
immune Response Evaluation Criteria in Solid Tumors Version 1.1 (iRECIST) for subjects in 
Part C (Arms 2 and 3) (Appendix I).  
Additional tumor types may be included in this study in future protocol amendments. Alternative 
dosing regimens, biopsy/biomarkers, and LV-based combinations may be tested in future 
amendments.  
For non-prostate cancer subjects, tumor assessment according to Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST v1.1) (Appendix H) will be performed every 6 weeks 
(±3 days) for the first 12 months after the first dose of LV and then every 12 weeks (±7 days) 
thereafter. Objective responses (complete response [CR] or partial response [PR]) will be 
confirmed with repeat scans 4–6 weeks after the first documentation of response.  
For prostate cancer subjects (Part B, Cohort 7), prostate-specific antigen (PSA) will be assessed 
every 3 weeks (±3 days). Soft tissue tumor assessment by computed tomography (CT) or 
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magnetic resonance imaging (MRI) and bone scans according to the Prostate Cancer Clinical 
Trials Working Group 3 (PCWG3) criteria will be assessed every 8 weeks (±7 days) for the first 
24 weeks, then every 12 weeks (±7 days) thereafter. 
Safety will be assessed throughout the study, and AE severity will be graded using the NCI 
CTCAE, version 5. 
3.1.1. 
Retreatment 
Retreatment of subjects who have progressed on LV monotherapy (Part A, Part B, and Part C 
Arm 1) or LV plus pembrolizumab (Part C Arm 2 and Arm 3) is not permitted. 
3.2. 
Discussion and Rationale for Study Design 
3.2.1. 
Rationale for Not Selecting Subjects Based Upon Detectable LIV-1 
Protein Expression 
LIV-1 is expressed in a variety of solid tumors (Section 1.1). LIV-1 expression is detected in the 
majority of breast cancer subtypes including TNBC (Modi 2018; Yau 2019). An IHC assay for 
LIV-1 showed that >90% of subjects treated with LV in the phase 1 study of LV monotherapy in 
mBC had a detectable level of LIV-1. Preliminary analyses comparing the magnitude of LIV-1 
expression with response to LV in 2 independent cohorts of the phase 1 study did not show 
conclusive correlation between LIV-1 expression by IHC and response. To date, 5 out of 
15 subjects that tested negative for LIV-1 expression by IHC assay have responded to LV, 
including 1 of 3 subjects with no detectable LIV-1 (Seagen Inc., data on file).  
Biomarker assessments will not be used for subject selection as it is currently not known if 
expression of LIV-1 or other biomarkers will impact treatment outcome. Based on the experience 
of LV in mBC as described in Section 1.2.4, LV activity may not be limited to LIV-1 expressing 
tumors or diminish in the absence of LIV-1 expression. However, in order to understand 
relationships between the biological characteristics of the tumors chosen for study and subject 
outcome, pretreatment tumor biopsies will be collected and used for retrospective biomarker 
assessments.  
3.2.2. 
Rationale for Selection of q3wk LV Dose 
LV will be administered at 2.5 mg/kg (maximum dose of 250 mg per infusion) on Day 1 of each 
21-day cycle in this open-label study. Dosing is based on the subject’s actual body weight, 
measured at the beginning of each cycle. For subjects weighing >100 kg, dosing will be based on 
a 100 kg maximum weight (calculated dose not to exceed 250 mg per infusion).  
This dose and regimen has been tested in 113 subjects with mBC, including LA/mTNBC, to 
date, including as 2L treatment in 47 subjects with LA/mTNBC. The regimen has been well 
tolerated, demonstrating an acceptable safety profile and encouraging clinical activity in the 
phase 1 study SGNLVA-001 (see Section 1.2.4). 
Increasing antitumor activity was observed with increasing dose levels of LV in heavily 
pretreated LA/mTNBC patients. Confirmed PR, disease control rate (DCR), and median duration 
of response (DOR) were higher in the 2.5 mg/kg dose level compared to the 2.0 mg/kg dose 
level.  
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However, in the 2.5 mg/kg dose cohort, the incidence of neutropenia (Grade ≥3), including 
febrile neutropenia and serious neutropenia, was higher, particularly at doses >200 mg per 
infusion. Five of 11 subjects treated at >200 mg experienced SAEs associated with neutropenia. 
Febrile neutropenia occurred in 2 of 11 subjects, including 1 treatment-related death due to 
sepsis. No other treatment-related deaths occurred on study. Dose modifications due to AEs were 
more common at 2.5 mg/kg when receiving >200 mg. In contrast, there were no reported cases 
of febrile neutropenia or neutropenia associated SAEs in 18 subjects dosed at 2.5 mg/kg when 
receiving <200 mg.  
Therefore, a recommended phase 2 dose of 2.5 mg/kg with a dose cap of 250 mg per infusion 
was selected, with subjects treated at a >200 mg dose per infusion required to receive 
prophylactic myeloid growth factor support (eg, granulocyte-colony stimulating factor [G-CSF]) 
to reduce the rate, severity, and complications of neutropenia, while maintaining the potential for 
responses. 
3.2.3. 
Rationale for Mandatory G-CSF for Subjects Receiving More than 
200 mg LV per Infusion in Part A 
As described in Section 3.2.2, evaluation of the 2.5 mg/kg dose indicated that febrile neutropenia 
was observed more frequently at a dose of 2.5 mg/kg when the total dose was >200 mg than 
when the total dose was ≤200 mg per infusion (Modi 2018). Thus, subjects who receive a dose of 
LV >200 mg per infusion will be required to receive prophylactic G-CSF support to reduce the 
rate, severity, and complications of neutropenia. A recent evaluation demonstrates that primary 
prophylactic G-CSF has reduced the rate of treatment emergent neutropenia, postbaseline 
decreased absolute neutrophil count (ANC), and neutropenic infections in subjects receiving 
2.5 mg/kg >200 mg LV (Seagen Inc., data on file). 
3.2.4. 
Rationale for Selection of q1wk LV Doses 
Multiple lines of evidence support that q1wk dosing may result in improved efficacy and safety 
of LV. 
The starting weekly dose of LV in Part B of SGNLVA-005 will be 1.0 mg/kg (Dose Level 0). 
This LV dose results in a pharmacokinetic area-under-the-curve (AUC) exposure similar to LV 
of 2.5 mg/kg q3wk. At these similar pharmacokinetic exposures, it is not anticipated that there 
will be a detriment in the clinical efficacy or safety profile. As described in Section 1.2.4.3, LV 
has been shown to be tolerable and without any DLTs up to 1.5 mg/kg/week. The safety profile 
of LV q1wk appears safe and tolerable, with most TEAEs being Grade 1–2 in severity.  
Further, while gastrointestinal toxicities (nausea, constipation, diarrhea, and vomiting) were 
among frequent AEs reported in subjects dosed with LV q3wk (Part A, B, C, and D of the study), 
LV q1wk appears to result in a numerically lower frequency of gastrointestinal toxicities 
compared to LV q3wk (Table 1 and Table 2). 
In addition, preliminary data indicated that tumor size reductions in breast cancer patients were 
observed at the lowest dose level evaluated (1.0 mg/kg/week) with increased activity observed at 
1.25 mg/kg q1wk (Seagen Inc., data on file). 
Pharmacokinetic modeling data derived from over 200 subjects previously treated with LV q3wk 
suggest improvements in the safety profile of LV q1wk dosing may be due in part to the reduced 
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maximum concentration (Cmax) compared to q3wk dosing (Seagen Inc., data on file). In addition, 
LV q1wk dosing is anticipated to result in higher trough concentration (Ctrough) levels (the lowest 
concentration reached by a drug before the next dose is administered), which are correlated with 
improved efficacy. 
Other ADCs have been shown to have improved safety, activity, or both when administered at 
different doses and more frequent regimens than those originally tested. For example, 
trastuzumab emtansine (T-DM1), has improved efficacy with similar safety profiles when dosed 
q1wk compared to q3wk (Beeram 2012) (Thuss-Patience 2017). 
3.2.5. 
Rationale for Selection of 2q3wk LV Dose (Part C) 
LV monotherapy has been extensively evaluated across a range of doses and schedules in 
subjects with mBC in the concurrently ongoing phase 1 study SGNLVA-001 (see 
Section 1.2.4.3). In Part E of this study, 81 patients with mBC received LV administered at 1.0, 
1.25, or 1.5 mg/kg weekly (q1wk). No DLTs were observed at any of the 3 starting doses 
evaluated in the dose escalation phase (Seagen Inc., data on file). 
Preliminary efficacy results from Part E of the SGNLVA-001 study are shown in Figure 1 in 
Section 1.2.4.4 (data cut 06-Jan-2021). There appears to be greater magnitude of tumor size 
reduction with increasing dose of LV q1wk with the 1.5 mg/kg dose having the highest 
proportion of patients with measurable response. However, the frequency of AEs generally 
appears to increase with increasing dose as well. Table 2 in Section 1.2.4.3 summarizes the most 
commonly reported AEs by dose in SGNLVA-001 (26-July-2021, Seagen Inc., data on file). Due 
to the high frequency of neutropenia at the LV 1.5 mg/kg q1wk dose, (67% of patients with 44% 
of patients having Grade ≥3), accrual to this expansion cohort was paused. Although higher 
efficacy had been observed with the 1.5 mg/kg dose level, the better safety and tolerability of the 
1.25 mg/kg dose led to further expansion of this cohort.  
In the patients treated with LV monotherapy at the 1.25 mg/kg q1wk dose level, the relative dose 
intensity started to decrease by Cycle 2 (C2) leading to 2 doses being administered in every 
3-week cycle. Similarly, most of the clinically significant neutropenia events in the 1.5 mg/kg 
dose level occurred after 3 weekly doses. Overall, these observations suggested that an LV drug 
holiday may be needed to mitigate AEs, including neutropenia, for long-term treatment. This is 
further supported by PK simulation which demonstrated that giving LV 1.5 mg/kg on Days 1 
and 8 every 21 days (2q3wk) would result in similar PK exposures as 1.25 mg/kg q1wk dosing 
schedule. Based on this rationale, the intermittent dosing schedule of LV 1.5 mg/kg 2q3wk is 
being explored as monotherapy in Part F of study SGNLVA-001. 
Additionally, efficacy results from Part C of study SGNLVA-002 evaluating LV at the 
1.25 mg/kg q1wk dose level in combination with pembrolizumab q3wk as frontline therapy in 
patients with LA/mTNBC showed encouraging activity in both PD-L1 high and low/negative 
disease. Confirmed objective responses were observed in 46% of patients, respectively, with 
3 patients (8%) having PD-L1 low/negative disease achieving a CR following treatment with the 
combination (Seagen Inc., data on file). However, frequent LV dose modifications were 
observed at the weekly dosing schedule which suggested that treatment holidays may be required 
for long-term dosing. Part D of study SGNLVA-002 is exploring the intermittent dosing 
schedule of LV 1.5 mg/kg 2q3wk in combination with pembrolizumab as 1L treatment in 
patients with PD-L1 low/negative LA/mTNBC (see Section 1.3.3.1). 
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In the current study SGNLVA-005, LV monotherapy has only been explored at the 1.25 mg/kg 
q1wk dosing schedule in patients with melanoma (Part B; Cohort 8). Interim results from this 
cohort showed preliminary signs of activity in this patient population, and the cohort was 
subsequently opened for expansion according to the prespecified protocol futility analysis 
criteria. Similar to what was observed in mBC, recent PK modeling based on the first 15 patients 
enrolled in Cohort 8 treated at the 1.25 mg/kg q1wk dose level also supports further evaluation 
of the LV 1.5 mg/kg 2q3wk schedule (Seagen Inc., data on file) to improve the overall safety 
profile and response durability in subjects with advanced melanoma. 
3.2.6. 
Rationale for Combining LV with Pembrolizumab in Part C 
Accumulating data suggests chemotherapeutic agents may activate the immune system by 
inducing tumor cell apoptosis and tumor-associated antigen release, a process termed ICD 
(Bracci 2014). Tumor-associated antigens are taken up by antigen presenting cells such as 
dendritic cells or macrophages which then traffic to tumor-draining lymph nodes and activate 
effector immune cells such as T-cells and natural killer (NK) cells. Activation and infiltration of 
these immune cells to the TME leads to a potent anti-tumor response. 
LV and PD(L)1 inhibitors act through distinct but complementary mechanisms of action. Data 
from preclinical studies of MMAE ADCs comprising the same linker and MMAE payload as 
LV, brentuximab vedotin (a CD30-directed ADC) and enfortumab vedotin (a nectin-4 directed 
ADC), showed potential to induce ICD, antigen presentation, and tumor immune infiltration 
(Gardai 2015; Liu 2020). These results suggest that the effects are due to the MMAE payload 
(Gardai 2015; Liu 2020). These ADCs induce hallmarks of ICD with innate immune cell 
migration and activate adaptive immune response within the TME (Cao 2017; Cao 2018). The 
addition of immune checkpoint inhibitors, such as a PD(L)1 inhibitor like pembrolizumab, to 
treatment with MMAE conjugated ADCs can further amplify the adaptive immune response by 
preventing T-cell exhaustion and loss of inflammatory effector functions, as well as increasing 
T-cell and NK cell trafficking to the TME (Stagg 2011; Muller 2014; Muller 2015; Huang 2022).  
A preliminary report using IHC and gene expression data from SGNLVA-001 and 
SGNLVA-002 studies that compared LV monotherapy to LV combined with pembrolizumab in 
subjects with LA/mTNBC showed that when subjects received both LV and pembrolizumab, 
there was evidence of enhanced immune activation in the TME. This included activation of 
adaptive immune response pathways and increased infiltration of CD8 T-cells in addition to 
macrophages (Pusztai 2020). 
The antitumor immune response patterns seen with combining immunotherapeutic agents, such 
as pembrolizumab and LV, may extend beyond the typical time course of responses seen with 
cytotoxic agents and can manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Standard RECIST criteria may therefore not provide an 
accurate assessment of disease progression for immunotherapeutic agents. Therefore, in addition 
to RECIST v1.1, iRECIST will be used by study sites to evaluate disease progression for 
determining eligibility of treatment continuation in Part C (Arms 2 and 3) to account for the 
appearance of possible new lesions and allow radiographic progression to be confirmed at a 
subsequent assessment (see Appendix I). 
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3.2.7. 
Rationale for Pembrolizumab Dose 
The planned dose of pembrolizumab for this study is 200 mg q3wk. Based on the totality of data 
generated in the Keytruda development program, 200 mg q3wk is an appropriate dose of 
pembrolizumab for adults across all indications. As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg q3wk to 
10 mg/kg every 2 weeks (q2wk) representing an approximate 5- to 7.5-fold exposure 
range (refer to the IB) 
• Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg q3wk  
• Clinical data showing meaningful improvement in benefit-risk including overall 
survival (OS) at 200 mg q3wk across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically-based PK [PBPK] 
analysis) at 200 mg q3wk. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg q3wk versus 10 mg/kg q2wk 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg q3wk versus 10 mg/kg q2wk (KN001 Cohort B3, KN001 Cohort F2 and KN006). All 
of these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 
200 mg fixed-dose) q3wk provided similar responses to the highest doses studied. Subsequently, 
flat dose- and exposure-response relationships were also observed in other tumor types including 
head and neck cancer, bladder cancer, gastric cancer, and classical Hodgkin Lymphoma, 
confirming 200 mg q3wk as the appropriate dose independent of the tumor type. These findings 
are consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg q3wk. First, PK data 
in KN001 evaluating target-mediated drug disposition conclusively demonstrated saturation of 
PD-1 in systemic circulation at doses much lower than 200 mg q3wk. Second, a PBPK analysis 
was conducted to predict tumor PD-1 saturation over a wide range of tumor penetration and 
PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg q3wk achieves full 
PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg q3wk fixed-dose and 2 mg/kg q3wk dose. Supported 
by these PK characteristics and given that fixed-dose has advantages of reduced dosing 
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complexity and reduced potential of dosing errors, the 200 mg q3wk fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
3.2.8. 
Blinding and Unblinding 
This is an open-label study. 
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4. 
STUDY POPULATION 
Subjects must meet all enrollment criteria to be eligible for this study. Eligibility criteria may not 
be waived by the investigator and are subject to review in the event of a good clinical practice 
audit and/or health regulatory authority inspection. 
4.1. 
Inclusion Criteria 
Eligibility for each of the solid tumor cohorts are listed below: 
• Cohort 1, SCLC (Part A and Part B): 
o Subjects must have pathologically-documented SCLC; 
o Must have extensive stage disease; 
o Must have disease progression during or following prior platinum-based 
systemic chemotherapy for extensive stage disease; 
o No more than 1 prior line of cytotoxic chemotherapy for extensive disease 
stage; 
o May have received prior anti-PD(L)1 therapy, unless contraindicated.  
o Mixed SCLC/neuroendocrine tumors with NSCLC histologies are not eligible. 
• Cohort 2, NSCLC-squamous (Part A and Part B): 
o Must have pathologically-documented squamous cell NSCLC; 
o Must have unresectable locally advanced or metastatic disease;  
o Must have disease progression during or following systemic therapy; 
▪ Subjects must have progressed during or after a platinum-based 
combination therapy administered for the treatment of metastatic disease. 
Maintenance therapy is permitted provided there was no progression after 
the initial platinum-based combination. Changing chemotherapy agents 
during platinum-based treatment for the management of toxicities is 
permitted provided no progression has occurred while on the initial 
therapy; or 
▪ Subjects must have progressed within 6 months of last dose of 
platinum-based adjuvant, neoadjuvant, or definitive chemotherapy, or 
concomitant chemoradiation regimen for early stage or locally advanced 
stage disease. 
o Subjects with known epidermal growth factor receptor (EGFR), anaplastic 
lymphoma kinase (ALK), reactive oxygen species (ROS), BRAF, or other 
actionable mutations are not eligible; 
o No more than 1 prior line of cytotoxic chemotherapy for their advanced 
disease; 
o Must have received prior anti-PD(L)1 therapy, unless contraindicated; 
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o Subjects with mixed histology NSCLC are eligible as long as the tumor is 
predominantly squamous histology. Mixed SCLC/neuroendocrine tumors with 
NSCLC histologies are not eligible. 
• Cohort 3, NSCLC–nonsquamous (Part A and Part B): 
o Must have pathologically-documented nonsquamous NSCLC; 
o Must have unresectable locally advanced or metastatic disease;  
o Must have disease progression during or following systemic therapy; 
▪ Subjects must have progressed during or after a platinum-based 
combination therapy administered for the treatment of metastatic disease. 
Maintenance therapy is permitted provided there was no progression after 
the initial platinum-based combination. Changing chemotherapy agents 
during platinum-based treatment for the management of toxicities is 
permitted provided no progression has occurred while on the initial 
therapy; or 
▪ Subjects must have progressed within 6 months of last dose of 
platinum-based adjuvant, neoadjuvant, or definitive chemotherapy, or 
concomitant chemoradiation regimen for early stage or locally advanced 
stage disease. 
o Subjects with known EGFR, ALK, ROS, BRAF, tropomyosin receptor kinase 
(TRK), or other actionable mutations are not eligible.  
o Must have had prior platinum-based chemotherapy; 
o No more than 1 prior line of cytotoxic chemotherapy for their advanced 
disease; 
o Must have received prior anti-PD(L)1 therapy, unless contraindicated; 
o Mixed tumors will be categorized by the predominant cell type. Subject is 
ineligible if the subject has predominantly squamous cell histology NSCLC or 
if small cell elements are present. 
• Cohort 4, HNSCC (Part A and Part B): 
o Must have pathologically-documented squamous cell carcinoma of the head 
and neck with primary tumor site arising from the oral cavity, oropharynx, 
hypopharynx, and larynx; tumors arising from the nasopharynx are excluded. 
o Must have unresectable locally recurrent or metastatic disease; 
o Must have disease progression during or following prior line of systemic 
therapy; 
▪ Disease progression after treatment with a platinum-containing regimen for 
recurrent (disease not amenable to curative treatment)/metastatic disease; 
or 
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▪ Recurrence/progression within 6 months of last dose of platinum therapy 
given as part of multimodal therapy in the curative setting (eg locally 
advanced stage) 
o No more than 1 line of cytotoxic chemotherapy for their advanced disease;  
o May have received prior anti-PD(L)1 therapy, unless contraindicated. 
• Cohort 5, esophageal-squamous (Part A and Part B): 
o Must have pathologically-documented squamous cell carcinoma of the 
esophagus; 
o Must have unresectable locally advanced or metastatic disease; 
o Must have disease progression during or following systemic therapy; 
o Must have had prior platinum-based chemotherapy; 
o No more than 1 line of cytotoxic chemotherapy for their advanced disease.  
• Cohort 6, gastric and GEJ adenocarcinoma (Part A and Part B): 
o Must have pathologically-documented gastric or GEJ adenocarcinoma; 
o Must have unresectable locally advanced or metastatic disease;  
o Must have received prior platinum-based therapy; 
o Must have disease progression during or following systemic therapy; 
o Subjects with known human epidermal growth factor receptor 2 (HER2) 
overexpression must have received prior HER2-targeted therapy; 
o No more than 1 line of prior cytotoxic chemotherapy for their advanced 
disease; 
o Subjects may have received prior anti-PD(L)1 therapy, unless contraindicated. 
• Cohort 7, CRPC (Part B only): 
o Must have histologically or cytologically confirmed adenocarcinoma of the 
prostate: 
▪ Subjects with components of small cell or neuroendocrine histology are 
excluded. 
o Must have metastatic castration-resistant disease: 
▪ Castration-resistant is defined as progressive disease following adequate 
medical or surgical (bilateral orchiectomy) castration and testosterone 
<50 ng/dL (<2.0 nM). 
o Must have been ≥28 days between cessation of androgen receptor-targeted 
therapy and start of study treatment; 
o Must have received no more than 1 prior line of 2nd generation androgen 
receptor-targeted therapy (eg, abiraterone acetate, enzalutamide, apalutamide, 
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or darolutamide) for metastatic castration-sensitive prostate cancer (CSPC) or 
CRPC; 
o No prior cytotoxic chemotherapy in the metastatic CRPC setting: 
▪ For subjects who received cytotoxic chemotherapy for CSPC, at least 
6 months must have elapsed between last dose of chemotherapy and start 
of study treatment; 
▪ No more than 1 prior line of cytotoxic chemotherapy for CSPC 
o Subjects with measurable and non-measurable disease are eligible if the 
following criteria are met: 
▪ A minimum starting PSA level ≥1.0 ng/mL; 
▪ Subjects with measurable soft tissue disease must have evidence of 
measurable soft tissue disease according to PCWG3 criteria. Previously 
normal (<1.0 cm) lymph nodes must have grown by ≥5 mm in the short 
axis to be considered to have progressed; 
▪ Subjects with nonmeasurable- disease (enrollment after interim analysis 
and no more than 15 subjects in total) must have documented rising PSA 
levels or appearance of new lesion according to PCWG3 (Appendix L): 
- 
PSA progression as defined by 2 increases in PSA level over a 
previous reference value (a minimum of 3 PSA values total) with an 
interval of ≥1 week between each assessment where the PSA value 
at screening should be ≥1 ng/mL, OR 
- 
Bone disease progression defined by 2 or more new lesions on bone 
scan 
o Subjects with known breast cancer gene (BRCA) mutations are excluded; 
o No prior radioisotope therapy or radiotherapy to ≥30% of bone marrow. 
• Cohort 8, melanoma (Part B and Part C): 
o Must have histologically or cytologically confirmed cutaneous malignant 
melanoma; 
▪ Subjects with mucosal, acral, or uveal melanoma are excluded. 
o Must have locally advanced unresectable or metastatic stage disease; 
o Must have measurable disease: 
▪ Lesions that have had prior intralesional therapies including talimogene 
laherparepvec (T-VEC) are not considered measurable; 
▪ Subjects with metastases limited to the skin (skin-only metastasis) are 
excluded. 
o Must have progressive disease following anti-PD(L)1 therapy; 
o No prior cytotoxic chemotherapy in the advanced disease setting; 
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o No more than 2 prior systemic therapies for advanced disease: 
▪ Adjuvant therapy within 6 months of diagnosis of advanced disease is 
considered as 1 line of therapy. 
▪ Prior anti-CTLA4 therapy is allowed; 
▪ Prior BRAF +/- mitogen-activated protein kinase kinase (MEK) inhibitor 
therapy:  
- 
Part B subjects: May have received BRAF +/- MEK inhibitor 
therapy if BRAF mutated; 
- 
Part C subjects: Must have received BRAF +/- MEK inhibitor 
therapy if BRAF mutated 
Inclusion criteria for Parts A, B, and C: 
1. Measurable disease according to RECIST v1.1 (Appendix H) as assessed by the 
investigator 
• A minimum of one non-nodal lesion ≥10 mm in the longest diameter from a 
non-irradiated area 
Or 
• Lymph node lesion ≥15 mm in the shortest diameter from a non-irradiated area 
• If target lesion(s) are located within previously irradiated area only, the subject can be 
enrolled only if there has been demonstrated progression in the “in field” lesion and 
upon approval of the sponsor’s medical monitor. 
2. Age of at least 18 years, or legal age according to local regulations, whichever is older. 
3. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 
(see Appendix J for conversion of performance status using Karnofsky and Lansky 
scales, if applicable) 
4. The following baseline laboratory data: 
• ANC ≥1500/µL assessed at least 2 weeks after growth factor support, if applicable 
• platelet count ≥100 x 109/L assessed at least 2 weeks after transfusion with blood 
products, if applicable 
• hemoglobin (≥8.0 g/dL) assessed at least 2 weeks after transfusion with blood 
products and/or growth factor support, if applicable 
• serum bilirubin ≤1.5 x upper limit of normal (ULN) or direct bilirubin ≤3 x ULN in 
subjects diagnosed with Gilbert’s syndrome 
• estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 using the 
Modification of Diet in Renal Disease (MDRD) study equation as applicable (see 
Section 7.6.3)  
• alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 x ULN 
(if liver metastases are present, then ≤3 x ULN is allowed) 
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5. Subjects of childbearing potential as defined in Section 4.3, under the following 
conditions: 
• Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL 
or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 
3 days prior to the first dose of LV. Subjects with false positive results and 
documented verification that the subject is not pregnant are eligible for participation. 
• Must agree not to try to become pregnant during the study and for at least 6 months 
after the final dose of study drug administration 
• Must agree not to breastfeed or donate ova, starting at time of informed consent and 
continuing through 6 months after the final dose of study drug administration 
• If sexually active in a way that could lead to pregnancy, must consistently use 
2 highly effective methods of birth control (as defined in Appendix K) starting at time 
of informed consent and continuing throughout the study and for at least 6 months 
after the final dose of study drug administration 
6. Subjects who can father children, under the following conditions: 
• Must agree not to donate sperm starting at time of informed consent and continuing 
throughout the study period and for at least 6 months after the final study drug 
administration 
• If sexually active with a subject of childbearing potential in a way that could lead to 
pregnancy, must consistently use 2 highly effective methods of birth control (as 
defined in Appendix K) starting at time of informed consent and continuing 
throughout the study and for at least 6 months after the final dose of study drug 
administration 
• If sexually active with a subject who is pregnant or breastfeeding, must consistently 
use one of 2 contraception options (as defined in Appendix K) starting at time of 
informed consent and continuing throughout the study and for at least 6 months after 
the final dose of study drug administration 
7. Available and adequate archival baseline tumor sample is required. If an archival baseline 
tumor sample is not available, a fresh biopsy sample may be submitted if medically 
feasible or the medical monitor should be contacted to review this requirement. Formalin 
fixed paraffin embedded (FFPE) blocks and core needle or excisional biopsy of 
metastatic site are preferred. 
8. The subject or the subject’s legally authorized representative must provide written 
informed consent. 
 
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4.2. 
Exclusion Criteria 
Parts A, B, and C 
1. Subjects with active concurrent malignancy or a previous malignancy within the past 
3 years are excluded. Exceptions are malignancies with a negligible risk of metastasis or 
death (eg, 5-year OS ≥90%), such as adequately treated carcinoma in situ of the cervix, 
non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or 
Stage I uterine cancer, and does not interfere with the evaluation of the study therapy 
efficacy or safety. 
2. Any anticancer therapy (such as cytotoxic chemotherapy, biologic therapy, 
immunotherapy etc.) within 3 weeks of starting study treatment. Subjects who are/were 
on adjuvant hormonal therapy for the treatment of malignancies with negligible risk of 
metastases (as described in exclusion criteria 1) are eligible. 
3. Subjects with known active central nervous system (CNS) lesions (including 
leptomeningeal metastasis) are excluded. Subjects with symptoms concerning for active 
CNS disease must have been evaluated and treated per institutional standard of care. 
Subjects with definitively treated brain metastasis (surgery and/or radiotherapy) are 
eligible if they meet the following criteria: 
• Asymptomatic from the CNS metastases 
• Completely off steroids; anti-convulsants at a stable dose are allowed. 
• No evidence of clinical and radiographic disease progression in the CNS for 
≥3 weeks after definitive radiotherapy and/or surgery 
4. Active viral, bacterial, or fungal infection requiring systemic treatment within 7 days 
prior to the first dose of LV. Routine antimicrobial prophylaxis is permitted. 
5. Subjects with any ongoing clinically significant toxicity (Grade 2 or higher, per the NCI 
CTCAE, v5.0) associated with prior treatment (including systemic therapy, radiotherapy, 
or surgery) are not permitted (except alopecia). 
6. Ongoing sensory or motor neuropathy of Grade ≥2 
7. Subjects with known and untreated hepatitis B, hepatitis C, or human immunodeficiency 
virus (HIV). Subjects are eligible if they are on a stable anti-viral treatment or have 
received curative therapy (check Appendix F for a list of drug-drug interactions). 
• Part C Arm 2 and Arm 3 only:  
o HIV+ subjects with a history of Kaposi sarcoma and/or Multicentric 
Castleman Disease are not eligible. 
o HIV+ subjects on anti-retroviral therapy (ART) must meet the following 
criteria to be eligible: 
▪ CD4+ T-cell count >350 cells/mm3 at time of screening 
▪ Confirmed HIV RNA level below 50 copies/ml or the lower limit of 
qualification (below the limit of detection) using the locally available 
assay at the time of screening and for at least 12 weeks prior to screening 
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▪ Stable ART regimen with no changes in drugs or dose modification for at 
least 4 weeks prior to study entry (Day 1) 
8. Current therapy with other systemic antineoplastic or investigational agents 
9. Subjects who are breastfeeding, pregnant, or planning to become pregnant from time of 
informed consent until 6 months after the final LV administration 
10. Known hypersensitivity to any excipient contained in the drug formulation of LV (all 
Parts) or pembrolizumab (Part C only). 
11. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction, or cardiac symptoms consistent with congestive 
heart failure, Class III-IV, by New York Heart Association criteria within 6 months prior 
to study enrollment (Appendix E). 
12. Has received prior radiotherapy within 2 weeks of start of study treatment. A subject is 
also excluded if radiotherapy occurred more than 2 weeks prior to start of study treatment 
but the subject has not recovered from radiation-related toxicities, requires 
corticosteroids, or has had radiation pneumonitis. 
13. Other serious or uncontrolled underlying medical condition that, in the opinion of the 
investigator, would impair the subject’s ability to receive or tolerate the planned 
treatment and follow-up (eg, active cardiac disease, active systemic infection, chronic 
conditions, any psychiatric or substance abuse disorders), interfere with the subject’s 
cooperation with the requirements of the trial, place the subject at undue risk of SAE, or 
make the subject unable to receive sustained therapy 
14. Has received a live vaccine within 30 days of the planned start of study therapy. Seasonal 
influenza vaccines for injection are generally inactivated and are allowed; however, 
intranasal influenza vaccines (eg, Flu-Mist) are live attenuated vaccines and are not 
allowed. 
Part C Only 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg CTLA-4, 
OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher 
immune-related adverse event (irAE). 
16. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with 
use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment. 
17. Has had an allogenic tissue/solid organ transplant. 
18. History of interstitial lung disease. 
19. Current pneumonitis, or history of (non-infectious, including radiation induced) 
pneumonitis that required steroids. 
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20. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
doses exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study treatment. The 
use of corticosteroids for physiological replacement may be approved after consultation 
with the sponsor. 
4.3. 
Childbearing Potential 
A subject of childbearing potential is anyone born female who has experienced menarche and 
who has not undergone surgical sterilization (eg, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months 
of amenorrhea in a subject over age 45 in the absence of other biological, physiological, or 
pharmacological causes. 
A subject who can father children is anyone born male who has testes and who has not 
undergone surgical sterilization (eg, vasectomy followed by a clinical test proving that the 
procedure was effective). 
4.4. 
Removal of Subjects From Therapy or Assessment 
Seagen Inc. or their designee must be notified if a subject is discontinued from study treatment or 
withdrawn from the study. The reason(s) for discontinuation/withdrawal must be documented in 
the subject’s medical records. 
4.4.1. 
Discontinuation of Study Treatment 
A subject’s study treatment may be discontinued for any of the following reasons: 
• Progressive disease (PD) 
• AE 
• Pregnancy 
• Investigator decision 
• Subject decision, non-AE  
Note: Ensure that subjects who decide to stop treatment because of an AE are not 
included in this rationale. 
• Study or cohort termination by sponsor 
• Other, non-AE 
Subjects who discontinue from study treatment will remain on study for follow-up unless they 
withdraw consent. 
For Part C Arm 2 and Arm 3: 
Patients who discontinue pembrolizumab may continue to receive LV with medical monitor 
approval. Similarly, patients that discontinue LV may continue to receive pembrolizumab with 
medical monitor approval. See Sections 5.2.4.3 and 5.3 for details. 
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Administration of pembrolizumab is limited to 35 cycles (approximately 2 years). The number of 
administrations is calculated starting with the first dose of pembrolizumab. 
4.4.2. 
Subject Withdrawal From Study 
Any subject may be withdrawn from the study for any of the following reasons: 
• Subject withdrawal of consent 
• Study or cohort termination by sponsor 
• Lost to follow-up 
• Death 
• Other 
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5. 
TREATMENTS 
5.1. 
Treatments Administered 
Part A (q3wk dosing): LV will be administered at a dose of 2.5 mg/kg as a 30-minute IV 
infusion on Day 1 of each 21-day cycle. For subjects weighing more than 100 kg, dosing will be 
capped at 250 mg per infusion. Any subject receiving >200 mg LV per infusion (weight >80 kg) 
is required to receive prophylactic G-CSF. 
Part B (q1wk dosing): LV will be administered at a dose of 1.0 or 1.25 mg/kg as a 30-minute 
IV infusion on Day 1, Day 8, and Day 15 of each 21-day cycle. The maximum dose will be 
200 mg per infusion. 
Part C (LV monotherapy or LV plus pembrolizumab combination): LV will be administered 
at a dose of 1.5 mg/kg (Arms 1 and 2) as a 30-minute IV infusion on Day 1 and Day 8 but not 
Day 15 of each 21-day cycle (2q3wk). The maximum dose will be 200 mg per infusion. For 
Arm 3, LV will be administered at a dose of 1.25 mg/kg as a 30-minute IV infusion on Day 1, 
Day 8, and Day 15 of each 21-day cycle (q1wk). The maximum dose will be 200 mg per 
infusion. For Arm 2 and Arm 3, pembrolizumab will be administered at a dose of 200 mg 
approximately 60–90 minutes after LV as a 30-minute IV infusion on Day 1 of each 21-day 
cycle (q3wk). 
5.2. 
Investigational Study Drug: LV 
Detailed information describing the preparation, administration, and storage of LV is located in 
the Pharmacy Instructions. 
5.2.1. 
Description 
LV is a sterile, preservative-free, white to off-white lyophilized cake or powder for reconstitution 
for IV administration. LV is supplied by Seagen Inc. in single-use glass vials. Each drug product 
vial contains LV for injection, trehalose, histidine, and polysorbate 80. Drug product vials are 
labeled with a nominal content of 40 mg/vial. Each vial contains 45 mg of LV. Enough overfill is 
included to allow for 40 mg of LV to be withdrawn for use. 
When reconstituted with 8.8 mL water for injection (WFI), United States Pharmacopeia (USP) 
grade or equivalent, the concentration of reconstituted LV product is 5 mg/mL. The reconstituted 
drug product is a clear to slightly opalescent, colorless to light yellow solution with no visible 
particulate matter. The pH is approximately 6.0. The reconstituted solution is subsequently 
diluted in sterile 0.9% Sodium Chloride for Injection, USP grade or equivalent, for IV 
administration. 
5.2.2. 
Method of Procurement 
LV will be provided by the sponsor or designee. 
5.2.3. 
Dose and Administration 
LV is administered by IV infusion given over approximately 30 minutes. LV must not be 
administered as an IV push or bolus. In the absence of infusion-related reactions (IRR), the 
infusion rate for all subjects should be calculated in order to achieve a 30-minute infusion period. 
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However, given the variability of infusion pumps from site to site, a window between –5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes –5 min/+10 min). 
LV can be administered via central venous access line (preferred) or peripheral IV. Clinical site 
staff should monitor the infusion site closely for redness, swelling, pain, and infection during and 
at any time after administration. Advise subjects to report redness or discomfort promptly at the 
time of administration or after infusion. The IV bag containing LV should not be mixed with 
other medications. 
Dosing is based on the subject’s actual body weight at the beginning of each cycle. 
Detailed instructions for dose preparation are provided in the Pharmacy Instructions. 
Part A (q3wk dosing): LV at a dose of 2.5 mg/kg (maximum dose of 250 mg per infusion) will 
be administered on Day 1 of each 21-day cycle by IV infusion given over approximately 
30 minutes. For subjects weighing greater than 100 kg, dose calculations will be based on 
100 kg for these individuals (including dose reductions). Rounding is permissible within 1 mg 
of nominal dose. Any subject receiving >200 mg LV per infusion (weight >80 kg) is required to 
receive prophylactic G-CSF. 
Part B (q1wk dosing): LV at a dose of 1.0 or 1.25 mg/kg will be administered on Day 1, Day 8, 
and Day 15 of each 21-day cycle. The maximum dose will be 200 mg per infusion. 
Part C (2q3wk or q1wk dosing): LV at a dose of 1.5 mg/kg will be administered on Day 1 and 
Day 8 but not Day 15 of each 21-day cycle (2q3wk) for Arm 1 and Arm 2. LV at a dose of 
1.25 mg/kg will be administered on Day 1, Day 8, and Day 15 of each 21-day cycle (q1wk) for 
Arm 3. The maximum dose of LV for all 3 arms will be 200 mg per infusion. For Arm 2 and 
Arm 3, pembrolizumab infusion must start approximately 60–90 minutes after administration of 
LV (see Section 5.3.3). 
5.2.3.1. 
Dosing Criteria 
The following laboratory criteria must be met on Day 1 of each cycle prior to LV administration: 
• Neutrophil count ≥1000/μL (≤ Grade 2) 
• Aspartate aminotransferase ≤ Grade 2 
• ALT ≤ Grade 2 
• Total bilirubin ≤ Grade 2 
In Part B and C, neutrophil count must be ≥1000/μL (≤ Grade 2) prior to LV administration on 
Day 8 and Day 15 (if receiving q1wk dosing) of each cycle. 
If the above criteria are not met on the day of dosing, hold the LV dose until the criteria are met. 
In addition, hold LV dosing for subjects with ≥ Grade 2 peripheral neuropathy (see Table 10). 
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5.2.4. 
Dose Modifications 
5.2.4.1. 
Part A (q3wk dosing) 
Dose modification guidelines for LV q3wk treatment-associated toxicity are described in 
Table 9. The maximum doses after modifications are: 
• 200 mg for subjects reduced to 2.0 mg/kg 
• 150 mg for subjects reduced to 1.5 mg/kg 
Table 9: 
Q3wk LV dose levels 
Dose Level  
Dose 
Maximum Dose 
Starting dose 
2.5 mg/kg 
250 mg 
–1 
2.0 mg/kg 
200 mg 
–2 
1.5 mg/kg 
150 mg 
Table 10 describes dose modifications for LV treatment-associated toxicity. 
Doses reduced for LV-related toxicity should not be re-escalated. 
If a subject has a clinically significant, unresolved AE on Day 1 of C2 or beyond, the start of the 
cycle may be delayed for up to 14 days. Delays of >14 days must be approved by the medical 
monitor. 
In the event a subject is unable to tolerate their dose level, additional treatment cycles (C2 or 
later) may be administered at a lower dose level upon approval by the medical monitor. 
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Table 10: 
Dose modifications for LV-associated toxicity (Part A; q3wk dosing) 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Peripheral 
neuropathya 
Continue at 
same dose 
level 
Withhold until toxicity 
resolves to ≤ Grade 1; 
then resume treatment at 
the next lower dose level 
Withhold until toxicity resolves to 
≤ Grade 1, then resume treatment at the 
next lower dose level 
Discontinue treatment 
Non-hematologica 
(except peripheral 
neuropathy and 
hyperglycemia) 
Continue at 
same dose 
level 
Continue at same dose 
level 
Withhold dose until toxicity is 
≤ Grade 2 or has returned to baseline, 
then resume treatment at same dose 
levelb 
Withhold dose until toxicity is ≤ Grade 2 or has 
returned to baseline, then reduce dose to the 
next lower dose level and resume treatment, or 
discontinue at the discretion of the 
investigatorb,c 
Hematologica 
Continue at 
same dose 
level 
Continue at same dose 
level 
Withhold until toxicity resolves to 
≤ Grade 2 or baselined,e. For 
neutropenia, strongly consider 
G-CSF support, then resume 
treatment at the same dose level. 
Prophylactic G-CSF support should 
be strongly considered for 
subsequent cycles. (See Appendix G) 
Withhold until toxicity resolves to ≤ Grade 2 or 
baselined,e. For neutropenia, strongly consider 
G-CSF support, then resume treatment at the 
same dose level. Prophylactic G-CSF support 
is required for all subsequent cycles. If 
Grade 4 neutropenia recurs despite G-CSF 
support, consider dose reduction to dose level 
–1 or discontinuation. (Appendix G) 
Febrile 
neutropeniaa 
 
 
G-CSF support is required for treatment of febrile neutropenia. Withhold until febrile 
neutropenia resolves and neutrophil count returns to ≤ Grade 2 or baseline then resume 
treatment at the same dose level. Prophylactic G-CSF is required for all subsequent 
cycles. If febrile neutropenia recurs despite G-CSF factor support, consider dose reduction 
to dose level –1 or discontinuation. 
Hyperglycemia 
Hold for blood glucose >250 mg/dL or >13.9 mmol/L. Resume treatment once elevated blood glucose has improved to ≤250 mg/dL or 
≤13.9 mmol/L and subject is clinically and metabolically stable (see Section 5.6 for detail). 
Note: For subjects weighing ≥100 kg, dosing will be based on 100 kg for these individuals with a maximum calculated dose of 250 mg per infusion when dosed 
at 2.5 mg/kg. 
a Only 2 dose reductions are allowed. Additional toxicities should be managed with dose delays 
b Subjects who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without interruption if a management plan consistent 
with institutional practice and regular monitoring are put in place 
c Treatment should be discontinued for subjects who experience Grade 4 infusion-related reactions  
d Support with blood product transfusions allowed per institutional standard of care 
e Subjects who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption 
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5.2.4.2. 
Part B (q1wk dosing) and Part C (Arm 3; q1wk dosing) 
In the event of an AE or lab criteria that prevents dosing of LV (see Section 5.2.3.1), the LV 
dose for the week should be withheld. LV may be resumed when the dosing criteria are met. If a 
dose(s) of LV is withheld, the corresponding visit may be skipped and resume the following 
week (eg, if the Day 8 dose is skipped, visits will resume on Day 15; if Day 8 and Day 15 doses 
are skipped, visits will resume of Day 1 of the following cycle). Day 1 of a cycle may be delayed 
but not skipped. 
Dose reduction of LV may be considered in the event of recurrent AE despite withheld doses. 
Dose re-escalation following dose reduction is not allowed. Dose levels for LV dose reductions 
in Part B and Part C (Arm 3) are shown in Table 11. 
For Part C (Arm 3), subjects who discontinue pembrolizumab due to a pembrolizumab-related 
AE (see Section 5.3.4) may continue LV. Similarly, subjects who discontinue LV for a 
LV-related AE may continue pembrolizumab. See Section 5.5.3 for details on managing 
overlapping AEs. 
Table 11: 
Q1wk LV dose reductions 
Starting Dose  
First Dose Reduction (mg/kg/wk) 
Second Dose Reduction (mg/kg/wk) 
Starting dose 1.0 mg/kg/wk 
0.75 
0.5 
Starting dose 1.25 mg/kg/wk 
1.0 
0.75 
For nonclinical events requiring alteration in dosing schedule (eg, holidays, scheduling 
conflicts), a +2 day dosing window is allowed. Nonclinical events that require skipping a 
dose(s), must be approved by sponsor medical monitor. At least 7 days must elapse between each 
administration of LV. 
Dose modification guidelines for LV q1wk treatment-associated toxicity are detailed in Table 12. 
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Table 12: 
Dose modifications for LV treatment-associated toxicity (Part B and Part C [Arm 3] q1wk dosing) 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Peripheral 
neuropathya 
Continue 
at same 
dose level 
Withhold until toxicity 
resolves to ≤ Grade 1; 
treatment may resume 
at the next lower dose 
level (see Table 11) 
Withhold until toxicity resolves to 
≤ Grade 1, then resume treatment at the 
next lower dose level (see Table 11) 
Discontinue treatment 
Hyperglycemia 
Hold for blood glucose >250 mg/dL or >13.9 mmol/L. Resume treatment once elevated blood glucose has improved to ≤250 mg/dL 
or ≤13.9 mmol/L and subject is clinically and metabolically stable (see Section 5.6 for details). 
Non-hematologica 
(except peripheral 
neuropathy and 
hyperglycemia) 
Continue 
at same 
dose level 
Continue at same dose 
level 
Withhold dose until toxicity is ≤ Grade 2 
or has returned to baseline, then resume 
treatment at same dose levelb 
Withhold dose until toxicity is ≤ Grade 2 or has 
returned to baseline, then reduce dose to the next 
lower dose level (see Table 11) and resume 
treatment, or discontinue at the discretion of the 
investigatorb,c 
Hematologica  
Continue 
at same 
dose level 
Continue at same dose 
level 
Withhold until toxicity resolves to 
≤ Grade 2 or baselined,e, then resume 
treatment at the same dose level. If the 
dose is held >48 hours, the dose may be 
omitted and dosing may resume on the 
next scheduled dosing day. See 
Sections 5.4.2 and 5.4.3 on allowed 
concomitant therapy and myeloid growth 
factors. 
Withhold until toxicity resolves to ≤ Grade 2 or 
baselined,e, then reduce dose to the next lower 
dose level (see Table 11) if treatment is 
resumedb,c. If the dose is held >48 hours, the dose 
may be omitted and dosing may resume on the 
next scheduled dosing day. If Grade 4 
neutropenia recurs, reduce dose to the next lower 
dose level (see Table 11) if treatment is resumed, 
or discontinue at the discretion of the 
investigator. See Sections 5.4.2 and 5.4.3 on 
allowed concomitant therapy and myeloid 
growth factors. 
Febrile neutropeniaa 
Not 
applicable 
Not applicable 
Withhold until febrile neutropenia resolves and neutrophil count returns to ≤ Grade 2 or 
baseline and then resume treatment at the next lower dose level (see Table 11). If the dose is 
held >48 hours, the dose may be omitted and dosing may resume on the next scheduled dosing 
day. If febrile neutropenia recurs, reduce dose to the next lower dose level (see Table 11) if 
treatment is resumed, or discontinue at the discretion of the investigator. See Sections 5.4.2 
and 5.4.3 on allowed concomitant therapy and myeloid growth factors. 
The maximum dose will be 200 mg per infusion for subjects enrolled in Part B and Part C (Arm 3). 
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a Only 2 dose reductions are allowed without prior medical monitor approval. Additional toxicities should be managed with dose delays. Medical monitor 
approval is needed for further dose reduction. 
b Subjects who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without interruption if a management plan consistent 
with institutional practice and regular monitoring are put in place. 
c Treatment should be discontinued for subjects who experience Grade 4 infusion-related reactions. 
d Support with blood product transfusions allowed per institutional standard of care. 
e Subjects who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption. 
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5.2.4.3. 
Part C (Arm 1 and Arm 2; 2q3wk dosing) 
In the event of an AE or lab criterion that prevents dosing of LV (see Section 7.6.1), the LV dose 
should be withheld until the dosing criteria are met. If the Day 1 dose is held, the Day 8 dose 
should not be given until 7 days later. 
In the event of an AE or lab criterion that prevents dosing of LV on Day 8 during the cycle (see 
Section 7.6.1), the LV dose for the week may be withheld up to 4 days for Arm 1 and Arm 2. LV 
may be resumed when the dosing criteria are met. If a dose of LV is withheld for more than 
4 days, the corresponding visit may be skipped and dosing resumed at the following visit (eg, if 
the Day 8 dose is skipped, visits will resume on Day 1 of the following cycle). Day 1 of a cycle 
may be delayed but not skipped.  
Dose reduction of LV may be considered in the event of recurrent AE despite withheld doses. 
Dose re-escalation following dose reduction is not allowed. Dose levels for LV dose reductions 
in Part C (Arms 1 and 2) are shown in Table 13 .  
For Arm 2, subjects who discontinue pembrolizumab due to a pembrolizumab-related AE (see 
Section 5.3.4) may continue LV. Similarly, subjects who discontinue LV for a LV-related AE 
may continue pembrolizumab. See Section 5.5.3 for details on managing overlapping AEs. 
Dose modification guidelines for LV 2q3wk treatment-associated toxicity are described in 
Table 13 (Arm 1 and Arm 2).  
Table 13: 
2q3wk LV dose levels 
Starting dose  
First dose reduction 
Second dose reductiona 
1.5 mg/kg 
1.25 mg/kg 
1.0 mg/kgb 
a If patients have more than 2 dose reductions (with medical monitor approval), dose will be the next appropriate 
reduced dose level determined by discussion between investigator and medical monitor.  
b The dose may be reduced to 0.75 mg/kg following approval from the medical monitor.  
For nonclinical events requiring alteration in dosing schedule (eg, holidays, scheduling 
conflicts), a +4-day dosing window is allowed. If more than a +4-day window is needed, the 
medical monitor must be consulted. The medical monitor must approve skipped dose(s) for 
nonclinical events. At least 7 days must elapse between administrations of LV. 
Table 14 describes dose modifications for LV treatment-associated toxicity for the 2q3wk 
schedule (Arm 1 and Arm 2). 
Doses reduced for LV-related toxicity should not be re-escalated. 
If a subject has a clinically significant, unresolved AE on Day 1 of C2 or beyond, the start of the 
cycle may be delayed for up to 14 days. Delays of >14 days must be approved by the medical 
monitor. 
In the event a subject is unable to tolerate their dose level, additional treatment cycles (C2 or 
later) may be administered at a lower dose level upon approval by the medical monitor. 
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Table 14: 
Dose modifications for LV-associated toxicity (Part C [Arms 1 and 2]; 2q3wk dosing) 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Peripheral 
neuropathya 
Continue at 
same dose 
level 
Withhold until toxicity 
resolves to ≤ Grade 1; 
then resume treatment at 
the next lower dose level 
(see Table 13)  
Withhold until toxicity resolves to 
≤ Grade 1, then resume treatment at the 
next lower dose level (see Table 13) 
Discontinue treatment 
Hyperglycemia 
Hold for blood glucose >250 mg/dL or >13.9 mmol/L. Resume treatment once elevated blood glucose has improved to ≤250 mg/dL or 
≤13.9 mmol/L and subject is clinically and metabolically stable (see Section 5.6 for detail). 
Non-hematologica 
(except peripheral 
neuropathy and 
hyperglycemia) 
Continue at 
same dose 
level 
Continue at same dose 
level 
Withhold dose until toxicity is 
≤ Grade 2 or has returned to baseline, 
then resume treatment at same dose 
levelb 
Withhold dose until toxicity is ≤ Grade 2 or has 
returned to baseline, then reduce dose to the 
next lower dose level (see Table 13) and resume 
treatment, or discontinue at the discretion of the 
investigatorb,c 
Hematologica 
Continue at 
same dose 
level 
Continue at same dose 
level 
Withhold until toxicity resolves to 
≤ Grade 2 or baselined,e. For 
neutropenia, strongly consider 
G-CSF support, then resume 
treatment at the same dose level. 
Prophylactic G-CSF support should 
be strongly considered for 
subsequent cycles. (See Appendix G) 
Withhold until toxicity resolves to ≤ Grade 2 or 
baselined,e. For neutropenia, strongly consider 
G-CSF support, then resume treatment at the 
same dose level. Prophylactic G-CSF support 
is required for all subsequent cycles. If 
Grade 4 neutropenia recurs despite G-CSF 
support, consider dose reduction to 
dose level –1 (see Table 13) or discontinuation. 
(Appendix G) 
Febrile 
neutropeniaa 
 
 
G-CSF support is required for treatment of febrile neutropenia. Withhold until febrile 
neutropenia resolves and neutrophil count returns to ≤ Grade 2 or baseline then resume 
treatment at the same dose level. Prophylactic G-CSF is required for all subsequent 
cycles. If febrile neutropenia recurs despite G-CSF factor support, consider dose reduction 
to dose level –1 (see Table 13) or discontinuation. 
The maximum dose will be 200 mg per infusion for patients enrolled in Part C. 
a Only 2 dose reductions are allowed without prior medical monitor approval. Additional toxicities should be managed with dose delays. Medical monitor 
approval is needed for further dose reduction. 
b Subjects who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without interruption if a management plan consistent 
with institutional practice and regular monitoring are put in place. 
c Treatment should be discontinued for subjects who experience Grade 4 infusion-related reactions. 
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d Support with blood product transfusions allowed per institutional standard of care. 
e Subjects who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption. 
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5.2.5. 
Storage and Handling 
Single-use vials containing LV must be stored under refrigeration set at 2–8 °C in an appropriate 
locked room accessible only to the pharmacist, investigator, or a duly designated person. 
Chemical and physical stability of the reconstituted drug product has been demonstrated for 
24 hours at 2–8 °C and at room temperature. However, LV drug product does not contain 
preservatives; therefore, from a microbiological standpoint, opened and reconstituted vials 
should be used immediately. If not used immediately, the in-use storage should not be longer 
than 24 hours under refrigeration set at 2–8 °C. The prepared dosing solution (reconstituted drug 
product solution and saline dilution in an IV bag or polypropylene syringe) should be 
administered within 8 hours after exposing to ambient temperature and light conditions. 
It is recommended that the drug product vials and solutions be protected from direct sunlight 
until the time of use. 
Do not shake reconstituted LV. 
Any partially used vials or prepared dosing solutions should be discarded by the site according to 
institutional drug disposal procedures. Unused vials may only be discarded by the site after 
authorization by the sponsor or designee. 
Specific instructions for the preparation, handling, storage, and accountability are found in the 
Pharmacy Manual. 
5.2.6. 
Packaging and Labeling 
LV is supplied in single-use glass vials. The drug product vials are labeled as SGN-LIV1A, the 
compound code. 
5.2.7. 
Preparation 
Recommended safety measures for handling and preparation include masks, protective clothing, 
gloves, and vertical laminar airflow safety cabinets. 
Before administration, LV must be reconstituted and diluted. Diluted solutions of LV are stable 
at a concentration range of 0.3 mg/mL to 2.5 mg/mL. The formulation contains no preservative 
and is intended for single use only; infusion solutions should be prepared and transferred using 
aseptic technique in a biosafety hood. 
Mixing of lot/batch numbers is not allowed for preparation of a single dose; however, use of a 
different lot/batch number is allowed for subsequent doses during treatment cycles. 
Detailed instructions for dose preparation are provided in the Pharmacy Instructions. 
5.3. 
Pembrolizumab 
Patients will receive pembrolizumab 200 mg in combination with LV. 
5.3.1. 
Description 
Pembrolizumab (MK-3475) will be supplied as a 100 mg/4 mL (25 mg/mL) solution in a 
single-use vial. 
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Pembrolizumab for injection is a sterile, preservative-free, clear to slightly opalescent, colorless 
to slightly yellow solution that requires dilution for IV infusion. Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab 
and is formulated in L-histidine, polysorbate, sucrose, and WFI USP. 
5.3.2. 
Method of Procurement 
Pembrolizumab will be provided to all study sites by the sponsor. In countries outside the US, 
pembrolizumab will also be relabeled by the sponsor, to meet country-specific regulatory 
requirements. 
5.3.3. 
Dose and Administration 
NOTE: Study treatment should begin as close as possible to the date on which the patient is 
enrolled. 
Study treatment of pembrolizumab will be administered on Day 1 of each 21-day cycle, after all 
procedures and assessments have been completed as detailed in Section 6.4 and Appendix D. 
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion given 
approximately 60–90 minutes after administration of LV. Sites should make every effort to target 
infusion timing to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps from site to site, a window between –5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes –5 min/+10 min). 
The pharmacy manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution. 
5.3.4. 
Dose Modifications 
5.3.4.1. 
Dose Modification and Toxicity Management for Immune-Related AEs 
Associated with Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications. Based on existing 
clinical study data, most irAEs were reversible and could be managed with interruptions of 
pembrolizumab, administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the 
evaluation. Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab 
and administer corticosteroids. Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab are provided in Table 15. 
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Table 15 
Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs 
are not controlled by corticosteroids.  
2. 
Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last 
pembrolizumab treatment.  
3. 
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAE v5.0) 
Action with 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitoring and follow-up  
Pneumonitis 
Grade 2 
Withhold  
Administer corticosteroids 
(initial dose of 1–2 mg/kg 
prednisone or equivalent) 
followed by taper 
Add prophylactic antibiotics 
for opportunistic infections 
Monitor patients for signs and symptoms of pneumonitis 
Evaluate patients with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid treatment 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea/Colitis 
Grade 2 or 3 
Withhold 
Administer corticosteroids 
(initial dose of 1–2 mg/kg 
prednisone or equivalent) 
followed by taper 
Monitor patients for signs and symptoms of enterocolitis 
(i.e., diarrhea, abdominal pain, blood or mucus in stool with or 
without fever) and of bowel perforation (i.e., peritoneal signs 
and ileus). 
Patients with ≥ Grade 2 diarrhea suspecting colitis should 
consider GI consultation and performing endoscopy to rule out 
colitis.  
Patients with diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV 
infusion. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
AST/ALT 
elevation or 
Increased bilirubin 
Grade 2a 
Withhold 
Administer corticosteroids 
(initial dose of 0.5–1 mg/kg 
prednisone or equivalent) 
followed by taper 
Monitor with liver function tests (consider weekly or more 
frequently until liver enzyme value returned to baseline or is 
stable) 
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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAE v5.0) 
Action with 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitoring and follow-up  
Grade 3b or 4c 
Permanently 
discontinue 
Administer corticosteroids 
(initial dose of 1–2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withholdd 
Initiate insulin replacement 
therapy for subjects with 
T1DM  
Administer anti-hyperglycemic 
in subjects with hyperglycemia 
Monitor subjects for hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.  
Monitor for signs and symptoms of hypophysitis (including 
hypopituitarism and adrenal insufficiency) 
Grade 3 or 4  
Withhold or 
permanently 
discontinue d 
Hyperthyroidism  
Grade 2 
Continue  
Treat with non-selective 
beta-blockers (eg, propranolol) 
or thionamides as appropriate  
Monitor for signs and symptoms of thyroid disorders. 
Grade 3 or 4  
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2–4 
Continue  
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of 
care 
Monitor for signs and symptoms of thyroid disorders. 
Nephritis: grading 
according to 
increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold  
Administer corticosteroids 
(prednisone 1–2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of renal function 
Grade 3 or 4  
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
Based on severity of AE, 
administer corticosteroids 
Ensure adequate evaluation to confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Asymptomatic 
cardiac enzyme 
elevation with 
Withhold 
Based on severity of AE, 
administer corticosteroids 
Ensure adequate evaluation to confirm etiology and/or exclude 
other causes 
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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAE v5.0) 
Action with 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitoring and follow-up  
clinical suspicion of 
myocarditis 
(previously CTCAE 
v4.0 Grade 1) 
Grade 2, 3, or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
Based on severity of AE, 
administer corticosteroids 
Ensure adequate evaluation to confirm etiology and/or exclude 
other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All other irAEs 
Persistent Grade 2 
Withhold 
Based on severity of AE, 
administer corticosteroids 
Ensure adequate evaluation to confirm etiology and/or exclude 
other causes 
Grade 3 
Withhold or 
discontinue based on 
the event e 
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinue 
AE(s)= adverse event(s); ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=Type 1 diabetes 
mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
NOTE: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline if baseline abnormal; 
bilirubin: >1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline if baseline abnormal; 
bilirubin: >3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN if baseline normal; >20.0 x baseline if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or 
≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
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5.3.4.2. 
 Dose Modification and Toxicity Management of Infusion Reactions 
Related to Pembrolizumab 
Pembrolizumab may 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 toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table 16. 
Table 16 
Pembrolizumab infusion reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at  
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs. 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
● IV fluids 
● Antihistamines 
● NSAIDs 
● Acetaminophen 
● Narcotics 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/hr to 
50 mL/hr). Otherwise, dosing will be held until 
symptoms resolve and the patient should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment. 
Patient may be premedicated 
1.5 h (±30 minutes) prior to 
infusion of pembrolizumab 
with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500–
1000 mg po (or equivalent 
dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
● Epinephrine** 
● IV fluids 
● Antihistamines 
● NSAIDs 
● Acetaminophen 
● Narcotics 
● Oxygen 
No subsequent dosing 
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NCI CTCAE Grade 
Treatment 
Premedication at  
Subsequent Dosing 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilator support 
indicated 
● Pressors 
● Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from further 
study drug treatment. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
5.3.4.3. 
Other Allowed Dose Interruption for Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or unforeseen circumstances not related to study therapy. Patients should 
be placed back on study therapy within 3 weeks of the originally scheduled dose and within 
42 days of the previously administered dose, unless otherwise discussed with the sponsor. The 
reason for interruption should be documented in the patient's study record. 
Patients who discontinue LV due to an LV-related AE (see Sections 5.2.4.2 and 5.2.4.3) may 
continue pembrolizumab with approval of the medical monitor if there is evidence of clinical 
benefit. The maximum allowed number of pembrolizumab cycles is 35 (approximately 2 years). 
5.3.5. 
Storage and Handling 
Pembrolizumab should be stored and handled per the pharmacy manual. 
5.3.6. 
Packaging and Labeling 
Pembrolizumab is commercially available in the US. 
5.3.7. 
Preparation 
Pembrolizumab should be prepared per the pharmacy manual. 
5.4. 
Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Day 1 (predose) through the safety reporting period. Any concomitant medication given for 
a study protocol-related AE should be recorded from the time of informed consent. 
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5.4.1. 
Required Concomitant Therapy 
G-CSF is required in the following situations. 
• Part A: Subjects who experience Grade 4 neutropenia or febrile neutropenia (any 
grade) in any cycle with LV treatment must receive G-CSF treatment during the 
cycle, and must receive prophylactic G-CSF for all subsequent cycles. 
• Part A: Subjects weighing over 80 kg and receiving >200 mg per infusion of LV in a 
cycle must be given prophylactic G-CSF, starting with their first dose of >200 mg per 
infusion. Once a subject receives G-CSF, it is strongly recommended that G-CSF 
continue to be administered to that subject at each subsequent cycle, regardless of 
weight change or LV dose, if it is deemed to be needed per investigator’s clinical 
judgment. 
• In Part B and Part C, primary prophylactic G-CSF is not required but is allowed (see 
Section 5.4.2 Allowed Concomitant Therapy and Section 5.4.3. Myeloid Growth 
Factors). 
The administration of G-CSF should be consistent with American Society of Clinical Oncology 
(ASCO) guidelines (Smith 2015) (Appendix G).  
• Prophylactic G-CSF should start 1 to 3 days after LV administration.  
• G-CSF (including pegfilgrastim) should not be given within 24 hours prior to the 
dose of LV.  
• If pegfilgrastim is used, a one-time dose per cycle is recommended.  
• If daily G-CSF for treatment of AEs is used, treat for at least 5 to 7 days, or until the 
ANC is >1000/mm3 (≤ Grade 2). 
If the subject is taking chronic suppressive or prophylactic anti-infectives (antiviral, antifungal, 
or antibacterial), documentation of investigations to ensure the absence of active infection must 
be completed prior to enrollment. The subject should continue suppressive or prophylactic 
anti-infectives for the duration of study participation. 
5.4.2. 
Allowed Concomitant Therapy 
The use of antibiotics including prophylactics, when applicable, is allowed. Subjects who are 
receiving P-glycoprotein (P-gp) or strong cytochrome P450 3A (CYP3A) inhibitors 
concomitantly with LV should be closely monitored for adverse reactions. Based upon 
evaluation of the anti-CD30 MMAE ADC brentuximab vedotin (ADCETRIS Prescribing 
Information, Seagen, Inc., Oct 2019), concomitant use of P-gp inhibitors or strong CYP3A4 
inhibitors has the potential to increase the exposure to MMAE (the cytotoxic component of LV 
and brentuximab vedotin). Concomitant use of P-gp inducers or strong CYP3A4 inducers could 
decrease exposure to MMAE. See Appendix F for a list of P-gp and CYP3A inducers and 
inhibitors. 
Therapy with bisphosphonates or other fracture prophylaxis agents are permitted. 
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5.4.2.1. 
Blood Product Transfusions 
Transfusions of blood products may be administered according to institutional standards. 
5.4.2.2. 
Premedication 
Routine premedication for infusion reactions should not be administered prior to the first dose of 
LV. However, subjects who experience IRRs may receive subsequent treatment with 
premedication. The use of intermittent high-dose corticosteroid treatment of >20 mg/day to 
prevent or manage hypersensitivity reactions, or other noncancer related symptoms, is allowed. 
For the management of infusion reactions, including recommended concomitant therapy, see 
Section 5.5.1. 
5.4.2.3. 
Radiotherapy 
Palliative radiotherapy (eg, treatment for stable symptomatic, non-target solitary lesion) may be 
considered on an exceptional case-by-case basis after consultation with the medical monitor, 
provided it does not interfere with assessment of tumor response per RECIST v1.1, put the 
subject at risk for increased or worsened AEs, and is not being used to treat PD. Palliative 
radiotherapy should be given no sooner than 2 weeks before or 2 weeks after treatment with LV. 
5.4.2.4. 
Supportive Care Medications 
It is recommended that subjects receive treatment for constipation, nausea, vomiting, or other 
gastrointestinal signs or symptoms. 
Although not required, subjects should be up-to-date on any recommended vaccinations prior to 
study entry. Seasonal inactivated (non-live) influenza vaccine is allowed. 
5.4.3. 
Myeloid Growth Factors  
See Section 5.4.1 and Appendix G. Subjects in any cohort of the study may receive G-CSF as 
clinically indicated. 
Myeloid growth factors (including pegfilgrastim) should not be given within 24 hours prior to 
any dose of LV. 
For subjects enrolled in Part B and C, long-acting myeloid growth factors (such as pegfilgrastim) 
may not be appropriate when LV is given weekly. Long-acting myeloid growth factors should 
only be given when there is sufficient time for the growth factors to have cleared and for growth 
stimulatory activity to have ceased. In addition, adherence to the 2015 ASCO guideline for the 
use of white blood cell growth factors is recommended for the management and/or prophylaxis 
of neutropenia and febrile neutropenia (Smith 2015). 
5.4.4. 
Prohibited Concomitant Therapy 
No other investigational drug, immunosuppressive medication, non-study systemic antineoplastic 
therapy, or approved anticancer treatment is permitted during the treatment period, including 
chemotherapy, endocrine therapy, biological response modifiers, surgery, immunotherapy, or 
radiotherapy (except palliative radiotherapy, see Section 5.4.2.3). Concurrent participation in 
another clinical trial of a medical intervention is not allowed. 
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5.4.4.1. 
Prohibited Concomitant Therapy for Pembrolizumab (Part C) 
Systemic glucocorticoids are prohibited for any purpose other than the following: 
• To modulate symptoms from an event of clinical interest of suspected immunologic 
etiology  
• As supportive care during transfusion or administration of G-CSF (Section 5.4.2.2).  
• For the prevention of emesis 
• To premedicate for IV contrast allergies 
• To treat chronic obstructive pulmonary disease (COPD) exacerbations (only 
short-term oral or IV use in doses >10 mg/day prednisone or equivalent) 
• For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent 
• Other glucocorticoid use except when used for the following purposes: 
o For topical use or ocular use 
o Intraarticular joint use 
o For inhalation in the management of asthma or COPD 
The use of physiologic doses of corticosteroids may be approved after consultation with the 
sponsor. 
5.5. 
Management of Adverse Reactions 
5.5.1. 
Management of Infusion Reactions 
5.5.1.1. 
LV 
IRRs may occur during the infusion of study treatment. The infusion should be administered at a 
site properly equipped and staffed to manage anaphylaxis should it occur. Routine premedication 
should not be administered for the prevention of IRRs prior to the first dose of LV.  
All supportive measures consistent with optimal subject care should be given throughout the 
study according to institutional standards. Supportive measures may include extending the 
infusion time and/or administering medications for IRRs. 
Subjects who have experienced a Grade 1 or Grade 2 IRR with LV should be premedicated for 
subsequent infusions.  
Subjects who experience a Grade 3 IRR may potentially receive additional treatment with LV at 
the discretion of the investigator after discussion with the medical monitor.  
Premedication for LV may include acetaminophen (or equivalent, eg, paracetamol), an 
antihistamine, and a corticosteroid administered 30–60 minutes prior to each infusion, or 
according to institutional standards.  
If anaphylaxis or a Grade 4 IRR occurs, LV should be immediately and permanently 
discontinued. 
See Section 7.6.1.2 for details regarding recording AEs of infusion reactions. 
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5.5.1.2. 
Pembrolizumab 
Details on IRRs for pembrolizumab are detailed in Section 5.3.4.2 and Table 16.  
See Section 7.6.1.2 for details regarding recording AEs of infusion reactions. 
5.5.1.3. 
Infusion-Related Reaction of Uncertain Cause 
If a patient experiences an IRR after receiving both study treatments and a single cause of the 
IRR cannot be determined, both sets of guidelines for IRRs must be followed. 
5.5.2. 
Management of Overdose 
5.5.2.1. 
LV Overdose 
In the event of an overdose of LV >10%, study personnel should: 
• Care for and medically stabilize the subject until there is no immediate risk of 
complications or death, if applicable. The subject should be closely monitored for 
adverse reactions, particularly neutropenia. Supportive care per institutional standards 
should be administered. Adherence to current clinical practice guidelines for the use 
of G-CSF is strongly recommended for the management of neutropenia and febrile 
neutropenia (Smith 2015). There is currently no known antidote for an overdose of 
LV. 
• Notify the medical monitor as soon as they become aware of the overdose, to discuss 
details of the overdose (eg, exact amount of LV administered, subject weight) and 
AEs, if any. 
5.5.2.2. 
Pembrolizumab Overdose 
For this trial, an overdose will be defined as ≥1000 mg (5 times the dose) of pembrolizumab. No 
specific information is available on the treatment of overdose of pembrolizumab. In the event of 
an overdose, the site should notify the sponsor as soon as they are aware of the overdose. The 
patient should be observed closely for signs of toxicity. Appropriate supportive treatment should 
be provided if clinically indicated. 
5.5.3. 
Management of Overlapping Toxicities 
The IBs for LV and pembrolizumab individually describe AEs commonly observed relative to 
individual study treatments, as well as less common serious findings. The respective IBs should 
be referenced when attributing causality; however, the final decision regarding causality is at the 
discretion of the investigator. 
5.5.4. 
Supportive Care Guidelines for Pembrolizumab 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined along with the dose modification guidelines in Section 5.3.4. 
Where appropriate, these guidelines include the use of oral or IV treatment with corticosteroids, 
as well as additional anti-inflammatory agents if symptoms do not improve with administration 
of corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms 
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may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance. Refer to Section 5.3.4 for guidelines 
regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
5.6. 
Management of Hyperglycemia 
Investigators should monitor blood glucose levels and are advised to perform additional 
assessments if any symptoms of hyperglycemia are observed, including a thorough evaluation 
for infection. In addition, if steroids are used to treat any other condition, blood glucose levels 
may require additional monitoring. If elevated blood glucose levels are observed, subjects should 
be treated according to local standard of care and referral to endocrinology may be considered. 
Subjects, especially those with a history of or ongoing diabetes mellitus or hyperglycemia, 
should be advised to immediately notify their physician if their glucose level becomes difficult to 
control or if they experience symptoms suggestive of hyperglycemia such as frequent urination, 
increased thirst, blurred vision, fatigue, and headache. 
Subjects who enter the study with elevated hemoglobin A1c (HbA1c) (≥6.5%) or fasting glucose 
(≥126 mg/dL or ≥7 mmol/L) at screening should receive glucose management prior to or within 
1 week of starting study treatment. 
Blood glucose may be measured by blood glucose meter or laboratory-performed blood glucose 
test. 
• Part A: random blood glucose should be checked prior to dosing on Day 1 of each 
21-day cycle.  
• Part B: random blood glucose should be checked prior to dosing on Days 1, 8, and 15 
of the first 2 cycles. For Cycle 3 and later, blood glucose should be checked on Day 1 
of each cycle, and may be checked on Day 8 and/or Day 15 if clinically indicated for 
subjects at risk of hyperglycemia. 
• Part C: random blood glucose should be checked prior to dosing on each dosing day 
of the first 2 cycles. For Cycle 3 and later, blood glucose should be checked on Day 1 
of each cycle, and may be checked on Day 8 and/or Day 15 if clinically indicated for 
subjects at risk of hyperglycemia. 
Parts A, B, and C: If blood glucose is >250 mg/dL or >13.9 mmol/L, testing may be repeated on 
same day of dosing. LV dose may be delivered on the same day when blood glucose has 
decreased to 250 mg/dL or lower and the subject is clinically and metabolically stable. LV 
should be withheld if repeated blood glucose is >250 mg/dL or >13.9 mmol/L (non-fasting or 
fasting). 
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Note: For AE reporting purposes, the severity of hyperglycemia in the NCI CTCAE, version 5, is 
graded by the medical management required to address hyperglycemia and not by the value of 
glucose measurement. 
5.7. 
Treatment Compliance 
IV administration of LV will be performed by study site staff and documented in source 
documents and the case report form (CRF). 
For Part C, IV administration of pembrolizumab will be performed by study site staff and 
documented in source documents and the CRF. 
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6. 
STUDY ACTIVITIES 
6.1. 
Schedule of Events 
A schedule of events is provided in Appendix A for baseline/screening and in Appendix B, 
Appendix C, and Appendix D for treatment. Study activities are listed by visit in this section and 
descriptions of all study assessments are presented in Section 7. AEs and concomitant 
medications will be recorded from Day 1 (predose) through the safety-reporting period (end of 
treatment [EOT] visit or 30 days after the last study treatment, whichever is later, with the 
exception of AEs of interest, which will be followed until resolution, death, or withdrawal of 
consent; see Section 7.6.1.3). Any study protocol-related AE (defined in Section 7.6.1.1) as well 
as any concomitant medications given for the treatment of the AE, should be recorded from the 
time of informed consent. 
6.2. 
Part A (q3wk dosing) 
6.2.1. 
Screening Visit (Days –28 to 1) 
• Informed consent 
• Study eligibility per inclusion/exclusion criteria 
• Medical history (see Section 7.1) 
• CT or MRI scans (CT/MRI) (see Section 7.2) 
• Brain CT or brain MRI 
• Confirm availability of adequate archival tumor sample for all subjects, if not 
available, a fresh biopsy may be collected if medically feasible (see Section 7.1.2 for 
details of requirements).  
• HbA1c and fasting blood glucose (see Section 7.6.3). If HbA1c or fasting glucose is 
elevated with confirmation upon repeat testing (HbA1c ≥6.5%, fasting glucose 
≥126 mg/dL or ≥7 mmol/L), the subject should receive glucose management before 
Cycle 1 (C1) Day 1 or within the first week of C1 (results to be submitted to ICON 
Results Integration Services [iRIS]). 
6.2.2. 
Baseline Visit (Days –7 to Day 1) 
• Physical exam (Section 7.6.4), including height and weight. Measurements of height 
obtained within the previous 12 months may be used. 
• Vital signs (Section 7.6.2) 
• Pregnancy test for subjects of childbearing potential (serum or urine pregnancy test; 
see Section 7.6.5) – must be performed within 3 days prior to administration of LV  
• ECOG performance status (Appendix J) 
• Complete blood count (CBC) with differential (see Section 7.6.3; results to be 
submitted to iRIS) 
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• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS) 
• Estimated GFR calculation (see Section 7.6.3; results to be submitted to iRIS) 
• Collection of concomitant medication information 
• Collection of AEs 
6.2.3. 
Treatment Cycle (Day 1 to Day 21) 
6.2.3.1. 
Day 1 
If baseline visit activities occur within 3 days prior to C1 Day 1, the following assessments do 
not need to be repeated at the C1 Day 1 visit:  
• Physical exam (Section 7.6.4) including weight 
• ECOG performance status (Appendix J) 
• CBC with differential 
• Serum chemistry panel and liver function tests 
• Pregnancy test  
Predose 
• Confirm subject meets dosing criteria (Section 5.2.3.1) 
• Physical exam (Section 7.6.4), including weight 
• Pregnancy test (serum or urine) for subjects of childbearing potential (see 
Section 7.6.5) – does not need to be repeated if it has been performed within 3 days 
prior to administration of LV  
• ECOG performance status (Appendix J) 
• Random blood glucose to be collected predose on the day of LV administration (see 
Section 5.6; results to be submitted to iRIS) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS) 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS)  
• Vital signs (within 60 minutes prior to the start of LV infusion, see Section 7.6.2) 
• Blood samples for PK and antitherapeutic antibody (ATA) assessment (C1-Cycle 5 
[C5] and every 5 cycles thereafter, see Section 7.3 for time points) 
• Blood samples for biomarker assessment (C1 to C6 only; see Section 7.4.1) 
• CT/MRI, if required: It is recommended that scans not be scheduled on the dosing 
day. It is recommended that scans done on the same day as Day 1 of subsequent 
cycles be completed and reviewed prior to infusion with LV. 
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• LV administration (within ± 2 days from Day 21 of the previous cycle; see 
Section 5.2.3) 
Postdose 
• Blood samples for postdose PK assessment (C1-C5 and every 5 cycles thereafter, see 
Section 7.3 for time points) 
• Vital signs (within 30 minutes of ending each infusion, and during infusion as 
clinically indicated see Section 7.6.2) 
• If available, submit tumor tissue samples for biomarker analysis as soon as 
reasonably possible after the subject has met all eligibility requirements (C1 only; see 
Section 7.4.2) 
6.2.3.2. 
Day 3 
• For subjects who receive >200 mg LV per infusion, start mandatory prophylactic 
G-CSF administration (may begin on Days 2, 3, or 4; see Section 5.4.1) 
o Other subjects who are to receive prophylactic G-CSF should start G-CSF 
(may begin on Days 2, 3, or 4) 
• Blood samples for PK assessment (visit window may be +1 day; C1 and Cycle 4 [C4] 
only, see Section 7.3)  
6.2.3.3. 
Day 8 (± 2 days) 
• Physical exam (C1 only; see Section 7.6.4) 
• CBC with differential (C1 and C2 only; see Section 7.6.3; results to be submitted to 
iRIS) 
• Serum chemistry panel and liver function tests (C1 and C2 only; see Section 7.6.3; 
results to be submitted to iRIS) 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 and Table 17 for 
time points)  
6.2.3.4. 
Day 15 (± 2 days) 
• Physical exam (C1 only; see Section 7.6.4) 
• CBC with differential (C1 and C2 only; see Section 7.6.3; results to be submitted to 
iRIS) 
• Serum chemistry panel and liver function tests (C1 and C2 only; see Section 7.6.3; 
results to be submitted to iRIS) 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 for time points) 
• Blood samples for biomarker assessment (C1 and C2 only; see Section 7.4.1) 
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6.3. 
Part B (q1wk dosing) 
6.3.1. 
Screening Visit (Days –28 to 1) 
• Informed consent 
• Study eligibility per inclusion/exclusion criteria 
• Medical history (see Section 7.1) 
• For prostate cancer subjects: 
o Bone scan (see Section 7.2.1) 
o PSA test (see Section 7.6.3) 
o Testosterone measurement (see Section 7.6.3; results to be submitted to iRIS) 
• CT/MRI (see Section 7.2) 
• Brain CT or brain MRI 
• Confirm availability of adequate archival tumor sample for all subjects, if not 
available, a fresh biopsy may be collected if medically feasible (see Section 7.1.2 for 
details of requirements).  
• HbA1c and fasting blood glucose (see Section 7.6.3). If HbA1c or fasting glucose is 
elevated with confirmation upon repeat testing (HbA1c ≥6.5%, fasting glucose 
≥126 mg/dL or ≥7 mmol/L), the subject should receive glucose management before 
C1 Day 1 or within the first week of C1 (results to be submitted to iRIS). 
6.3.2. 
Baseline Visit (Days –7 to Day 1) 
• Physical exam (Section 7.6.4), including height and weight. Measurements of height 
obtained within the previous 12 months may be used. 
• Vital signs (Section 7.6.2) 
• Pregnancy test for subjects of childbearing potential (serum or urine pregnancy test; 
see Section 7.6.5) – must be performed within 3 days prior to administration of LV  
• ECOG performance status (Appendix J) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS) 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS) 
• Estimated GFR calculation (see Section 7.6.3; results to be submitted to iRIS) 
• Collection of concomitant medication information 
• Collection of AEs 
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6.3.3. 
Treatment Cycle (Day 1 to Day 21) 
6.3.3.1. 
Day 1 
If baseline visit activities occur within 3 days prior to C1 Day 1, the following assessments do 
not need to be repeated at the C1 Day 1 visit:  
• Physical exam (Section 7.6.4) including weight 
• ECOG performance status (Appendix J) 
• CBC with differential 
• Serum chemistry panel and liver function tests 
• Pregnancy test  
• PSA test for prostate cancer subjects 
Predose 
• Confirm subject meets dosing criteria (Section 5.2.3.1) 
• Physical exam (Section 7.6.4), including weight 
• Pregnancy test (serum or urine) for subjects of childbearing potential (see 
Section 7.6.5) – does not need to be repeated if it has been performed within 3 days 
prior to administration of LV  
• ECOG performance status (Appendix J) 
• Random blood glucose to be collected prior to dosing on Day 1 of each 21-day cycle 
(see Section 5.6; results to be submitted to iRIS) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS) 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS)  
• Vital signs (within 60 minutes prior to the start of LV infusion, see Section 7.6.2) 
• Blood samples for PK and ATA assessment (C1-C5 and every 5 cycles thereafter, see 
Section 7.3 for time points) 
• Blood samples for biomarker assessment (C1 to C6 only; see Section 7.4.1) 
• Review CT/MRI, if applicable (see Section 7.2)  
• For prostate cancer subjects: 
o Review bone scan, if applicable (see Section 7.2)  
o PSA test (see Section 7.6.3) 
• LV administration (a +2 day dosing window is allowed for subsequent dosing within 
a cycle; see Section 5.2.3). For nonclinical events requiring skipping a dose(s), must 
consult with and obtain approval by sponsor medical monitor. At least 7 days must 
elapse between administrations of LV. 
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Postdose 
• Blood samples for postdose PK assessment (C1-C5 and every 5 cycles thereafter, see 
Section 7.3 for time points) 
• Vital signs (within 30 minutes of ending each infusion, and during infusion as 
clinically indicated; see Section 7.6.2) 
• If available, submit tumor tissue samples for biomarker analysis as soon as 
reasonably possible after the subject has met all eligibility requirements (C1 only; see 
Section 7.4.2) 
6.3.3.2. 
Day 3 
• Blood samples for PK assessment (visit window may be +1 day; C1 and C4 only, see 
Section 7.3)  
6.3.3.3. 
Day 8 (± 2 days) 
Predose 
• Confirm subject meets dosing criteria (Section 5.2.3.1) 
• Physical exam (Section 7.6.4) (C1 only) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS), Cycles 1 
and 2 only 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS), Cycles 1 and 2 only 
• Random blood glucose in Cycles 1 and 2. Following C2, random blood glucose may 
be collected as indicated in subjects at risk for hyperglycemia. (see Section 5.6; 
results to be submitted to iRIS) 
• Vital signs (within 60 minutes prior to the start of LV infusion, see Section 7.6.2) 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 for time points)  
• LV administration (a +2 day dosing window is allowed for subsequent dosing within 
a cycle; see Section 5.2.3). For nonclinical events requiring skipping a dose(s), must 
consult with and obtain approval by sponsor medical monitor. At least 7 days must 
elapse between administrations of LV. 
Postdose 
• Vital signs (within 30 minutes of ending each infusion, and during infusion as 
clinically indicated; see Section 7.6.2) 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 for time points) 
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6.3.3.4. 
Day 15 (± 2 days) 
Predose 
• Confirm subject meets dosing criteria (Section 5.2.3.1) 
• Physical exam (C1 only; see Section 7.6.4) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS), Cycles 1 
and 2 only 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS), Cycles 1 and 2 only 
• Random blood glucose in Cycles 1 and 2. Following C2, random blood glucose may 
be collected as indicated in subjects at risk for hyperglycemia. (see Section 5.6; 
results to be submitted to iRIS) 
• Vital signs (within 60 minutes prior to the start of LV infusion, see Section 7.6.2) 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 for time points) 
• Blood samples for biomarker assessment (C1 and C2 only; see Section 7.4.1) 
• LV administration (a +2 day dosing window is allowed for subsequent dosing within 
a cycle; see Section 5.2.3). For nonclinical events requiring skipping a dose(s), must 
consult with and obtain approval by sponsor medical monitor. At least 7 days must 
elapse between administrations of LV. 
Postdose 
• Vital signs (within 30 minutes of ending each infusion, and during infusion as 
clinically indicated; see Section 7.6.2) 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 for time points) 
6.4. 
Part C (monotherapy and pembrolizumab combination) 
6.4.1. 
Screening Visit (Days –28 to 1) 
• Informed consent 
• Study eligibility per inclusion/exclusion criteria 
• Medical history (see Section 7.1) 
• CT/MRI (see Section 7.2) 
• Brain CT or brain MRI 
• Confirm availability of adequate archival tumor sample for all subjects, if not 
available, a fresh biopsy may be collected if medically feasible (see Section 7.1.2 for 
details of requirements). 
• HbA1c and fasting blood glucose (see Section 7.6.3). If HbA1c or fasting glucose is 
elevated with confirmation upon repeat testing (HbA1c ≥6.5%, fasting glucose 
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≥126 mg/dL or ≥7 mmol/L), the subject should receive glucose management before 
C1 Day 1 or within the first week of C1 (results to be submitted to iRIS). 
• Arm 2 and Arm 3: Thyroid function test (detailed in Section 7.6.3).  
6.4.2. 
Baseline Visit (Days –7 to Day 1) 
• Physical exam (Section 7.6.4), including height and weight. Measurements of height 
obtained within the previous 12 months may be used. 
• Vital signs (Section 7.6.2) 
• Pregnancy test for subjects of childbearing potential (serum or urine pregnancy test; 
see Section 7.6.5) – must be performed within 3 days prior to administration of LV  
• ECOG performance status (Appendix J) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS) 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS) 
• Estimated GFR calculation (see Section 7.6.3; results to be submitted to iRIS) 
• Collection of concomitant medication information 
• Collection of AEs 
6.4.3. 
Treatment Cycle (Day 1 to Day 21) 
6.4.3.1. 
Day 1 
If baseline visit activities occur within 3 days prior to C1 Day 1, the following assessments do 
not need to be repeated at the C1 Day 1 visit:  
• Physical exam (Section 7.6.4) including weight 
• ECOG performance status (Appendix J) 
• CBC with differential 
• Serum chemistry panel and liver function tests 
• Pregnancy test  
Predose 
• Confirm subject meets dosing criteria (Section 5.2.3.1) 
• Physical exam (Section 7.6.4), including weight 
• Pregnancy test (serum or urine) for subjects of childbearing potential (see 
Section 7.6.5) – does not need to be repeated if it has been performed within 3 days 
prior to administration of LV  
• ECOG performance status (Appendix J) 
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• Random blood glucose to be collected prior to dosing on Day 1 of each 21-day cycle 
(see Section 5.6; results to be submitted to iRIS) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS) 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS)  
• Arm 2 and Arm 3: Thyroid function tests (detailed in Section 7.6.3); to include 
thyroid-stimulating hormone (TSH), T3 or free T3, and free T4). Day 1 of each 
odd-numbered cycle only (i.e. Cycles 1, 3, 5, 7, etc). 
• Vital signs:  
o Arm 1: within 60 minutes prior to the start of LV infusion, see Section 7.6.2 
o Arm 2 and Arm 3: within 60 minutes prior to LV infusion, within 60 minutes 
prior to pembrolizumab infusion, see Section 7.6.2 
• Blood samples for PK and ATA assessment (C1 to C5 and every 5 cycles thereafter, 
see Section 7.3 for time points) 
• Blood samples for biomarker assessment (C1 to C6 only; see Section 7.4.1) 
• Review CT/MRI, if applicable (see Section 7.2)  
• Arm 1, Arm 2, and Arm 3: LV administration (a +4 day dosing window for Arm 1 
and Arm 2 and a +2 day window for Arm 3) is allowed for subsequent dosing within 
a cycle; see Sections 5.2.3, 5.2.4.2, and 5.2.4.3. For nonclinical events requiring 
skipping a dose(s), must consult with and obtain approval by sponsor medical 
monitor. At least 7 days must elapse between administrations of LV. 
• Arm 2 and Arm 3: Pembrolizumab will be administered 60–90 minutes following 
LV. For nonclinical events requiring skipping a dose(s), must consult with and obtain 
approval by sponsor medical monitor.  
Postdose 
• Vital signs: 
o Arm 1: within 30 minutes of ending each LV infusion, and during infusion as 
clinically indicated; see Section 7.6.2 
o Arm 2 and Arm 3: within 2 hours of ending each infusion, and during 
infusion/s as clinically indicated; see Section 7.6.2 
• Blood samples for PK assessment (see Section 7.3 for time points) 
6.4.3.2. 
Day 3 
• Blood samples for PK assessment (visit window may be +1 day; C1 and C4 only, see 
Section 7.3)  
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6.4.3.3. 
Day 8 (± 2 days) 
Predose 
• Confirm subject meets dosing criteria (Section 5.2.3.1) 
• Physical exam (Section 7.6.4) (C1 only) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS), Cycles 1 
and 2 only 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS), Cycles 1 and 2 only 
• Random blood glucose in Cycles 1 and 2. Following Cycle 2, random blood glucose 
may be collected as indicated in subjects at risk for hyperglycemia. (see Section 5.6; 
results to be submitted to iRIS) 
• Vital signs (within 60 minutes prior to the start of LV infusion, see Section 7.6.2) 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 for time points)  
• Arm 1, Arm 2, and Arm 3: LV administration (a +4 day dosing window for Arm 1 
and Arm 2 and a +2 day window for Arm 3). See Sections 5.2.3, 5.2.4.2, and 5.2.4.3. 
For nonclinical events requiring skipping a dose(s), must consult with and obtain 
approval by sponsor medical monitor. At least 7 days must elapse between 
administrations of LV. 
Postdose 
• Vital signs: 
o Arm 1: within 30 minutes of ending each LV infusion, and during infusion as 
clinically indicated; see Section 7.6.2 
o Arm 2 and Arm 3: within 2 hours of ending each infusion, and during 
infusion/s as clinically indicated; see Section 7.6.2 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 for time points) 
6.4.3.4. 
Day 15 (± 2 days) 
Note: Subjects in Arm 1 and Arm 2 will require the following: 
• CBC with differential (–2-day window; see Section 7.6.3; results to be submitted to 
iRIS), Cycles 1 and 2 only 
• Physical exam (C1 only; see Section 7.6.4) 
 
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The following is for Arm 3 only: 
Predose  
• Confirm subject meets dosing criteria (Section 5.2.3.1) 
• Physical exam (C1 only; see Section 7.6.4) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS), Cycles 1 
and 2 only 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS), Cycles 1 and 2 only 
• Random blood glucose in Cycles 1 and 2. Following C2, random blood glucose may 
be collected as indicated in subjects at risk for hyperglycemia. (see Section 5.6; 
results to be submitted to iRIS) 
• Vital signs (within 60 minutes prior to the start of LV infusion, see Section 7.6.2) 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 for time points) 
• Blood samples for biomarker assessment (C1 and C2 only; see Section 7.4.1) 
• LV administration (a +2 day dosing window is allowed for subsequent dosing within 
a cycle; see Sections 5.2.3 and Section 5.2.4.2). For nonclinical events requiring 
skipping a dose(s), must consult with and obtain approval by sponsor medical 
monitor. At least 7 days must elapse between administrations of LV. 
Postdose 
• Vital signs (within 2 hours of ending each infusion, and during infusion(s) as 
clinically indicated; see Section 7.6.2) 
• Blood samples for PK assessment (C1 and C4 only; see Section 7.3 for time points) 
6.5. 
On treatment Response Assessments 
Time points for radiographic exams for patients with RECIST v1.1 measurable tumor lesions or 
bone scan should be calendar based and do not depend on cycle visits. It is recommended that 
scans not be scheduled on the dosing day. It is recommended that scans done on the same day as 
Day 1 of subsequent cycles be completed and reviewed prior to infusion with LV. 
The schedule of response assessments should not be adjusted for dose delays, dose interruptions, 
or other reasons for changes in the timing of a subject’s study activities. Imaging should be 
conducted on the following schedule (Sections 6.5.1 and 6.5.2) until treatment is discontinued 
for any of the following reasons: disease progression, unacceptable toxicity, investigator 
decision, consent withdrawal, study termination by the sponsor, pregnancy, or death, whichever 
comes first. For all tumor cohorts, imaging should also be performed whenever disease 
progression is suspected. 
6.5.1. 
For non-prostate cancer subjects (Cohorts 1–6, and 8): 
• Every 6 weeks (±3 days) for 12 months after the first dose of LV 
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• Every 12 weeks (±7 days) thereafter 
Objective responses (CR or PR) will be confirmed with repeat scans 4–6 weeks after the first 
documentation of response.  
6.5.2. 
For prostate cancer subjects (Cohort 7): 
• PSA assessment every 3 weeks (±3 days) per calendar 
• CT/MRI scan every 8 weeks (±7 days) per calendar for the first 24 weeks, then every 
12 weeks (±7 days) thereafter 
• Bone scan every 8 weeks (±7 days) per calendar for the first 24 weeks, then every 
12 weeks (±7 days) thereafter 
6.6. 
End of Treatment Visit (30 to 37 days after last dose of study drug) 
Subjects will continue to receive LV until disease progression, unacceptable toxicity, 
investigator decision, consent withdrawal, study termination by the sponsor, pregnancy, or death, 
whichever comes first. 
Regardless of time since last dose, EOT visits should be completed prior to administration of a 
new therapy. EOT visits should occur within 30 to 37 days after the last dose of LV unless 
delayed due to an AE. If EOT evaluations are completed before 30 days after the last study 
treatment, the subject will be contacted 30 to 37 days following the subject’s last study treatment 
to assess for AEs and concomitant medications. 
• Physical examination (Section 7.6.4), including weight 
• Vital signs (Section 7.6.2) 
• Pregnancy test for subjects of childbearing potential (see Section 7.6.5) 
• ECOG performance status (Appendix I) 
• CBC with differential (see Section 7.6.3; results to be submitted to iRIS) 
• HbA1c (see Section 7.6.3; results to be submitted to iRIS) 
• Serum chemistry panel and liver function tests (see Section 7.6.3; results to be 
submitted to iRIS) 
• CT/MRI scan (see Section 7.2 for details); not required if previous scan was 
completed within 4 weeks prior to EOT  
• Blood samples for PK and ATA assessment (see Section 7.3 for time points) 
• Blood samples for biomarker assessment (see Section 7.4.1) 
• For prostate cancer subjects: 
o PSA assessment (see Section 7.6.3) 
o Bone scan (see Section 7.2.1), not required if previous scan was completed 
within 4 weeks prior to EOT 
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6.7. 
Follow-up 
All subjects will be followed for survival until death or study closure, whichever occurs first. 
Survival and subsequent anticancer therapy follow-up may be conducted with clinic visits or 
telephone calls. 
For subjects who discontinue study treatment for reasons other than progression, the following 
assessments will be conducted every 6 weeks (± 3 days) for 12 months after the first dose of LV 
and every 12 weeks (± 7 days) thereafter, until disease progression, initiation of a new anticancer 
therapy, investigator decision, consent withdrawal, study termination by the sponsor, pregnancy, 
or death, whichever comes first: 
• Physical examination (see Section 7.6.4) 
• Pregnancy test for subjects of childbearing potential 24 weeks after the last dose of 
LV (see Section 7.6.5) 
• CT/MRI scan (see Section 7.2 for details); after a year of follow-up, reduce frequency 
to institution’s standard of care 
• In subjects who discontinue study treatment due to pregnancy, response assessments 
should be conducted as appropriate 
For prostate cancer subjects who discontinue study treatment for reasons other than progression, 
the following assessments will be conducted until disease progression, initiation of a new 
anticancer therapy, investigator decision, consent withdrawal, study termination by the sponsor, 
or death, whichever comes first: 
• Physical examination every 12 weeks (±7 days) (see Section 7.6.4) 
• PSA assessment every 12 weeks (±7 days) 
• Bone scan every 12 weeks (±7 days) (see Section 7.2.1) 
• Soft tissue tumor assessment (CT/MRI) every 12 weeks (±7 days) until disease 
progression for subjects with measurable disease 
6.8. 
End of Study/End of Follow-up 
The date the subject met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. 
If a subject requests to be withdrawn from follow-up, this request must be documented in the 
source documents. When a subject withdraws consent, the sponsor should be notified as soon as 
possible. If the subject withdraws from study, the study staff may use a public information 
source (eg, county records) to obtain information about survival status only. 
Three follow-up attempts must be documented in the source documents before a subject is 
declared lost to follow-up. The sponsor should be notified as soon as possible if this occurs. 
The study will be closed 3 years after the last subject receives the last dose, or when no subjects 
remain in follow-up, whichever occurs first. 
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7. 
STUDY ASSESSMENTS 
7.1. 
Screening/Baseline Assessments 
Only subjects who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Subject medical history includes a thorough review of significant past medical history, current 
conditions, any treatment for prior malignancies and response to prior treatment, and any 
concomitant medications. 
A brain scan (head CT with contrast/brain MRI) and CT with contrast/MRI scan for baseline 
tumor imaging should be performed to assess disease at screening. 
For prostate cancer subjects, a bone scan should be performed to assess disease at screening. 
Required assessments for all subjects at screening and/or baseline are described in Sections 6.2 
and 6.3, Section 7.6, and Appendix A. 
7.1.1. 
Tumor Tissue After Treatment 
If a tumor tissue sample is obtained as part of standard of care at any time during the study (until 
disease progression after treatment with LV), with the subject’s consent, a part of that sample or 
an additional sample obtained during the same procedure may be collected and submitted to the 
sponsor for biomarker testing. 
Biomarker assessments that will be performed using tumor tissue are outlined in Section 7.4.2. 
7.1.2. 
Tumor Sample Requirements and Collection 
Tumor tissue samples must be available for submission (see Section 7.4.2).  
• Available and adequate archival baseline tumor sample is required. If an archival 
baseline tumor sample is not available, a fresh biopsy sample may be submitted if 
medically feasible or the medical monitor should be contacted to review this 
requirement.  
• FFPE blocks are requested. If an FFPE block is not available, 30 unstained slides are 
required or contact medical monitor for alternative submission possibilities. Core 
needle or excisional biopsy is preferred. If neither is possible, discuss with medical 
monitor whether biopsy obtained via alternative methods may be appropriate. 
• If a tumor tissue sample is obtained as part of standard of care during the study, a part 
of that sample is requested to be submitted to the sponsor with the subject’s consent. 
• Unscheduled tumor biopsies performed while the subject is on study should be made 
available to the sponsor if feasible and if subject consents to the submission of this 
tissue. For example, if a biopsy on residual tumor is performed at EOT or at 
progression, a sample should be sent to sponsor (if available).  
7.2. 
Response/Efficacy Assessments 
The determination of antitumor activity will be based on objective response assessments made 
by the investigator according to the RECIST v1.1 (Appendix H) (Eisenhauer 2009) and treatment 
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decisions by the investigator will be based on these assessments for Parts A–C (Arm 1 only). For 
subjects in Part C (Arms 2 and 3), treatment decisions by the investigator will be based on 
iRECIST (see Appendix I) (Seymour 2017). Clinical response of CR, PR, SD, or PD will be 
determined at each assessment. In addition, images will be collected by an independent review 
facility for possible future analysis. 
For non-prostate cancer subjects, responses (CR or PR) will be confirmed 4–6 weeks after first 
documentation of response.  
For all subjects, tumor imaging should also be performed whenever disease progression is 
suspected. 
Measures of anticancer activity will be assessed by either CT with contrast or MRI scans at 
protocol-specified time points. A diagnostic quality CT is required unless medically 
contraindicated. 
For prostate cancer subjects, PSA response is defined as a reduction from baseline PSA level of 
at least 50%, maintained for at least 3 weeks. The duration of PSA response is defined as the 
time between the first evaluation at which the response criteria are met and the first 
documentation of PSA progression. Early increase in PSA within 12 weeks, when followed by 
subsequent decline, is ignored in determining this endpoint. 
For subjects unable to tolerate contrast-enhanced CT assessments, MRI imaging is acceptable. 
MRI scans may not be appropriate to assess lung parenchymal lesions and CT without contrast 
enhancement is acceptable in such situations. Subjects must be evaluated with the same 
imaging modality throughout the study for efficacy assessments. If any other radiographic or 
disease assessment examination is conducted per standard of care, the assessment information 
will be collected in the CRF. 
Further details are provided in the study imaging manual. 
Tumor assessments will continue until the subject has radiologically-confirmed disease 
progression per RECIST v1.1 by the investigator according to Sections 6.4, 6.6, and 6.7. 
Subjects who discontinue study treatment for reasons other than objective disease progression by 
RECIST v1.1 (see Appendix H) will continue to receive tumor assessments according to 
Section 6.7.  
For Part C Arms 2 and 3, because of the possibility of an initial increase in tumor burden caused 
by immune cell infiltration in the setting of a T-cell response (termed pseudoprogression) with 
pembrolizumab treatment, radiographic progression per RECIST v1.1 may not be indicative of 
true disease progression. The iRECIST criteria allow for continued treatment beyond apparent 
progression of disease in order to confirm response (see Appendix I). In patients who have initial 
evidence of radiological PD per RECIST v1.1 in Part C (Arms 2 and 3), it is at the discretion of 
the treating physician whether to continue a patient on study treatment until repeat imaging is 
obtained. This clinical judgment decision should be based on the patient’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. Patients may 
receive study treatment while waiting for confirmation of PD if they are clinically stable as 
defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression 
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• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
When feasible, patients should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some patients can have a transient tumor flare in the first few months after the 
start of immunotherapy, but with subsequent disease response. Patients that are deemed clinically 
unstable are not required to have repeat imaging for confirmation of PD. 
Subjects’ clinical data must be available for CRF source verification. Copies of tumor images 
must be made available for review by the sponsor (or its designee), upon request. 
7.2.1. 
Tumor Cohort-Specific Imaging Requirements 
For subjects with SCLC, NSCLC, gastric, GEJ adenocarcinoma, or melanoma, imaging must 
include chest, abdomen, and pelvis. Other specific regions of disease involvement should also be 
imaged. 
For subjects with head and neck cancer, imaging of the neck and chest are required. Other 
specific regions of disease involvement should also be imaged.  
For subjects with esophageal squamous cell cancer, imaging of the chest and abdomen are 
required. Other specific regions of disease involvement should also be imaged. 
For subjects with prostate cancer, cross-sectional imaging of the chest, abdomen, pelvis, as well 
as bone scintigraphy are required. Other specific regions of disease involvement should also be 
imaged. 
7.3. 
Pharmacokinetic and Immunogenicity Assessments 
Blood samples for PK and ATA assessment will be collected at protocol-specified time points 
per the schedules provided in Table 17, Table 18, and Table 19. Sensitive, validated 
immunoassay or liquid chromatography with tandem mass spectrometry (LC/MS/MS) assays, as 
appropriate, will be used to measure the concentrations of LV (ADC), total antibody, and 
MMAE in plasma and ATA in serum. Remaining PK samples will be archived for possible 
analysis of other LV-related species.  
For Part C Arms 2 and 3, additional PK and ATA samples will be collected and archived for 
possible analysis of pembrolizumab concentrations and levels of ATAs to pembrolizumab, 
respectively. 
Refer to the Laboratory Manual for information on collection, processing, storage, and shipment 
of samples.
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Table 17: 
Pharmacokinetic, immunogenicity, and biomarker sample collection time points – 21 day cycles (Part A; q3wk dosing) 
Cycle 
Study 
Day 
Time 
Window 
Relative Time 
PK 
ATA 
Serum 
Plasma 
Blood 
Cell 
Pellet 
Archived 
tumor 
specimen 
Tumor 
biopsy 
(FFPE) 
Screening –28 to 1 N/A 
N/A 
N/A 
 
 
 
 
 
Xa 
1 and 4 
Day 1 
Pre-dose 
within 4 hrb 
START of infusion 
X 
X 
X 
X 
X 
 
 
End of 
infusion 
within 
15 min 
END of infusion 
X 
 
 
 
 
 
 
2 hr 
±15 min 
X 
 
 
 
 
 
 
4 hr 
±15 min 
X 
 
 
 
 
 
 
Day 3 
48 hr 
+24 hr 
START of infusion 
Xc 
 
 
 
 
 
 
Day 8 
168 hr 
±48 hr 
X 
 
 
 
 
 
 
Day 15 
336 hr 
±48 hr 
X 
 
Xd 
Xd 
Xd 
 
 
2 
Day 1 
Pre-dose 
within 4 hr 
START of infusion 
X 
X 
X 
X 
X 
 
 
End of 
infusion 
within 
15 min 
END of infusion 
X 
 
 
 
 
 
 
Day 15 
336 hr 
±48 hr 
START of infusion 
 
 
X 
X 
X 
 
 
3, 5, and 
every 5th 
cycle 
thereafter 
Day 1 
Pre-dose 
within 4 hr 
START of infusion 
X 
X 
Xe 
Xe 
Xe 
 
 
End of 
infusion 
within 
15 min 
END of infusion 
X 
 
 
 
 
 
 
6 
Day 1 
Pre-dose 
within 4 hr 
START of infusion 
 
 
X 
X 
X 
 
 
EOT 
X 
X 
X 
X 
 
 
 
Additional biopsy 
 
 
 
 
 
 
Xa 
a See Section 7.1.2 for details. 
b Cycle 1, Day 1 pre-dose window is 24 hours. 
c Blood draws at indicated time points may be obtained by a visiting nurse service. 
d Draw only for Cycle 1 and Cycle 2. 
e Cycle 3 and Cycle 5 only.  
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Table 18: 
Pharmacokinetic, immunogenicity, and biomarker sample collection time points – 21 day cycles (Part B; q1wk dosing) 
Cycle 
Study Day Time 
Window 
Relative Time 
PK 
ATA 
Serum 
Plasma 
Blood 
Cell 
Pellet 
Archived 
tumor 
specimen 
Tumor 
biopsy 
(FFPE) 
Screening 
–28 to 1 
N/A 
N/A 
N/A 
 
 
 
 
 
Xa 
1 and 4 
Day 1 
Pre-dose 
within 4 hrb 
START of infusion 
X 
X 
X 
X 
X 
 
 
End of infusion 
within 15 min 
END of infusion 
X 
 
 
 
 
 
 
2 hr 
±15 min 
X 
 
 
 
 
 
 
4 hr 
±15 min 
X 
 
 
 
 
 
 
Day 3 
48 hr 
+24 hr 
START of infusion 
Xc 
 
 
 
 
 
 
Day 8 
Predose 
within 4 hr 
START of infusion 
X 
 
 
 
 
 
 
End of infusion 
Within 15 min 
END of infusion 
X 
 
 
 
 
 
 
Day 15 
Predose 
Within 4 hr 
START of infusion 
X 
 
Xd 
Xd 
Xd 
 
 
End of infusion 
within 15 min 
END of infusion 
X 
 
 
 
 
 
 
2 
Day 1 
Pre-dose 
within 4 hr 
START of infusion 
X 
X 
X 
X 
X 
 
 
End of infusion 
within 15 min 
END of infusion 
X 
 
 
 
 
 
 
Day 15 
Pre-dose 
within 4 hr 
START of infusion 
 
 
X 
X 
X 
 
 
3, 5, and 
every 5th 
cycle 
thereafter 
Day 1 
Pre-dose 
within 4 hr 
START of infusion 
X 
X 
Xe 
Xe 
Xe 
 
 
End of infusion 
within 15 min 
END of infusion 
X 
 
 
 
 
 
 
6 
Day 1 
Pre-dose 
within 4 hr 
START of infusion 
 
 
X 
X 
X 
 
 
EOT 
X 
X 
X 
X 
 
 
 
Additional biopsy 
 
 
 
 
 
 
Xa 
a See Section 7.1.2 for details. 
b Cycle 1, Day 1 pre-dose window is 24 hours. 
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c Blood draws at indicated time points may be obtained by a visiting nurse service. 
d Draw only for Cycle 1 and Cycle 2. 
e Cycle 3 and Cycle 5 only.  
 
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Table 19: 
Pharmacokinetic, immunogenicity, and biomarker sample collection time points – 21 day cycles (Part C; 2q3wk, q1wk) 
Cycle 
Study 
Day 
Time 
Window 
Relative Time 
LV PK 
Pembrolizumab 
PK 
LV ATA 
Pembrolizumab 
ATA 
Serum Plasma 
Blood 
Cell 
Pellet 
Archived 
tumor 
specimen 
Tumor 
biopsy 
(FFPE) 
Screening –28 to 1 
N/A 
N/A 
N/A 
 
 
 
 
 
 
 
Xa 
 
1 and 4 
Day 1 
Pre-dose of LV within 4 hrb 
START of LV 
infusion 
X 
X 
X 
X 
X 
X 
X 
 
 
End of LV 
infusion 
within 15 min 
END of LV 
infusion 
X 
 
 
 
 
 
 
 
 
End of 
Pembrolizumab 
infusion 
Within 15 min 
End of 
Pembrolizumab 
infusion 
 
Xc 
 
 
 
 
 
 
 
2 hr 
±15 min 
END of LV 
infusion 
X 
 
 
 
 
 
 
 
 
4 hr 
±15 min 
END of LV 
infusion 
X 
 
 
 
 
 
 
 
 
Day 3 
48 hr 
+24 hr 
START of LV 
infusion 
Xc d 
 
 
 
 
 
 
 
 
Day 8 
Predose of LV 
within 4 hr 
START of LV 
infusion 
X 
 
 
 
 
 
 
 
 
End of LV 
infusion 
Within 15 min 
END of LV 
infusion 
X 
 
 
 
 
 
 
 
 
Day 15 
Predose of LV 
Within 4 hr 
START of LV 
infusion 
Xe 
 
 
 
Xf 
Xf 
Xf 
 
 
End of LV 
infusion 
within 15 min 
END of LV 
infusion 
Xe 
 
 
 
 
 
 
 
 
2 
Day 1 
Pre-dose of LV within 4 hr 
START of LV 
infusion 
X 
X 
X 
X 
X 
X 
X 
 
 
End of LV 
infusion 
within 15 min 
END of LV 
infusion 
X 
 
 
 
 
 
 
 
 
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Cycle 
Study 
Day 
Time 
Window 
Relative Time 
LV PK 
Pembrolizumab 
PK 
LV ATA 
Pembrolizumab 
ATA 
Serum Plasma 
Blood 
Cell 
Pellet 
Archived 
tumor 
specimen 
Tumor 
biopsy 
(FFPE) 
Day 15 
Pre-dose of LV  within 4 hr 
START of LV 
infusion 
 
 
 
 
Xf 
Xf 
Xf 
 
 
3, 5, and 
every 5th 
cycle 
thereafter 
Day 1 
Pre-dose of LV within 4 hr 
START of LV 
infusion 
X 
X 
X 
X 
Xg 
Xg 
Xg 
 
 
End of LV 
infusion 
within 15 min 
END of LV 
infusion 
X 
 
 
 
 
 
 
 
 
6 
Day 1 
Pre-dose of LV within 4 hr 
START of LV 
infusion 
 
 
 
 
X 
X 
X 
 
 
EOT 
X 
X 
X 
X 
X 
X 
 
 
 
Additional biopsy 
 
 
 
 
 
 
 
 
Xa 
a See Section 7.1.2 for details. 
b Cycle 1, Day 1 pre-dose window is 24 hours. 
c Cycle 1 only 
d Blood draws at indicated time points may be obtained by a visiting nurse service. 
e Arm 3 only 
f Draw only for Cycle 1 and Cycle 2 for Arm 3 only 
g Cycle 3 and Cycle 5 only 
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7.4. 
Biomarker Studies 
Samples for exploratory biomarkers will be collected at protocol -specified time points per the 
schedules provided in Table 17, Table 18, and Table 19. Biomarker assessments will not be used 
for subject selection. Correlative studies will be conducted to gain a better understanding of 
target-response relationship, predictive biomarkers, mechanisms of action, resistance 
mechanisms, and pharmacodynamics. Methods of analysis may include IHC, next generation 
sequencing, polymerase chain reaction (PCR), multiplex immunofluorescence, flow cytometry, 
immunoassays, and proteomic methodologies such as enzyme-linked immunosorbent assay 
(ELISA) and microvesicle assessment. 
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed if, during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are too few samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early, completion of biomarker 
assessments is based on justification and intended utility of the data. 
7.4.1. 
Biomarkers in Blood 
The primary effects of LV on tumor cells may lead to changes in the activation state of local, 
tumor-associated, and peripheral immune cells. Biomarker assessments in blood samples may 
include measurement of baseline and drug-induced changes in circulating proteins, blood cell 
populations, immunoassays, gene expression, cytogenetics, genetic polymorphisms, somatic 
mutations associated with cancer, and circulating immune function and disease markers. LV 
interactions with peripheral blood cells and tissues may also be monitored. These may provide 
insight into treatment-related changes in activation state of peripheral immune system associated 
with LV-induced tumor cell death. 
7.4.2. 
Biomarkers in Tumor Tissue 
To understand the relationship between the biological characteristics of tumors before treatment 
and subject outcomes, tissue from biopsies taken prior to enrollment will be examined. Biopsies 
will be assessed for specific pharmacodynamic, predictive, and prognostic biomarkers in the 
tumor to compare the effects of treatment with LV. If tissue is available from a standard of care 
biopsy collected after enrollment (until disease progression after treatment with LV), it may also 
be examined. 
7.5. 
Biospecimen Repository 
In the US only, for subjects who provide additional consent, remaining de-identified unused 
blood and/or tissue may be retained by Seagen Inc. and used for future research, including but 
not limited to the evaluation of targets for novel therapeutic agents, the biology of ADC 
sensitivity and resistance mechanisms, and the identification of biomarkers of ADCs. Blood and 
tissue samples donated for future research may be retained for a period of up to 25 years. If 
additional consent is not provided, any remaining biological samples will be destroyed after the 
study has been completed and all applicable regulatory obligations have been met. 
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7.6. 
Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including SAEs, recording of concomitant medication, and measurements of 
protocol-specified physical examination findings, vital signs, pregnancy testing, and laboratory 
tests. Safety assessments will be performed at prespecified time points through the EOT visit and 
in some circumstances beyond the EOT visit. AEs and SAEs will be reported through the EOT 
visit or 30 days after the last study treatment, whichever is later (see Section 7.6.1.3). For Part C 
Arm 2 and Arm 3, AEs and SAEs will be reported through the EOT visit or 90 days after the last 
study treatment, whichever is later (see Section 7.6.1.3). 
An ongoing, real-time review of subject safety and SAEs will be conducted by the sponsor’s 
Drug Safety Department. 
7.6.1. 
Adverse Events 
7.6.1.1. 
Definitions 
Adverse Event 
According to the International Council for Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 Code of Federal Regulations (CFR) 312.32, 
investigational new drug (IND) Safety Reporting, an AE is any untoward medical occurrence in 
a subject or clinical investigational subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions CRF: 
• From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded. A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure.  
• All medical conditions present or ongoing predose on study Day 1 should be 
recorded. 
• All AEs (regardless of relationship to study drug) should be recorded from study 
Day 1 (during and post-dose) through the end of the safety reporting period (see 
Section 7.6.1.3). Complications that occur in association with any procedure 
(eg, biopsy) should be recorded as AEs whether or not the procedure was protocol 
mandated. 
• Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
In general, an abnormal laboratory value should not be recorded as an AE unless it is associated 
with clinical signs or symptoms, requires an intervention, results in a SAE, or results in study 
termination or interruption/discontinuation of study treatment. When recording an AE resulting 
from a laboratory abnormality, the resulting medical condition rather than the abnormality itself 
should be recorded (eg, record “anemia” rather than “low hemoglobin”). 
 
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Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
Life threatening: 
The AEs placed the subject at immediate risk of death. This classification does not 
apply to an AE that hypothetically might cause death if it were more severe. 
Hospitalization: 
The AE resulted in hospitalization or prolonged an existing inpatient hospitalization. 
Hospitalizations for elective medical or surgical procedures or treatments planned 
before the signing of informed consent in the study or routine check-ups are not SAEs 
by this criterion. Admission to a palliative unit or hospice care facility is not 
considered to be a hospitalization. Hospitalizations or prolonged hospitalizations for 
scheduled therapy of the underlying cancer or study target disease need not be 
captured as SAEs. 
Disabling/ 
incapacitating: 
An AE that resulted in a persistent or significant incapacity or substantial disruption 
of the subject’s ability to conduct normal life functions. 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a subject exposed to the molecule or study 
treatment regimen before conception or during pregnancy. 
Medically significant: 
The AE did not meet any of the above criteria, but could have jeopardized the subject 
and might have required medical or surgical intervention to prevent one of the 
outcomes listed above or involves suspected transmission via a medicinal product of 
an infectious agent. Potential drug-induced liver injury (DILI) also is considered a 
medically significant event (see Section 7.6.1.2 for the definition of potential DILI.) 
Adverse Event Severity 
AE severity should be graded using the NCI CTCAE, version 5. These criteria are provided in 
the study manual. 
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity of 
an AE. ‘Serious’ is a regulatory definition and serves as a guide to the sponsor for defining 
regulatory reporting obligations (see definition for SAEs, above). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment (LV monotherapy or LV plus 
pembrolizumab combination therapy) should be evaluated by the investigator using the 
following criteria: 
 
 
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Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such as: 
A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome) 
One or more occurrences of an event that is not commonly associated with drug exposure, but 
is otherwise uncommon in the population exposed to the drug (eg, tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (eg, due to underlying disease or occurs commonly 
in the study population), or a temporal sequence cannot be established with the onset of the AE 
and administration of the study treatment, or a causal relationship is considered biologically 
implausible 
7.6.1.2. 
Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during subject 
questioning, discovered during physical examination, laboratory testing and/or other means by 
recording them on the CRF and/or SAE form, as appropriate. 
Eliciting Adverse Events 
An open-ended or non-directed method of questioning should be used at each study visit to elicit 
the reporting of AEs. 
Recording Adverse Events 
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions CRF: 
• Description including onset and resolution dates 
• Whether it met SAE criteria 
• Severity 
• Relationship to study treatment or other causality 
• Outcome 
Diagnosis vs. Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
report the individual symptom as a separate AE. 
Important exceptions for this study are adverse reactions associated with the infusion of LV. For 
IRRs, do not use the NCI CTCAE terms of “cytokine release syndrome,” “acute infusion 
reaction,” or “allergic or hypersensitivity reaction.” Instead, record each sign or symptom as an 
individual AE. If multiple signs or symptoms occur with a given infusion-related event, each 
sign or symptom should be recorded separately with its level of severity. 
 
 
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Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and an SAE form. 
The following should be considered when recording SAEs: 
• Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF. 
• For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
Progression of the Underlying Malignancy 
Since progression of underlying malignancy is being assessed as an efficacy variable, it should 
not be reported as an AE or SAE. The terms “Disease Progression”, “Progression of Disease”, or 
“Malignant disease progression” and other similar terms should not be used to describe an AE or 
SAE. However, clinical symptoms of progression may be reported as AEs or SAEs if the 
symptom cannot be determined as exclusively due to progression of the underlying malignancy 
or does not fit the expected pattern of progression for the disease under study. In addition, 
complications from progression of the underlying malignancy should be reported as AEs or 
SAEs. 
Pregnancy 
It is the responsibility of investigators or their designees to report any pregnancy or lactation 
(spontaneously reported to them) that occurs in a subject (or partner of a male subject) during the 
trial. If a subject becomes pregnant while on study, the site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or terminated. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation must be reported by the investigator if they cause the subject to be excluded from the 
trial. 
Notification to Drug Safety: Complete a Pregnancy Report Form for all pregnancies and 
lactations that occur from the time of treatment allocation until 6 months after the final dose of 
study drug, or 30 days following the last dose of study drug if the subject initiates new anticancer 
therapy, whichever is earlier. Include any pregnancies that occur in the partner of a male study 
subject. Only report pregnancies that occur in a male subject’s partner if the estimated date of 
conception is after the male subject’s first study drug dose. Email or fax to the sponsor’s Drug 
Safety Department within 24 hours of becoming aware of a pregnancy. All pregnancies will be 
monitored for the full duration; all perinatal and neonatal outcomes should be reported. Infants 
should be followed for a minimum of 8 weeks. 
Collection of data on the CRF: All pregnancies (as described above) that occur within 30 days of 
the last dose of study drug will also be recorded on the Adverse Events and Pre-Existing 
Conditions CRF. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
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SAEs. Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.6.1.1) should be reported as SAEs. Such events must be reported within 
24 hours to the sponsor either by electronic media or paper. Electronic reporting procedures can 
be found in the electronic data capture data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent). 
Potential Drug-Induced Liver Injury 
The observation of the critical importance of altered liver function has been referred to 
informally as Hy’s Law (Reuben 2004). Hy’s Law can be used to estimate severity and the 
likelihood that a study drug may cause an increased incidence of severe hepatotoxicity. 
The absence of hepatotoxicity in clinical trials provides a limited predictive value for potential 
hepatotoxicity in the clinical setting(s) being studied. However, finding 1 Hy’s Law case in 
clinical trials is ominous; finding 2 cases is highly predictive of a potential for severe 
drug-induced liver injury (DILI). 
Definition 
Briefly, potential Hy’s Law cases include the following 3 components: 
1. Aminotransferase (ALT and/or AST) elevation >3 x ULN 
AND 
2. Total bilirubin >2 x ULN, without initial findings of cholestasis (i.e., elevated serum 
alkaline phosphatase), 
AND 
No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
Reporting Requirements 
Any potential Hy’s Law case should be handled as a suspected unexpected serious adverse 
reaction (SUSAR) associated with the use of the drug and reported promptly to the 
sponsor. 
Reporting should include all available information and should initiate close follow-up until 
complete resolution of the problem and completion of all attempts to obtain supplementary data. 
Follow-up for Abnormal Laboratory Results Suggesting Potential DILI 
In general, an increase of serum ALT or AST to >3 x ULN should be followed by repeat testing 
within 48 to 72 hours of serum ALT, AST, alkaline phosphatase, and total bilirubin, to confirm 
the abnormalities and to determine whether they are worsening. 
Appropriate medical assessment should be initiated to investigate potential confounding factors 
and alternative causes of hepatotoxicity. During this investigation, consider holding study drug. 
The guidance documents below are included in the study binder. 
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• FDA Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, 2009. 
• Health Canada Guidance Document; Pre-market Evaluation of Hepatotoxicity in 
Health Products, 2012. 
7.6.1.3. 
Reporting Periods for Adverse Events and Serious Adverse Events 
For LV monotherapy (Part A, Part B, Part C Arm 1), the safety reporting period for all AEs and 
SAEs is from study Day 1 (predose) through the EOT visit or 30 days after the last study 
treatment, whichever is later. For pembrolizumab and LV combination therapy (Part C Arms 2 
and 3), the reporting period for all AEs and SAEs is from study Day 1 (predose) through the 
EOT visit or 90 days after the last study treatment, whichever is later. However, all study 
protocol-related AEs are to be recorded from the time of informed consent. All SAEs that occur 
after the safety reporting period and are considered study treatment-related in the opinion of the 
investigator should also be reported to the sponsor. 
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or the 
subject dies or withdraws consent. All non-serious AEs will be followed through the safety 
reporting period. Certain non-serious AEs of interest may be followed until resolution, return to 
baseline, or study closure. In particular, these include AEs of peripheral neuropathy in all 
subjects. 
7.6.1.4. 
Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to the 
sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a minimum, 
the following should be included: 
• Subject number 
• Date of event onset 
• Description of the event 
Study treatment, if known 
The completed SAE form and SAE Fax Cover Sheet are to be emailed or faxed to the sponsor’s 
Drug Safety Department within 24 hours (see email or fax number specified on the SAE report 
form). 
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes available. 
7.6.1.5. 
Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 7.6.1.4). 
The sponsor will report all SAEs, including SUSARs, to regulatory authorities as required per 
local legislation or regulatory reporting requirements. 
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In the US, endpoints that assess disease-related mortality or major morbidity, as well as other 
SAEs that are not study endpoints but are known consequences of the underlying disease or 
condition that are anticipated to occur in the study population, should not be reported to the FDA 
as individual IND safety reports per the final rule amending the IND safety reporting 
requirements under 21 CFR 312.32 and the FDA’s guidance Safety Assessment for IND Safety 
Reporting Guidance for Industry (draft guidance December 2015). 
In this study, the SAEs that do not require individual IND safety reports to the FDA are 
progression of the underlying cancer. These anticipated SAEs will be reviewed periodically by 
the Seagen Drug Safety Department. If upon review, an SAE is occurring at a higher rate than 
that which would be expected for the study population, then an IND safety report for the SAE 
will be submitted to the FDA. 
7.6.1.6. 
Events of Clinical Interest 
Selected non-serious and serious AEs are also known as Events of Clinical Interest (ECIs) and 
must be reported to the Sponsor within 24 hours of awareness. 
ECIs for this trial include: 
1. An overdose of either study product, as defined in Section 5.5.2, and is not associated 
with clinical symptoms or abnormal laboratory results. 
2. An elevated AST or ALT lab value that is ≥3 x ULN, and an elevated total bilirubin lab 
value that is ≥2 x ULN and, at the same time, an alkaline phosphatase lab value that is 
<2 x ULN, as determined by way of protocol-specified laboratory testing, or unscheduled 
laboratory testing.* 
*Note: These criteria are based upon 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 trial site guidance for assessment and follow-up of 
these criteria can be found in the Investigator Trial File Binder (or equivalent). It may also be 
appropriate to conduct additional evaluation for an underlying etiology in the setting of 
abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline phosphatase that 
do not meet the criteria noted above. In these cases, the decision to proceed with additional 
evaluation will be made through consultation between the study investigators and the medical 
monitor. However, abnormalities of liver blood tests that do not meet the criteria noted above are 
not ECIs for this trial. 
7.6.2. 
Vital Signs 
Vital sign measurements are to include heart rate, systolic and diastolic blood pressure, and 
temperature. All vital signs should be measured after the subject has been sitting/resting. 
Part A: Vital signs will be measured on Day 1 of each cycle and recorded within 60 minutes 
prior to the start of LV infusion and within 30 minutes after completion of LV infusion.  
Part B: Vital signs will be measured on Day 1, Day 8, and Day 15 of each cycle and recorded 
within 60 minutes prior to the start of LV infusion and within 30 minutes after completion of LV 
infusion. 
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Part C: Vital signs will be measured on Day 1 and Day 8 of each cycle in Arm 1 and Arm 2, or 
on Day 1, Day 8, and Day 15 of each cycle in Arm 3. Vital signs will be recorded within 
60 minutes prior to the start of LV infusion, within 30 minutes after completion of LV infusion, 
and during infusion as clinically indicated (Arm 1). Vital signs should be measured within 
60 minutes prior to LV infusion, within 60 minutes prior to pembrolizumab infusion (Day 1 
only), within 2 hours of ending each infusion, and during infusion(s) as clinically indicated 
(Arm 2 and Arm 3). 
7.6.3. 
Clinical Laboratory Tests 
The following safety laboratory assessments will be performed by local laboratories at the 
designated time points (see Appendix A, Appendix B, Appendix C, and Appendix D) during the 
course of the study. Results of all clinical laboratory tests except pregnancy and PSA tests are to 
be submitted to iRIS. Instructions for submission to iRIS are located in the iRIS Manual.  
• Serum chemistry panel: including sodium, potassium, blood urea nitrogen/blood urea, 
creatinine, calcium, albumin, and magnesium. 
• Liver function tests including total bilirubin, alkaline phosphatase, ALT, and AST 
• CBC with differential: white blood count, hemoglobin, hematocrit and platelets; and 
the differential including, but not limited to, neutrophils, lymphocytes, and monocytes 
• PSA test (prostate cancer patients only) 
• Testosterone measurement (at Screening, prostate cancer patients only) 
• Blood glucose  
o Fasting blood glucose is only required at screening. If fasting blood glucose is 
elevated, a repeat assessment must be obtained. 
• HbA1c: if HbA1c is elevated during screening, HbA1c assessment must be repeated 
to confirm 
• The estimated GFR should be calculated using the MDRD equation as applicable, 
with serum creatinine (Scr) reported in mg/dL.  
 
GFR (mL/min/1.73 m2) = 175 x (Scr)–1.154 x (Age)–0.203 x (0.742 if female) x (1.212 if 
African American) 
• Thyroid function tests, including TSH, T3 or free T3, and free T4 (Part C Arm 2 and 
Arm 3). 
7.6.4. 
Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. For adult subjects only, 
measurements of height obtained within the prior 12 months may be utilized. 
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7.6.5. 
Pregnancy Testing 
For subjects of childbearing potential, a serum or urine β-hCG pregnancy test with sensitivity of 
at least 25 mIU/mL will be performed at baseline, within 3 days prior to Day 1 of each treatment 
cycle, at the EOT visit, and 24 weeks after EOT. A negative pregnancy result is required before 
the subject may receive LV on Day 1 of each 21-day cycle. Pregnancy tests may also be repeated 
as requested per institutional review board (IRB)/independent ethics committee (IEC) or if 
required by local regulations. 
7.7. 
Appropriateness of Measurements 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. 
Response will be assessed according to RECIST v1.1 (Appendix H) (Eisenhauer 2009), which 
are standardized criteria for evaluating response in solid tumors. The intervals of evaluation in 
this protocol are considered appropriate for disease management. 
Immunogenicity is commonly assessed for biologics; therefore, standard tests will be performed 
to detect the possible presence of specific antibodies to LV. PK assessments are also common in 
clinical studies to help characterize dose-exposure-response relationships. 
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8. 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1. 
Site Training and Monitoring Procedures 
A study manual with instructions for study compliance and CRF completion will be provided. 
Prior to the enrollment of subjects at the site, Seagen Inc. or its designated clinical and medical 
personnel will review the following items with the investigator and clinic staff: 
• The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes 
• Current IB /package insert 
• Recording and reporting AEs and SAEs 
• Enrollment goals and study timelines 
• The CRF completion process and source documentation requirements 
• Monitoring requirements 
• IRB/IEC review and approval process 
• Informed consent process 
• Good clinical practice guidelines and related regulatory documentation requirements 
• Key study team roles and responsibilities 
• Investigational product storage, accountability, labeling, dispensing and record 
keeping 
• Subject coding and randomization (if applicable) 
• Study samples/specimen collection, handling and shipping 
• Protocol compliance 
• Clinical study record keeping, document retention, and administrative requirements 
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment and 
workload at each site. During monitoring visits, the Seagen Inc. representative or designee will 
typically review regulatory documentation, CRFs, source documentation, and investigational 
product storage, preparation, and accountability. The CRFs will be reviewed for completeness, 
adherence to the provided guidelines, and accuracy compared to the source documents. The 
investigators must ensure that the monitor is allowed to inspect all source documents pertinent to 
study subjects, and must cooperate with the monitor to ensure that any problems noted in the 
course of the trial are resolved. The investigator must maintain a comprehensive and centralized 
filing system of all study-related documentation that is suitable for inspection by Seagen Inc. or 
its designated monitors and by quality assurance auditors, or representatives of regulatory 
authorities. 
8.2. 
Data Management Procedures 
Seagen Inc. will provide CRF Completion Guidelines for electronic CRF (eCRF) data entry. 
Study specific data management procedures will be maintained in the data management plan. 
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Queries resulting from edit checks and/or data verification procedures will be posted 
electronically in the eCRF. 
8.3. 
Access to Source Data 
The investigator will permit the sponsor’s representatives to monitor the study as frequently as 
the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect subject confidentiality are to be employed during 
monitoring. The CRFs and related source documents will typically be reviewed in detail by the 
monitor at each site visit. Original source documents or certified copies are needed for review. 
This review includes inspection of data acquired as a requirement for participation in this study 
and other medical records as required to confirm that the information contained in the CRFs, 
such as disease assessments, AEs, and concomitant medications, is complete and correct. Other 
study records, such as correspondence with the sponsor and the IRB/IEC and screening and drug 
accountability logs will also be inspected. All source data and study records must also be 
available for inspection by representatives of regulatory authorities and the IRB/IEC. 
8.4. 
Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
• The selection of qualified investigators and appropriate study centers. 
• Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
• Periodic monitoring visits by the designated monitor(s). 
• CRFs will be reviewed for accuracy and completeness during monitoring visits to the 
study centers and/or by centralized monitoring. Any discrepancies will be resolved 
with the investigator or designees as appropriate. 
8.5. 
Quality Assurance Procedures 
The Research and Development Quality group or its designee may conduct audits at the clinical 
site or other study-related facilities and organizations. Audit reports will be retained by the 
Research and Development Quality group of Seagen Inc. as part of the written record. 
8.6. 
Data Handling and Record Keeping 
8.6.1. 
Data Handling 
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data 
reported on the CRF that is derived from source documents should be consistent with the source 
documents or the discrepancies should be explained. 
Any change or correction to a CRF will be maintained in an audit trail within the electronic data 
capture system. Data changes may only be made by those individuals so authorized. The 
investigator should retain records of the changes and corrections, written and/or electronic. 
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8.6.2. 
Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation (such 
as original laboratory reports, inpatient or office patient records) for the maximum period 
required by the country and institution in which the study will be conducted, or for the period 
specified by Seagen Inc., whichever is longer. The investigator must contact Seagen Inc. prior to 
destroying any records associated with the study. If the investigator withdraws from the study 
(due to relocation, retirement, etc.), the records shall be transferred to a mutually agreed upon 
designee, such as another investigator or IRB/IEC. Notice of such transfer will be provided in 
writing to Seagen Inc. 
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9. 
DATA ANALYSIS METHODS 
9.1. 
Determination of Sample Size 
Up to approximately 414 subjects may be enrolled in the study, including up to 72 subjects in 
Part A (q3wk dosing) with each cohort having up to 12 subjects, up to 252 subjects in Part B 
(q1wk dosing) with each cohort having up to 30 subjects, and approximately 90 subjects in 
Part C (monotherapy or combination with pembrolizumab) with each arm having 30 subjects.  
Additional cohorts may also be added in future protocol amendments for additional indications, 
alternative dosing schedule, biopsy/biomarker analysis, and LV based combination therapy.  
The sample size is not based on power calculations for a formal hypothesis testing but is selected 
to provide a degree of characterization of commonly occurring AEs in the safety profile and/or a 
reasonable estimation precision of ORR. 
For a sample size of 30 subjects per cohort/arm, assuming confirmed ORR is between 10% and 
50%, and confirmed PSA response rate for CRPC is between 10% and 50%, the 2-sided 90% 
exact confidence interval (CI) are summarized below: 
Confirmed ORR* 
90% Exact CI (N=30) 
10% 
(3%, 24%) 
20% 
(9%, 36%) 
30% 
(17%, 47%) 
40% 
(25%, 57%) 
50% 
(34%, 66%) 
*Including confirmed PSA response rate for CRPC cohort 
This sample size of 30 subjects per cohort/arm would additionally provide the following 
probabilities of observing at least 1 patient having an AE, as summarized below.  
True AE Incidence Rate 
Probability of Observing at Least One Patient Having 
an AE  
(N=30) 
5% 
79% 
10% 
96% 
In Part B, the initial 12 subjects enrolled across the tumor cohorts per dose level will be 
evaluated for safety after the 12th patient completes the first cycle of treatment. The sample size 
of 12 allows for a reasonable likelihood of observing a given AE in at least 1 subject even when 
the incidence of the specific AE is low. 
The table below shows the probability of observing an AE in at least 1 subject out of 12 subjects 
for different underlying incidence of AEs. 
 
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Underlying AE Incidence 
Probability of Observing the AE in 1 or More Subjects 
Out of 12 Subjects 
1% 
11% 
5% 
46% 
10% 
72% 
9.2. 
Study Endpoint Definitions 
9.2.1. 
Confirmed ORR 
Confirmed ORR is defined as the proportion of subjects who achieve a confirmed CR or PR 
according to RECIST v1.1 as assessed by the investigator. Subjects who do not have at least 
2 post-baseline response assessments (initial response and confirmation scan) will be counted as 
non-responders. 
9.2.2. 
Confirmed PSA Response Rate 
Confirmed PSA response rate is defined as the proportion of subjects with a reduction from 
baseline PSA level of at least 50%, measured twice ≥3 weeks apart. 
9.2.3. 
Disease Control Rate 
DCR is defined as the proportion of subjects who achieve a confirmed CR or PR according to 
RECIST v1.1 as assessed by the investigator, or meet the SD criteria at least once after start of 
study treatment at a minimum interval of 5 weeks or 7 weeks for prostate cancer subjects. 
Subjects who do not have at least 1 post-baseline response assessment will be counted as 
non-responders. 
9.2.4. 
Duration of Response 
DOR is defined as the time from the first documentation of objective response (CR or PR that is 
subsequently confirmed) to the first documentation of PD or death due to any cause, whichever 
comes first. 
DOR data will be censored as described below: 
• Subjects who do not have PD and are still on study at the time of an analysis will be 
censored at the date of last disease assessment documenting absence of PD. 
• Subjects who started a new anticancer treatment prior to documentation of PD will be 
censored at the date of last disease assessment prior to the start of new treatment. 
• Subjects who are removed from the study prior to documentation of PD will be 
censored at the date of last disease assessment documenting absence of PD. 
DOR will only be calculated for subjects who achieve a confirmed CR or PR as measured by 
RECIST v1.1 for all tumors. 
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PSA-DOR is defined as the time from the first documentation of PSA response (subsequently 
confirmed at least 3 weeks apart) to the first documentation of PSA progression or death due to 
any cause, whichever comes first.  
9.2.5. 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the time from the start of study treatment to the first 
documentation of PD by RECIST v1.1 or clinical PD or by PSA progression (prostate cancer 
cohort) or death due to any cause, whichever comes first. PSA-PFS is defined in Section 9.2.7. 
The same censoring rules as outlined in Section 9.2.4 for DOR will be applied to PFS. Subjects 
lacking an evaluation of tumor response after their first dose of study drug will have their event 
time censored at Day 1. 
9.2.6. 
Overall Survival 
OS is defined as the time from the start of study treatment to date of death due to any cause. In 
the absence of death, survival time will be censored at the last date the subject is known to be 
alive (i.e., date of last contact). 
9.2.7. 
Prostate-Specific Antigen Progression-Free Survival 
PSA-PFS is defined as the time from the start of study treatment to first occurrence of PSA 
progression or death, whichever comes first. 
9.3. 
Statistical and Analytical Plans 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the statistical analysis plan (SAP). A change to the data analysis methods described in 
the protocol will require a protocol amendment only if it alters site conduct (eg, adding baseline 
assessments to define a subgroup). The SAP will be finalized prior to database lock. Any key 
changes to the methods described in the final SAP will be described in the clinical study report. 
9.3.1. 
General Considerations 
In general, descriptive statistics will be presented that include the number of observations, mean, 
median, standard deviation, minimum and maximum for continuous variables, and the number 
and percentages per category for categorical variables. 
The 2-sided 90% exact CI using Clopper-Pearson method (Clopper 1934) will be calculated for 
the response rates where applicable (eg, ORR). 
For time-to-event endpoints, the median survival time will be estimated using the Kaplan-Meier 
method; the associated 90% CI will be calculated based on the complementary log-log 
transformation (Collett 1994). 
9.3.1.1. 
Randomization and Blinding 
This is an open-label study. Blinding will not be performed. Cohorts in Part A and Part B are 
single-arm. The cohort in Part C has 3 randomized arms. 
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For Part C, approximately 90 subjects will be randomized to 1 of the 3 arms with 30 subjects per 
arm: Arm 1 (monotherapy 2q3wk), Arm 2 (2q3wk combination with pembrolizumab), Arm 3 
(q1wk combination with pembrolizumab). The randomization ratio will be 2:1:1 until Arm 1 
enrolls 30 subjects. This will ensure that Arm 1 reaches the target enrollment sooner. Thus, of 
the first 60 subjects, 30 subjects will be enrolled in Arm 1, 15 subjects will be enrolled in Arm 2 
and 15 subjects will be enrolled in Arm 3. Afterwards, the remaining subjects will be 
randomized in a 1:1 ratio to either Arm 2 or Arm 3. Randomization will be stratified according to 
BRAF mutational status (wild-type versus mutated).  
9.3.1.2. 
Adjustments for Covariates 
No adjustments for covariates are planned in the analyses. 
9.3.1.3. 
Handling of Dropouts and Missing Data 
Missing data will not be imputed unless otherwise specified. Missing AE start date and/or end 
date will be imputed while calculating duration of events and treatment-emergent status. Missing 
subsequent anticancer treatment start date will be imputed while deriving the time-to-event 
endpoints as applicable. Censoring rules will be applied for the analysis of time-to-event 
endpoints. Details will be provided in the SAP.  
9.3.1.4. 
Multicenter Studies 
There are multiple centers in this study, however it is not anticipated that any center will accrue 
enough subjects to warrant an analysis by center. 
9.3.1.5. 
Multiple Comparisons and Multiplicity 
No multiple comparisons are planned in this study. 
9.3.1.6. 
Data Transformations and Derivations 
Time variables based on 2 dates (eg, start date and end date) will be calculated as (end date – 
start date +1 [in days]) unless otherwise specified in the planned analysis section. 
Baseline values used in all statistical analyses will be the most recent non-missing measurement 
prior to the first dose of study drug unless otherwise specified. 
9.3.1.7. 
Analysis Sets 
The full analysis set (FAS) includes all subjects who received any amount of study drug. All 
efficacy analyses will be based on the FAS. 
The safety analysis set includes all subjects who received any amount of study drug, and thus is 
equivalent to the FAS. All safety analyses will be based on the safety analysis set. 
The efficacy evaluable analysis set includes subjects who received any amount of study drug and 
had at least one post-baseline disease assessment per RECIST v1.1 or had clinical progression 
per investigator judgment or discontinued from study.  
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The PSA evaluable analysis set includes subjects in the prostate cancer cohort who received any 
amount of study drug and had both baseline and at least one evaluable post-baseline PSA 
measurements. 
9.3.1.8. 
Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. Detailed 
methodology will be provided in the SAP. 
9.3.1.9. 
Timing of Analyses 
The primary analysis will be conducted when all treated subjects in a cohort have been followed 
for at least 6 months or come off study, whichever comes first. Subsequent data cutoff dates may 
be defined to allow for more precise estimates of time-to-event endpoints. 
Interim analysis for futility will be performed separately for each cohort in Part A and Part B 
after approximately 12 subjects of a given cohort have been treated and are efficacy evaluable 
post-baseline. 
9.3.2. 
Subject Disposition 
An accounting of study subjects by disposition will be tabulated and the number of subjects in 
each analysis set will be summarized. Subjects who discontinue study treatment and subjects 
who withdraw from the study will be summarized with reason for discontinuation or withdrawal. 
9.3.3. 
Subject Characteristics 
Demographics and other baseline characteristics will be summarized by cohort for the FAS. 
Details will be provided in the SAP. 
9.3.4. 
Treatment Administration 
Treatment administration will be summarized by cohort for the safety analysis set. Summary 
statistics for duration of therapy, number of cycles per subject, and the number and percentage of 
subjects treated at each cycle will be presented. Details will be provided in the SAP. 
9.3.5. 
Efficacy Analyses 
The primary analysis of efficacy endpoints will be based on the FAS. Supplemental analysis of 
efficacy endpoints may be performed using the efficacy evaluable analysis set. For the prostate 
cancer cohort, the confirmed PSA response rate and PSA-PFS will be based on the PSA 
evaluable analysis set. 
9.3.5.1. 
Primary Efficacy Analyses 
The primary endpoint of this study for all tumor types is the confirmed ORR per investigator 
assessment. The ORR is defined as the proportion of subjects who achieve a confirmed CR or 
PR according to RECIST v1.1. The ORR of each cohort and its exact 2-sided 90% CI using the 
Clopper-Pearson method (Clopper 1934) will be calculated. 
For prostate cancer, confirmed PSA response per investigator assessment is another primary 
endpoint. The confirmed PSA response is defined as a reduction from baseline PSA level of at 
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least 50%, measured twice ≥3 weeks apart. The confirmed PSA response rate and its exact 
2-sided 90% CI using the Clopper-Pearson method (Clopper 1934) will be calculated. 
9.3.5.2. 
Secondary Efficacy Analyses 
The DCR will be estimated for each cohort and the 90% CIs will be calculated using the 
Clopper-Pearson method. 
The DOR, PFS, and OS for each cohort, PSA-DOR and PSA-PFS for the prostate cancer cohort 
will be estimated using the Kaplan-Meier methodology, and the medians and associated 90% CIs 
will be calculated. Kaplan-Meier plots will be provided as appropriate.  
9.3.6. 
Pharmacokinetic and Immunogenicity Analyses 
LV (ADC), total antibody, and MMAE concentrations will be summarized with descriptive 
statistics at each PK sampling time point. Selected PK parameters for LV, total antibody, and 
MMAE will be estimated by noncompartmental analysis and summarized using descriptive 
statistics. These data may be combined with PK data from other clinical trials with LV for 
population PK and exploratory exposure-response analyses. 
The incidence of ATA will be summarized using the safety analysis set. 
9.3.7. 
Biomarker Analyses 
Relationships of biomarker parameters (eg, baseline values, absolute and relative changes from 
baseline) to efficacy, safety, and PK parameters will be explored. Relationships and associated 
data that are determined to be of interest will be summarized. Details will be described separately 
in the SAP or Biomarker Analysis Plan. 
9.3.8. 
Safety Analyses 
All safety analyses will be performed by cohort and overall using the safety analysis set. 
9.3.8.1. 
Extent of Exposure 
Duration of treatment, number of cycles, total dose, and dose intensity will be summarized. Dose 
modifications, including dose delay, dose reduction, and unplanned dose adjustment, will be 
summarized. Details will be provided in the SAP. 
9.3.8.2. 
Adverse Events 
An overview of AEs will provide a tabulation of the incidence of all AEs, TEAEs, 
treatment-related AEs, Grade 3 and higher TEAEs, SAEs, treatment-related SAEs, deaths, and 
AEs leading to study treatment discontinuation. AEs will be defined as treatment emergent if 
they are newly occurring or worsen following study treatment. 
TEAEs will be listed and summarized by Medical Dictionary for Regulatory Activities 
(MedDRA), preferred term, severity, and relationship to study drug. In the event of multiple 
occurrences of the same AE with the same preferred term in 1 subject, the AE will be counted 
once as the occurrence. AEs leading to premature discontinuation of study drug will be 
summarized and listed in the same manner. 
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9.3.8.3. 
Deaths and Serious Adverse Events 
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal outcome 
will be listed. 
9.3.8.4. 
Clinical Laboratory Results 
Summary statistics of laboratory results and changes from baseline will be tabulated by 
scheduled visit. Grading of laboratory values will be assigned programmatically per the NCI 
CTCAE v5.0. Shift tables comparing the worst post-baseline to baseline CTCAE grade will be 
presented. Laboratory values will be listed with grade per CTCAE and flagged when values are 
outside the normal reference range. 
9.3.8.5. 
Other Safety Analyses 
Vital Signs 
Vital signs data will be listed. Summary statistics of vital signs and change from baseline may be 
tabulated where appropriate. 
ECOG Status 
ECOG status will be summarized for each visit. Shifts from baseline to the best and worst 
postbaseline score may be tabulated. 
9.3.9. 
Interim Analyses 
Interim analysis for futility will be performed separately for each cohort in Part A and Part B 
after approximately 12 subjects of a given cohort have been treated with a specific LV dose and 
schedule (LV q3wk at 2.5 mg/kg, LV q1wk at 1.0 mg/kg, or LV q1wk at 1.25 mg/kg 
[Section 3.1]) and are efficacy evaluable post-baseline. Enrollment to each cohort may be held 
after approximately 12 subjects for interim futility analysis of the respective cohorts. 
The Bayesian predictive probability of success (PPoS) approach will be used to determine the 
futility criteria (Lee 2008). At the time of each interim analysis, the PPoS will be calculated. 
PPoS is the probability of achieving “success” should the cohort be continued to the maximum 
sample size of 30 given the data observed at interim, and a cohort is considered “success” if the 
posterior probability that the ORR exceeds the response rate of current standard of care 
(i.e., 15% for SCLC, 10% for NSCLC-squamous, 15% for NSCLC-nonsquamous, 10% for 
HNSCC, 10% for esophageal-squamous, 15% for gastric and GEJ adenocarcinoma, 10% for 
melanoma, and 30% for CRPC as referenced in Section 3.1) is greater than 90%.  
The ORR observed at interim will be counted as a response for the calculation of PPoS. Table 20 
summarizes the PPoS based on the number of responses observed among the first 12 subjects. 
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Table 20: 
PPoS based on response among the first 12 subjects 
No. of 
responsesa 
among the 
first 
12 subjects 
Predictive Probability of Success 
SCLC 
(p0=15%) 
NSCLC-squamous 
(p0=10%) 
NSCLC-nonsquamous 
(p0=15%) 
HNSCC 
(p0=10%) 
Esophageal-squamous 
(p0=10%) 
Gastric or GEJ 
adenocarcinoma 
(p0=15%) 
Melanoma 
(p0=10%) 
CRPC 
(p0=30%) 
0 
0.05% 
0.2% 
0.05% 
0.2% 
0.2% 
0.05% 
0.2% 
0.0007% 
1 
2% 
8% 
2% 
8% 
8% 
2% 
8% 
0.05% 
2 
16% 
36% 
16% 
36% 
36% 
16% 
36% 
0.8% 
3 
45% 
73% 
45% 
73% 
73% 
45% 
73% 
6% 
4 
77% 
94% 
77% 
94% 
94% 
77% 
94% 
21% 
5 
94% 
100% 
94% 
100% 
100% 
94% 
100% 
48% 
p0 is the response rate of current standard of care of each cohort 
a Including both confirmed and unconfirmed CR or PR observed at interim 
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If the PPoS is <10% (i.e., ≤1 response among the first 12 subjects, or ≤3 responses among the 
first 12 prostate cancer subjects), the data indicates that it is unlikely the ORR will be better than 
the response rate of current standard of care at the end of the cohort given interim results and the 
cohort could be stopped early due to insufficient activity. On the other hand, if the PPoS is 
>90%, the data suggests that if the same trend continues, there is a high probability to conclude a 
“success” at the end of the cohort. The PFS and OS will also be evaluated at the time of the 
interim analysis. Based on the efficacy and safety data, together with the PPoS, a cohort may be 
stopped early by the sponsor.  
The predictive probability method allows the PPoS be computed at any interim time and 
provides flexibility in monitoring treatment activity continuously after the initial interim 
analysis. 
In addition to the interim analysis for futility, interim data from the study may be presented at 
scientific meetings such as the annual meetings of the ASCO and the European Society for 
Medical Oncology. 
Continuous monitoring of the benefit-risk profile will be conducted and continuation of 
enrollment to the cohort may be altered depending on the benefit-risk profile. 
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10. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 (R2); FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil 2013), and all applicable regulatory requirements. 
10.1. 
Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to the 
subject in simple terms using the IRB/IEC approved informed consent document and for 
ensuring subjects are re-consented when the informed consent document is updated during the 
study, if required. The investigator will ensure that written informed consent is obtained from 
each subject, or legally acceptable representative, if applicable to this study, by obtaining the 
signature and date on the informed consent document prior to the performance of protocol 
evaluations or procedures. 
For phase 1 studies, it is preferable for a subject to provide consent themselves. If informed 
consent is obtained from a legally acceptable representative for a subject who is unable to 
provide informed consent at study entry (if applicable), but the subject is later able to provide 
informed consent, the investigator must obtain written informed consent from the subject. 
10.2. 
Ethical Review 
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at the 
investigative site(s). The name and address of the reviewing ethics committee are provided in the 
investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
• Protocol and amendments 
• Informed consent document and updates 
• Clinical IB and updates 
• Relevant curricula vitae, if required 
• Required safety and SAE reports 
• Any additional submissions required by the site’s IRB/IEC 
The investigator must provide the following documentation to the sponsor or its designee: 
• The IRB/IEC periodic (eg, quarterly, annual) re-approval of the protocol. 
• The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
• The IRB/IEC receipt of safety and SAE reports, as appropriate. 
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10.3. 
Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in the 
applicable guidelines on good clinical practice, and all applicable local and/or regional laws, 
rules, and regulations. 
10.3.1. 
Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators and 
name and address of the research facilities are included in the investigator file. 
10.3.2. 
Protocol Amendments and Study Termination 
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate an 
immediate hazard to a study subject) must be approved by the sponsor prior to seeking approval 
from the IRB/IEC, and prior to implementing. The investigator is responsible for enrolling 
subjects who have met protocol eligibility criteria. Protocol deviations must be reported to the 
sponsor and the local IRB/IEC in accordance with IRB/IEC policies. 
The sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination. 
10.4. 
Study Documentation, Privacy and Records Retention 
To protect the safety of participants in the study and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study. If requested, the 
investigator will provide the sponsor, its licensees and collaborators, applicable regulatory 
agencies, and applicable IRB/IEC with direct access to original source documents or certified 
copies. 
Records containing subject medical information must be handled in accordance with local and 
national laws, rules, and regulations and consistent with the terms of the subject authorization 
contained in the informed consent document for the study (the Authorization). Care should be 
taken to ensure that such records are not shared with any person or for any purpose not 
contemplated by the Authorization. Furthermore, CRFs and other documents to be transferred to 
the sponsor should be completed in strict accordance with the instructions provided by the 
sponsor, including the instructions regarding the coding of subject identities. 
In compliance with local and/or regional regulations, this trial may be registered and trial results 
may be posted on public registries, such as ClinicalTrials.gov. 
10.5. 
Clinical Trial Agreement 
Payments by the sponsor to investigators and institutions conducting the trial, requirements for 
investigators’ insurance, the publication policy for clinical trial data, and other requirements are 
specified in the clinical trial agreement. 
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11. 
REFERENCES 
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Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor 
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Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic 
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Cao AT, Higgins S, Stevens N, Gardai SJ, Sussman D. Additional mechanisms of action of 
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Cao AT, Law CL, Gardai SJ, Heiser RA. Brentuximab vedotin-driven immunogenic cell death 
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Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with 
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Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
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Collett D. Interval-censored survival data. Modelling survival data in medical research. London, 
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Crawford J, Caserta C, Roila F, ESMO Guidelines Working Group. Hematopoietic growth 
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Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
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melanoma tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80. 
 
Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28(29):4531-8. 
 
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Dressman MA, Walz TM, Lavedan C, et al. Genes that co-cluster with estrogen receptor alpha in 
microarray analysis of breast biopsies. Pharmacogenomics J. 2001;1(2):135-41. 
 
Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-
myeloablative but lymphodepleting chemotherapy for the treatment of patients with 
refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-57. 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev. 2010;236:219-42. 
 
Gardai SJ, Epp A, Law CL. Brentuximab vedotin-mediated immunogenic cell death. Cancer Res. 
2015;75(15 Suppl):Abstract 2469. 
 
George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. 
Nature. 2015;524(7563):47-53. 
 
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2005;23:515-48. 
 
Han H, Diab S, Alemany C, et al. Open label phase 1b/2 study of ladiratuzumab vedotin in 
combination with pembrolizumab for first-line treatment of patients with unresectable 
locally-advanced or metastatic triple-negative breast cancer. Cancer Res. 2020;80(4 
Suppl):Abstract PD1-06. 
 
Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies 
potentiates cancer therapeutic immunity. Cancer Res. 2005;65(3):1089-96. 
 
Huang L, Wang R, Xie K, et al. A HER2 target antibody drug conjugate combined with anti-PD-
(L)1 treatment eliminates hHER2+ tumors in hPD-1 transgenic mouse model and 
contributes immune memory formation. Breast Cancer Res Treat. 2022;191(1):51-61. 
 
Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous CD4+ T 
cells against NY-ESO-1. N Engl J Med. 2008;358(25):2698-703. 
 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin Trials. 
2008;5(2):93-106. 
 
Liu BA, Olson D, Snead K, et al. Enfortumab vedotin, an anti-Nectin-4 ADC demonstrates 
bystander cell killing and immunogenic cell death anti-tumor activity mechanisms of 
action in urothelial cancers. Cancer Res. 2020;80(16 Suppl):Abstract 5581. 
 
Manning DL, Daly RJ, Lord PG, Kelly KF, Green CD. Effects of oestrogen on the expression of 
a 4.4 kb mRNA in the ZR-75-1 human breast cancer cell line. Mol Cell Endocrinol. 
1988;59(3):205-12. 
 
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Manning DL, Robertson JF, Ellis IO, et al. Oestrogen-regulated genes in breast cancer: 
association of pLIV1 with lymph node involvement. Eur J Cancer. 1994;30A(5):675-8. 
 
Modi S, Pusztai L, Forero A, et al. Phase 1 study of the antibody-drug conjugate SGN-LIV1A in 
patients with heavily pretreated triple-negative metastatic breast cancer. Cancer Res. 
2018;78(Suppl 4):Abstract PD3-14. 
 
Muller P, Kreuzaler M, Khan T, et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast 
cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med. 
2015;7(315):315ra188. 
 
Muller P, Martin K, Theurich S, et al. Microtubule-depolymerizing agents used in antibody-drug 
conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol 
Res. 2014;2(8):741-55. 
 
Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. 
Clin Cancer Res. 2007;13(7):2151-7. 
 
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell 
receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71. 
 
Olson DJ, Eroglu Z, Brockstein B, et al. Pembrolizumab plus ipilimumab following anti-PD-
1/L1 failure in melanoma. J Clin Oncol. 2021;39(24):2647-55. 
 
Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell 
activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543-53. 
 
Pilon-Thomas S, Mackay A, Vohra N, Mule JJ. Blockade of programmed death ligand 1 
enhances the therapeutic efficacy of combination immunotherapy against melanoma. J 
Immunol. 2010;184(7):3442-9. 
 
Pusztai L, Lu H, Hale C, et al. Systemic administration of ladiratuzumab vedotin alone or in 
combination with pembrolizumab results in significant immune activation in the tumor 
microenvironment in metastatic breast cancer patients. J Immunother Cancer. 
2020;8(Suppl 3):A198. 
 
Reuben A. Hy's law. Hepatology. 2004;39(2):574-8. 
 
Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25. 
 
Robert C, Ribas A, Schachter J, et al. Pembrolizumab versus ipilimumab in advanced melanoma 
(KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, 
controlled, phase 3 study. Lancet Oncol. 2019;20(9):1239-51. 
 
Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant 
Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials 
Working Group 3. J Clin Oncol. 2016;34(12):1402-18. 
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Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-52. 
 
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the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 
2004;574(1-3):37-41. 
 
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: 
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2015;33(28):3199-212. 
 
Spranger S, Koblish HK, Horton B, et al. Mechanism of tumor rejection with doublets of CTLA-
4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of 
CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 
2014;2:3. 
 
Stagg J, Loi S, Divisekera U, et al. Anti-ErbB-2 mAb therapy requires type I and II interferons 
and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci USA. 
2011;108(17):7142-7. 
 
Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy 
for squamous cell carcinoma. Cancer Res. 2003;63(19):6501-5. 
 
Sussman D, Nesterova A, Westendorf L, et al. LIV-1 antibody-drug conjugate: a novel 
therapeutic agent for breast and prostate cancer. Cancer Res. 2011;71(8):Abstract 3620. 
 
Sussman D, Smith LM, Anderson ME, et al. SGN-LIV1A: a novel antibody-drug conjugate 
targeting LIV-1 for the treatment of metastatic breast cancer. Mol Cancer Ther. 
2014;13(12):2991-3000. 
 
Taylor KM, Morgan HE, Johnson A, Hadley LJ, Nicholson RI. Structure-function analysis of 
LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc 
transporters. Biochem J. 2003;375(Pt 1):51-9. 
 
Thuss-Patience PC, Shah MA, Ohtsu A, et al. Trastuzumab emtansine versus taxane use for 
previously treated HER2-positive locally advanced or metastatic gastric or gastro-
oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-
label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18(5):640-53. 
 
Tozlu S, Girault I, Vacher S, et al. Identification of novel genes that co-cluster with estrogen 
receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse 
transcription-PCR approach. Endocr Relat Cancer. 2006;13(4):1109-20. 
 
Tsai M, Han HS, Montero AJ, et al. Weekly ladiratuzumab vedotin monotherapy for metastatic 
triple-negative breast cancer. Ann Oncol. 2021;32(Suppl 5):S474-5. 
 
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Unno J, Satoh K, Hirota M, et al. LIV-1 enhances the aggressive phenotype through the 
induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells. 
Int J Oncol. 2009;35(4):813-21. 
 
Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010;37(5):430-9. 
 
Yau C, Brown-Swigart L, Asare S, et al. LIV-1 expression in primary breast cancers in the I-
SPY 2 trial. Cancer Res. 2019;79(Suppl 4):Abstract P3-10-14. 
 
Zhang X, Schwartz JC, Guo X, et al. Structural and functional analysis of the costimulatory 
receptor programmed death-1. Immunity. 2004;20(3):337-47. 
 
Zhu Y, Qiu P, Ji Y. TCGA-assembler: open-source software for retrieving and processing TCGA 
data. Nat Methods. 2014;11(6):599-600. 
 
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APPENDIX A. 
SCHEDULE OF EVENTS FOR SCREENING/BASELINE 
(PARTS A, B, AND C) 
 
Assessment 
Screening/Baseline 
 
Day (D) 
D –28 to 1 
D –7 to 1 
 
Visit window 
 
 
Screening/ Baseline 
Assessments  
Inclusion/Exclusion, medical history 
X 
 
Informed consent 
X 
 
Tumor biopsy 
Xa 
 
Pregnancy test (females of childbearing potential only) 
 
Xb 
HbA1c and fasting blood glucose 
Xc 
 
PSA (prostate cancer subjects) 
X 
 
Testosterone (prostate cancer subjects) 
X 
 
Brain CT or MRI 
X 
 
Safety Assessments 
Physical exam 
 
Xd 
Weight 
 
X 
CBC with differential 
 
X 
Chemistry panel and liver function tests 
 
X 
Thyroid function teste 
X 
 
eGFR 
 
X 
Vital signs 
 
X 
ECOG performance status 
 
X 
Concomitant medications 
Related to study 
procedures 
AE collection 
Response Baseline 
Assessments 
CT/MRIf 
X 
 
 
CT/MRI for prostate cancer subjectsf 
X 
 
 
Bone scan for prostate cancer subjectsf 
X 
 
a Archived sample or fresh biopsy if archived sample is not available, see Section 6; (fine-needle aspiration and 
bone samples are not suitable). 
b Pregnancy test must be performed within 3 days prior to C1 Day 1. 
c If either baseline HbA1c or baseline fasting glucose is elevated, repeat assessments must be obtained, see 
Section 7.6.3. 
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d Include assessment of height. 
e Part C, Arm 2 and 3 only. See Section 7.6.3 . 
f See Section 7.2.1 for tumor cohort specific imaging requirements. Submit copies of images to sponsor’s designee 
for central review (see Section 6.6). 
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APPENDIX B. 
SCHEDULE OF EVENTS FOR TREATMENT (Q3WK DOSING; PART A) 
 
Assessment 
Enrollment 
Cycle 1 
Cycle 2+ 
EOT 
F/U 
Day 
Within 7D  
of 1st dose 
D1 
D3 
D8 
D15 
D1 
D3 
D8 
D15 
Within 30–37D 
of last dosea 
Every 6 or 
12 weeks 
Visit window 
 
± 2db 
+ 1d 
± 2d 
± 2d 
± 2d 
+ 1d 
± 2d 
± 2d 
 
± 3d or 
± 7d 
 
Confirm subject meets dosing criteria 
 
X 
 
 
 
X 
 
 
 
 
 
Treatment 
LV administration 
Submit eligibility confirmation to  
sponsor prior to treatment 
X 
 
 
 
X 
 
 
 
 
 
G-CSF 
 
Xc 
 
 
 
Xc 
 
 
 
 
Safety 
Assessments 
Pregnancy test  
(females of childbearing potential only) 
Xd 
 
 
 
X 
 
 
 
X 
Xe 
HbA1c 
 
 
 
 
 
 
 
 
X 
 
Physical exam 
Xd 
 
X 
X 
X 
 
 
 
X 
Xf 
Weight 
Xd 
 
 
 
X 
 
 
 
X 
 
CBC with differential 
Xd 
 
X 
X 
X 
 
Xg 
Xg 
X 
 
Chemistry panel and liver function tests 
Xd 
 
X 
X 
X 
 
Xg 
Xg 
X 
 
Random blood glucose 
X 
 
 
 
X 
 
 
 
 
 
Vital signsk 
X 
 
 
 
X 
 
 
 
X 
 
ECOG performance status 
Xd 
 
 
 
X 
 
 
 
X 
 
Concomitant medications 
Related to 
study 
procedures 
Collect from Day 1 predose to EOT or 30 days post last dose, whichever is later 
 
AE collection 
Biomarker 
Assessments 
Blood samples for biomarker assessment 
(see Section 7.4.1) 
 
See Table 17 
 
Tumor biopsy for research (see 
Section 7.4.2) 
 
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Assessment 
Enrollment 
Cycle 1 
Cycle 2+ 
EOT 
F/U 
Day 
Within 7D  
of 1st dose 
D1 
D3 
D8 
D15 
D1 
D3 
D8 
D15 
Within 30–37D 
of last dosea 
Every 6 or 
12 weeks 
Visit window 
 
± 2db 
+ 1d 
± 2d 
± 2d 
± 2d 
+ 1d 
± 2d 
± 2d 
 
± 3d or 
± 7d 
PK/ATA 
Samples for PK testing (see Section 7.3) 
 
See Table 17 
 
Samples for ATA testing (see Section 7.3) 
 
Response 
Assessments 
CT/MRIh 
 
Every 6 weeks (± 3 days) for the first 12 months, then every 
12 weeks (± 7 days) thereafteri 
Xj 
Xf 
Survival follow-up contact 
 
 
Xf 
D=day, F/U=follow-up. 
a EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT evaluations are completed before 30 days following the last study treatment, 
conduct a phone screen 30–37 days following the subject’s last study treatment to ensure that no changes in AE profile have occurred. 
b Visit window does not apply to C1, Day 1. 
c For subjects receiving >200 mg LV per infusion (weigh >80 kg at baseline), prophylactic G-CSF administration is required after LV administration (may begin on Days 2, 
3, or 4). If pegfilgrastim is used, a one-time dose per cycle is recommended. If daily myeloid growth factor support is used, treat for least 5–7 days or until the ANC is 
>1000/mm3 (≤ Grade 2); see Section 5.4.1. 
d Not required in Cycle 1 if baseline was assessed within 3 days prior to first dose of study drug. 
e Only tested once at 24 weeks after last dose of LV. 
f Every 6 weeks (± 3 days) for the first 12 months after the first dose of LV, then every 12 weeks (± 7 days) thereafter. Continue to assess until disease progression. After a 
year of follow-up, reducing scanning frequency to institutional standard of care 
g Required only for Cycle 2.  
h See Section 7.2.1 for tumor cohort-specific imaging requirements. Submit copies of images to independent review facility. 
i If required, it is recommended that scans not be scheduled on the dosing day. It is recommended that scans done on the same day as Day 1 of subsequent cycles be completed 
and reviewed prior to infusion with LV. 
j Not required if conducted within 4 weeks prior to EOT. 
k Vital signs to be within 60 minutes prior to the start of LV infusion and within 30 minutes after completion of LV infusion. 
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APPENDIX C. 
SCHEDULE OF EVENTS FOR TREATMENT (Q1WK DOSING; PART B) 
 
Assessment 
Enrollment 
Cycle 1 
Cycle 2+ 
EOT 
F/U 
Day 
Within 7D 
of 1st dose 
D1 
D3 
D8 
D15 
D1 
D3 
D8 
D15 
Within 
30–37D 
of last 
dosea 
Every 6 
or 
12 weeks  
Visit window 
 
± 2db 
+ 1d 
± 2d 
± 2d 
± 2d 
+ 1d 
± 2d 
± 2d 
 
± 3d or 
± 7d 
 
Confirm subject meets dosing criteria 
 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
PSA testc 
 
Xd 
 
 
 
X 
 
 
 
X 
X 
Treatment 
LV administration 
Submit eligibility confirmation to  
sponsor prior to treatment 
X 
 
Xk 
Xk 
Xk 
 
Xk 
Xk 
 
 
Safety 
Assessments 
Pregnancy test (serum or urine; females of 
childbearing potential only) 
Xd 
 
 
 
X 
 
 
 
X 
Xe 
HbA1c 
 
 
 
 
 
 
 
 
X 
 
Physical exam 
Xd 
 
X 
X 
X 
 
 
 
X 
Xf 
Weight 
Xd 
 
 
 
X 
 
 
 
X 
 
CBC with differential 
Xd 
 
Xm 
Xm 
X 
 
Xm 
Xm 
X 
 
Serum chemistry panel and liver function 
tests 
Xd 
 
Xm 
Xm 
X 
 
Xm 
Xm 
X 
 
Random blood glucosej 
X 
 
Xj 
Xj 
X 
 
Xj 
Xj 
 
 
Vital signsl 
X 
 
X 
X 
X 
 
X 
X 
X 
 
ECOG performance status 
Xd 
 
 
 
X 
 
 
 
X 
 
Concomitant medications 
Related to 
study 
procedures 
Collect from Day 1 predose to EOT or 30 days post last dose, whichever is later 
 
AE collection 
Biomarker 
Assessments 
Blood samples for biomarker assessment  
(see Section 7.4.1) 
 
See Table 18 
 
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Assessment 
Enrollment 
Cycle 1 
Cycle 2+ 
EOT 
F/U 
Day 
Within 7D 
of 1st dose 
D1 
D3 
D8 
D15 
D1 
D3 
D8 
D15 
Within 
30–37D 
of last 
dosea 
Every 6 
or 
12 weeks  
Visit window 
 
± 2db 
+ 1d 
± 2d 
± 2d 
± 2d 
+ 1d 
± 2d 
± 2d 
 
± 3d or 
± 7d 
Tumor biopsy for research (see 
Section 7.4.2) 
 
PK/ATA 
Samples for PK testing (see Section 7.3) 
 
See Table 18 
 
Samples for ATA testing (see Section 7.3) 
 
Response 
Assessments 
CT/MRI for non-prostate cancer subjectsg 
 
Every 6 weeks (±3 days) for the first 12 months, then every 
12 weeks (±7 days) thereafterh 
Xi 
Xf 
CT/MRI for prostate cancer subjectsg 
 
Every 8 weeks (±7 days) for the first 24 weeks, then every 12 weeks 
(±7 days) thereafterh 
Xi 
Xf 
Bone scan (prostate cancer subjects only)g 
 
Every 8 weeks (±7 days) for the first 24 weeks, then every 12 weeks 
(±7 days) thereafterh 
Xi 
Xf 
Survival follow-up contact 
 
 
Xf 
D=day, F/U=follow-up. 
a EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT evaluations are completed before 30 days following the last study treatment, conduct a 
phone screen 30–37 days following the subject’s last study treatment to ensure that no changes in AE profile have occurred. 
b Visit window does not apply to Cycle 1, Day 1. 
c PSA test on Day 1 of each cycle or, once every 3 weeks (±3 days) per calendar. For F/U, PSA test every 12 weeks (±7 days). 
d Not required in Cycle 1 if baseline was assessed within 3 days prior to first dose of study drug. 
e Only tested once at 24 weeks after last dose of LV. 
f Every 6 weeks (± 3 days) for the first 12 months after the first dose of LV, then every 12 weeks (± 7 days) thereafter. Continue to assess until disease progression. After a year of 
follow-up, reduce scanning frequency to institution’s standard of care. For F/U in prostate cancer subjects, CT/MRI and bone scans every 12 weeks (±7 days) 
g See Section 7.2.1 for tumor cohort-specific imaging requirements. Submit copies of images to independent review facility. 
h If required, it is recommended that scans not be scheduled on the dosing day. It is recommended that scans done on the same day as Day 1 of subsequent cycles be completed 
and reviewed prior to infusion with LV. 
i Not required if conducted within 4 weeks prior to EOT. 
j Random blood glucose should be checked prior to dosing on Day 1 of each 21-day cycle; and on Day 8 and Day 15 of Cycle 1 and 2. Following Cycle 2, it may be checked on 
days 8 and 15 as indicated, particularly in subjects at risk for hyperglycemia (Section 5.6). 
k A +2 day dosing window is allowed. At least 7 days must elapse between administrations of LV. 
l Vital signs to be within 60 minutes prior to the start of LV infusion and within 30 minutes after completion of LV infusion 
m Only required for Cycle 1 and Cycle 2.
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APPENDIX D. 
SCHEDULE OF EVENTS FOR TREATMENT (PART C) 
Arms 1 and 2 (2q3wk dosing) 
 
Assessment 
Enrollment 
Cycle 1 
Cycle 2+ 
EOT 
F/U 
Day 
Within 7D  
of 1st dose 
D1 
D3 
D8 
D15 
D1 
D3 
D8 
D15 
Within 30–37D 
of last dosea 
Every 6 or 
12 weeks 
Visit window 
 
0db 
+ 1d 
+ 4d 
– 2d 
+ 4d 
+ 1d 
+ 4d 
– 2d 
 
± 3d or 
± 7d 
 
Confirm subject meets dosing criteria 
 
X 
 
X 
 
X 
 
X 
 
 
 
Treatment 
LV administration 
Submit eligibility confirmation to  
sponsor prior to treatment 
X 
 
Xc 
 
Xc 
 
Xc 
 
 
 
Pembrolizumab administration (Arm 2) 
X 
 
 
 
X 
 
 
 
 
 
Safety 
Assessments 
Pregnancy test  
(females of childbearing potential only) 
Xd 
 
 
 
X 
 
 
 
X 
Xe 
HbA1c 
 
 
 
 
 
 
 
 
X 
 
Physical exam 
Xd 
 
X 
X 
X 
 
 
 
X 
Xf 
Weight 
Xd 
 
 
 
X 
 
 
 
X 
 
CBC with differential 
Xd 
 
Xg 
Xg 
X 
 
Xg 
Xg 
X 
 
Chemistry panel and liver function tests 
Xd 
 
Xg 
 
X 
 
Xg 
 
X 
 
Random blood glucoseh 
X 
 
X 
 
X 
 
 
 
 
 
 
Thyroid function tests (Arm 2)i 
On Day 1 of each odd-numbered cycle while on treatment (eg, Cycles 1, 3, 5, etc) 
 
 
Vital signsj 
X 
 
X 
 
X 
 
X 
 
X 
 
 
ECOG performance status 
Xd 
 
 
 
X 
 
 
 
X 
 
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Assessment 
Enrollment 
Cycle 1 
Cycle 2+ 
EOT 
F/U 
Day 
Within 7D  
of 1st dose 
D1 
D3 
D8 
D15 
D1 
D3 
D8 
D15 
Within 30–37D 
of last dosea 
Every 6 or 
12 weeks 
Visit window 
 
0db 
+ 1d 
+ 4d 
– 2d 
+ 4d 
+ 1d 
+ 4d 
– 2d 
 
± 3d or 
± 7d 
 
Concomitant medications 
Related to 
study 
procedures 
Arm 1: Collect from Day 1 predose to EOT or 30 days post last dose, whichever is later 
Arm 2: Collect from Day 1 predose to EOT or 90 days post last dose, whichever is later 
 
 
AE collection 
Related to 
study 
procedures 
Biomarker 
Assessments 
Blood samples for biomarker assessment 
(see Section 7.4.1) 
 
See Table 19 
 
Tumor biopsy for research (see 
Section 7.4.2) 
 
PK/ATA 
Samples for PK testing (see Section 7.3) 
 
See Table 19  
 
Samples for ATA testing (see Section 7.3) 
 
Response 
Assessments 
CT/MRIk 
 
Every 6 weeks (± 3 days) for the first 12 months, then every 
12 weeks (± 7 days) thereafterl 
Xm 
Xf 
Survival follow-up contact 
 
 
Xf 
2q3wk=dosing on Day 1 and Day 8 but not Day 15 of each 21-day cycle; D=day; F/U=follow-up 
a EOT evaluations should be obtained before the initiation of non protocol therapy. If EOT evaluations are completed before 30 days following the last study 
treatment, conduct a phone screen 30–37 days following the subject’s last study treatment to ensure that no changes in AE profile have occurred. 
b Visit window does not apply to C1, Day 1. 
c A +4 day dosing window is allowed. At least 7 days must elapse between administrations of LV. 
d Not required in Cycle 1 if baseline was assessed within 3 days prior to first dose of study drug. 
e Only tested once at 24 weeks after last dose of LV 
f Every 6 weeks (± 3 days) for the first 12 months after the first dose of LV, then every 12 weeks (± 7 days) thereafter. Continue to assess until disease 
progression. After a year of follow up, reducing scanning frequency to institutional standard of care 
g Only required for Cycle 1 and Cycle 2. 
h Random blood glucose should be checked prior to dosing on each dosing day of the first 2 cycles. For Cycle 3 and later, blood glucose should be checked on 
Day 1 of each cycle and may be checked on Day 8 if clinically indicated, particularly in subjects at risk for hyperglycemia (Section 5.6). 
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i Thyroid function tests include TSH, T3 or free T3, and free T4 
j Arm 1: Vital signs to be within 60 minutes prior to the start of LV infusion, within 30 minutes after completion of LV infusion, and during infusion as 
clinically indicated.  
Arm 2: Vital signs to be within 60 minutes prior to the start of LV infusion, within 60 minutes prior to pembrolizumab infusion (Day 1 only), within 2 hours of 
ending each infusion, and during infusion(s) as clinically indicated. 
k See Section 7.2.1 for tumor cohort specific imaging requirements. Submit copies of images to independent review facility. 
l If required, it is recommended that scans not be scheduled on the dosing day. It is recommended that scans done on the same day as Day 1 of subsequent cycles 
be completed and reviewed prior to infusion with LV. 
m Not required if conducted within 4 weeks prior to EOT. 
 
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Arm 3 (q1wk dosing) 
 
Assessment 
Enrollment 
Cycle 1 
Cycle 2+ 
EOT 
F/U 
Day 
Within 7D  
of 1st dose 
D1 
D3 
D8 
D15 
D1 
D3 
D8 
D15 
Within 30–37D 
of last dosea 
Every 6 or 
12 weeks 
Visit window 
 
+ 2db 
+ 1d 
+ 2d 
+ 2d 
+ 2d 
+ 1d 
+ 2d 
+ 2d 
 
± 3d or 
± 7d 
 
Confirm subject meets dosing criteria 
 
X 
 
X 
X 
X 
 
X 
X 
 
 
Treatment 
LV administration 
Submit eligibility confirmation to  
sponsor prior to treatment 
X 
 
Xc 
Xc 
Xc 
 
Xc 
Xc 
 
 
Pembrolizumab administration  
X 
 
 
 
X 
 
 
 
 
 
Safety 
Assessments 
Pregnancy test  
(females of childbearing potential only) 
Xd 
 
 
 
X 
 
 
 
X 
Xe 
HbA1c 
 
 
 
 
 
 
 
 
X 
 
Physical exam 
Xd 
 
X 
X 
X 
 
 
 
X 
Xf 
Weight 
Xd 
 
 
 
X 
 
 
 
X 
 
CBC with differential 
Xd 
 
Xg 
Xg 
X 
 
Xg 
Xg 
X 
 
Chemistry panel and liver function tests 
Xd 
 
Xg 
Xg 
X 
 
Xg 
Xg 
X 
 
Random blood glucoseh 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
Thyroid function testsi 
On Day 1 of each odd-numbered cycle while on treatment (eg, Cycles 1, 3, 5, etc) 
 
 
Vital signsj 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
ECOG performance status 
Xd 
 
 
 
X 
 
 
 
X 
 
 
Concomitant medications 
Related to 
study 
procedures 
Collect from Day 1 predose to EOT or 90 days post last dose, whichever is later 
 
 
AE collection 
Biomarker 
Assessments 
Blood samples for biomarker assessment 
(see Section 7.4.1) 
 
See Table 19  
 
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Assessment 
Enrollment 
Cycle 1 
Cycle 2+ 
EOT 
F/U 
Day 
Within 7D  
of 1st dose 
D1 
D3 
D8 
D15 
D1 
D3 
D8 
D15 
Within 30–37D 
of last dosea 
Every 6 or 
12 weeks 
Visit window 
 
+ 2db 
+ 1d 
+ 2d 
+ 2d 
+ 2d 
+ 1d 
+ 2d 
+ 2d 
 
± 3d or 
± 7d 
Tumor biopsy for research (see 
Section 7.4.2) 
 
PK/ATA 
Samples for PK testing (see Section 7.3) 
 
See Table 19  
 
Samples for ATA testing (see Section 7.3) 
 
Response 
Assessments 
CT/MRIk 
 
Every 6 weeks (± 3 days) for the first 12 months, then every 
12 weeks (± 7 days) thereafterl 
Xm 
Xf 
Survival follow-up contact 
 
 
Xf 
D=day; F/U=follow-up; q1wk=dosing on Day 1, Day 8, and Day 15 of each 21-day cycle 
 
a EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT evaluations are completed before 30 days following the last study 
treatment, conduct a phone screen 30–37 days following the subject’s last study treatment to ensure that no changes in AE profile have occurred. 
b Visit window does not apply to C1, Day 1. 
c A +2 day dosing window is allowed. At least 7 days must elapse between administrations of LV. 
d Not required in Cycle 1 if baseline was assessed within 3 days prior to first dose of study drug. 
e Only tested once at 24 weeks after last dose of LV. 
f Every 6 weeks (± 3 days) for the first 12 months after the first dose of LV, then every 12 weeks (± 7 days) thereafter. Continue to assess until disease 
progression. After a year of follow up, reducing scanning frequency to institutional standard of care 
g Only required for Cycle 1 and Cycle 2. 
h Random blood glucose should be checked prior to dosing on each dosing day of the first 2 cycles. For Cycle 3 and later, blood glucose should be checked on 
Day 1 of each cycle and may be checked on Day 8 and/or Day 15 if clinically indicated, particularly in subjects at risk for hyperglycemia (Section 5.6) 
i Thyroid function tests include TSH, T3 or free T3, and free T4 
j Vital signs to be within 60 minutes prior to the start of LV infusion, within 60 minutes prior to pembrolizumab infusion (Day 1 only), within 2 hours of ending 
each infusion, and during infusion(s) as clinically indicated. 
k See Section 7.2.1 for tumor cohort specific imaging requirements. Submit copies of images to independent review facility. 
l If required, it is recommended that scans not be scheduled on the dosing day. It is recommended that scans done on the same day as Day 1 of subsequent cycles 
be completed and reviewed prior to infusion with LV. 
m Not required if conducted within 4 weeks prior to EOT. 
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APPENDIX E. 
NEW YORK HEART ASSOCIATION CLASSIFICATION 
On-line source: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_3
06328_Article.jsp 
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APPENDIX F. 
P-GP AND CYP3A INDUCERS/INHIBITORS 
Subjects who are receiving P-gp or CYP3A4 inhibitors concomitantly with LV should be closely 
monitored for adverse reactions. Based upon evaluation of the anti-CD30 MMAE ADC 
brentuximab vedotin (Adcetris) (ADCETRIS Prescribing Information, Seagen Inc., 
March 2018), concomitant use of P-gp inhibitors or strong CYP3A4 inhibitors has the potential 
to increase the exposure to MMAE (the cytotoxic component of LV and brentuximab vedotin). 
Concomitant use of P-gp inducers or strong CYP3A4 inducers could decrease exposure to 
MMAE. 
Additional new drugs and marketed drugs may be identified as inducers/inhibitors with 
continued research.  
P-gp Inhibitors 
Strong CYP3A Inhibitors 
amiodarone 
boceprevir 
carvedilol  
clarithromycin 
clarithromycin 
cobicistat 
dronedarone 
conivaptan 
itraconazole 
danoprevir and ritonavir 
lapatinib 
diltiazem 
lopinavir and ritonavir 
elvitegravir and ritonavir 
propafenone 
grapefruit juice 
quinidine 
idelalisib 
ranolazine 
indinavir and ritonavir 
ritonavir 
itraconazole 
saquinavir and ritonavir 
ketoconazole 
telaprevir 
lopinavir and ritonavir 
tipranavir and ritonavir 
nefazodone  
verapamil 
nelfinavir  
 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
 
posaconazole 
 
ritonavir 
 
saquinavir and ritonavir 
 
telaprevir 
 
tipranavir and ritonavir 
 
troleandomycin 
 
voriconazole 
P-gp Inducers/Strong CYP3A Inducers 
 
avasimibe 
 
carbamazepine  
 
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phenytoin 
 
rifampin 
 
St John’s wort 
 
tipranavir/ritonavir* 
 
* P-gp inducer only 
Note: Any additional P-gp inducers/inhibitors or strong CYP3A inducers/inhibitors that are identified or become 
commercially available while the clinical trial is ongoing should also be closely monitored for adverse reactions. 
 
 
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APPENDIX G. 
PROPHYLACTIC GRANULOCYTE-COLONY STIMULATING 
FACTOR (G-CSF) THROUGHOUT SUPPORT 
RECOMMENDATIONS 
In Part A: Starting with the first cycle of LV and continuing through subsequent cycles, 
prophylactic G-CSF is recommended for subjects who have approximately 20% or higher risk of 
febrile neutropenia. Subjects who receive >200 mg of LV per infusion (weight >80 kg for dose 
level 2.5 mg/kg) must be given prophylactic G-CSF, starting with their first dose of >200 mg. It 
is also strongly recommended that these subjects continue to receive prophylactic G-CSF at 
subsequent cycles regardless of the LV dose. Therefore, subjects to receive >200 mg LV per 
infusion must not have contraindications to G-CSF and must be willing to receive them. 
Strongly consider primary prophylaxis when allowed per protocol based on subject, disease, and 
treatment risk factors, including the following: 
● Age ≥65 years 
● Advanced disease 
● Previous chemotherapy or radiation therapy 
● Pre-existing neutropenia or bone marrow 
involvement with tumor 
● Infection 
● Open wounds or recent surgery 
● Poor performance status or poor nutritional 
status 
● Poor renal function 
● Liver dysfunction, most notably elevated 
bilirubin 
● Cardiovascular disease 
● Multiple comorbid conditions 
In Part A: Secondary prophylaxis with G-CSF is required for all subsequent cycles for 
subjects who experience Grade 4 neutropenia or febrile neutropenia of any grade in any cycle 
while on LV (for which primary prophylaxis was not received), must receive G-CSF in all 
subsequent cycles. G-CSF support is also required for treatment of febrile neutropenia. 
In Part B and Part C: Secondary prophylaxis with G-CSF is recommended for all 
subsequent cycles for subjects who experience a neutropenic complication with a previous cycle 
of therapy (for which primary prophylaxis was not received) when dose reduction or delay may 
compromise treatment outcome with LV. In Part B and Part C, primary prophylactic G-CSF is 
not required but is allowed. 
In Part B and Part C: Treatment with G-CSF is strongly recommended for subjects with 
fever and neutropenia who are at high risk for infection-associated complications or who have 
prognostic factors that are predictive of poor clinical outcomes. High-risk features include: 
● Sepsis syndrome (hypotension and 
multi-organ dysfunction) 
● Age >65 years 
● Profound neutropenia  
(absolute neutrophil count <0.1 x 109/L) 
● Neutropenia expected to last >7 days 
● Uncontrolled primary disease 
● Pneumonia 
● Invasive fungal infection 
● Other clinically documented infections 
● Hospitalization at time of fever 
● Prior episode of febrile neutropenia 
As per ASCO guidelines, prophylactic G-CSF should start 1–3 days after LV administration. 
G-CSF (including pegfilgrastim) should not be given within 24 hours prior to the dose of LV. If 
pegfilgrastim is used, a one-time dose per cycle is recommended. If daily G-CSF is used, treat 
for least 5–7 days or until the ANC is >1000/mm3 (≤ Grade 2). Refer to the Prescribing 
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Information for the applicable G-CSF to determine the appropriate administration window for 
use with LV. 
Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical 
Practice Guideline Update 
Guideline Question 
How should colony-stimulating factors (CSFs) be used in people with cancer? 
Target Population 
Adults or children with a solid tumor or lymphoma treated with chemotherapy 
Target Audience 
Medical oncologists, hematologists, oncology nurses, other clinicians who care for people with cancer, and 
patients 
Methods 
An Update Committee was convened to update clinical practice guideline recommendations based on a 
systematic review of the medical literature. 
Key Points 
● Primary prophylaxis with a CSF starting with the first cycle and continuing through subsequent cycles 
of chemotherapy is recommended in patients who have an approximately 20% or higher risk for 
febrile neutropenia based on patient-, disease- and treatment-related factors. Primary CSF prophylaxis 
should also be administered in patients receiving dose-dense chemotherapy when considered 
appropriate. Consideration should be given to alternative, equally effective, and safe chemotherapy 
regimens not requiring CSF support when available. (Type: evidence based, benefits outweigh harms. 
Evidence quality: high. Strength of recommendation: strong.) 
● Secondary prophylaxis with a CSF is recommended for patients who experienced a neutropenic 
complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in 
which a reduced dose or treatment delay may compromise disease-free or overall survival or treatment 
outcome. In many clinical situations, dose reduction or delay may be a reasonable alternative. (Type: 
evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: 
strong.) 
● CSFs should not be routinely used for patients with neutropenia who are afebrile. (Type: evidence 
based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.) 
● CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with 
fever and neutropenia. However, CSFs should be considered in patients with fever and neutropenia 
who are at high risk for infection-associated complications or who have prognostic factors predictive 
of poor clinical outcomes. (Type: evidence based, benefits outweigh harms. Evidence quality: high. 
Strength of recommendation: strong.) 
● Dose-dense regimens with CSF support should only be used if supported by convincing efficacy data 
or within an appropriately designed clinical trial. Efficacy data support the use of dose-dense 
chemotherapy in the adjuvant treatment of high-risk breast cancer and the use of high-dose intensity 
methotrexate, vinblastine, doxorubicin, and cisplatin in urothelial cancer. There are limited and 
conflicting data on the value of dose-dense regimens with CSF support in non-Hodgkin lymphoma, 
and it cannot routinely be recommended at this time. (Type: evidence based, benefits outweigh harms. 
Evidence quality: high for breast cancer and lymphoma; intermediate for urothelial cancer. Strength of 
recommendation: strong for breast cancer and lymphoma; moderate for urothelial cancer.) 
● CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize 
peripheral-blood progenitor cells. Choice of mobilization strategy depends in part on type of cancer 
and type of transplantation. (Type: evidence based, benefits outweigh harms. Evidence quality: strong. 
Strength of recommendation: high.) 
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● CSFs should be administered after autologous stem-cell transplantation to reduce the duration of 
severe neutropenia. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength 
of recommendation: strong.) 
● CSFs may be administered after allogeneic stem-cell transplantation to reduce the duration of severe 
neutropenia. (Type: evidence based. Evidence quality: low. Strength of recommendation: weak). 
● Prophylactic CSFs for patients with diffuse aggressive lymphoma age ≥65 years treated with curative 
chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) should be 
considered, particularly in the presence of comorbidities. (Type: evidence based, benefits outweigh 
harms. Evidence quality: intermediate. Strength of recommendation: moderate.) 
● The use of CSFs in pediatric patients will almost always be guided by clinical protocols. As in adults, 
the use of CSFs is reasonable as primary prophylaxis for pediatric patients with a high likelihood of 
febrile neutropenia. Similarly, the use of CSFs for secondary prophylaxis or for therapy should be 
limited to high-risk patients. (Type: evidence based, benefits outweigh harms. Evidence quality: high. 
Strength of recommendation: strong.) 
● For pediatric indications in which dose-intense chemotherapy is known to have a survival benefit, 
such as Ewing sarcoma, CSFs should be used to enable the administration of these regimens. (Type: 
evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: 
strong.) 
● CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or 
nonrelapsed acute myeloid leukemia who do not have an infection. (Type: informal consensus. 
Evidence quality: intermediate. Strength of recommendation: moderate.) 
● Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become 
available) can be used for the prevention of treatment-related febrile neutropenia. The choice of agent 
depends on convenience, cost, and clinical situation. There have been no additional data comparing 
granulocyte CSFs and granulocyte-macrophage CSFs since the 2006 update; therefore, there is no 
change in the recommendation regarding their therapeutic equivalency. (Type: evidence based, 
benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.) 
● Current recommendations for the management of patients exposed to lethal doses of total-body 
radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, 
include the prompt administration of CSFs or pegylated granulocyte CSFs. (Type: formal consensus 
[by others], benefits outweigh harms. Evidence quality: intermediate. Strength of recommendation: 
moderate.) 
Qualifying Statements 
The Update Committee did not provide recommendations regarding the use of CSFs in adult patients with acute 
myeloid leukemia or myelodysplastic syndromes. 
Additional Resources 
More information, including a Data Supplement with additional evidence tables, a Methodology Supplement with 
information about evidence quality and strength of recommendations, slide sets, and clinical tools and resources, 
is available at www.asco.org/guidelines/wbcgf. Patient information is available at www.cancer.net. 
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that 
all patients should have the opportunity to participate. 
Reference: (Smith 2015) 
Refer to the Prescribing Information for the applicable G-CSF to determine the appropriate 
administration window for use with LV. 
The choice of G-CSF is as determined by investigator. 
Reference: (Crawford 2010; Smith 2015). 
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APPENDIX H. 
RECIST VERSION 1.1 
Response Evaluation Criteria in Solid Tumors 
Term 
Definition 
Complete response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes must have 
reduction in short axis to <10 mm. 
Partial response (PR) 
A ≥30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 0.5 cm. The appearance of one or 
more new lesions is also considered progression. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
Measurable lesion 
Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of 10 mm by CT 
scan (CT slice thickness no greater than 5 mm). 
From RECIST v1.1 (Eisenhauer 2009) 
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APPENDIX I. 
IRECIST: GUIDELINES FOR RESPONSE CRITERIA FOR USE IN 
TRIALS TESTING IMMUNOTHERAPEUTICS 
Response will also be assessed using iRECIST guidelines for determining eligibility of treatment 
continuation (Seymour 2017). Immunotherapeutics may result in infiltration of immune cells 
leading to transient increase in the size in malignant lesions, or undetectable lesions becoming 
detectable. The criteria are identical to those of RECIST Version 1.1 in many respects but have 
been adapted to account for instances where an increase in tumor burden, or the appearance of 
new lesions, does not reflect true tumor progression. 
Key differences are described below. All responses defined using iRECIST guidelines are 
designated with a prefix; iRECIST time-point and best responses will be recorded separately. 
Confirming Disease Progression 
Unlike RECIST Version 1.1, the iRECIST guidelines require the confirmation of progression 
and use the terms iUPD (unconfirmed progression) and iCPD (confirmed progression). 
Confirmatory scans should be performed at least 4 weeks, but no longer than 8 weeks after 
iUPD. 
For iCPD to be confirmed, further increase in tumor burden, compared to the last assessment, 
must be seen as evidenced by 1 or more of the following: 
• Continued increase in tumor burden (from iUPD) where RECIST Version 1.1 
definitions of progression had been met (from nadir) in target, non-target disease or 
new lesions 
o Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum 
o Continued unequivocal progression in non-target disease with an increase in 
tumor burden 
o Increase in size of previously identified new lesion(s) (an increase of at least 
5 mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions. 
• RECIST Version 1.1 criteria are met in lesion types (target or non-target or new 
lesions) where progression was not previously identified, including the appearance of 
additional new lesions. 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD (stable disease), iPR (partial 
response), or iCR (confirmed response) if those criteria are met compared to baseline). 
New Lesions 
New lesions should be assessed and measured as they appear using RECIST Version 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis [or 15 mm in short 
axis for nodal lesions], and recorded as New Lesions-Target [NLT] and New Lesion-Non-Target 
[NLNT]) to allow clear differentiation from baseline target and non-target lesions. 
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New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, 
the measurements of target lesions should NOT be included in the sum of measures of original 
target lesions identified at baseline.  
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APPENDIX J. 
PERFORMANCE STATUS SCALES CONVERSION 
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APPENDIX K. 
GUIDANCE ON CONTRACEPTION 
For the purposes of this guidance, complete abstinence, if consistent with the subject’s preferred 
lifestyle, is an acceptable form of contraception. Complete abstinence is defined as abstinence 
starting from the time of informed consent and continuing throughout the study and until the end 
of systemic exposure (at least 6 months after the final dose of study drug; see Section 4.1).  
Acceptable methods for highly effective birth control (preventing conception) 
Subjects who are of childbearing potentiala or whose partners are of childbearing potentiala and who are 
sexually active in a way that could lead to pregnancy may choose any TWO of the following methods: 
● Hormonal methods of contraception (excluding progestin-only pills; method must be associated with 
inhibition of ovulation), unless contraindicated 
● Intrauterine device with failure rate <1% 
● Tubal ligation 
● Vasectomy (at least 90 days from the date of surgery with a semen analysis documenting 
azoospermia) 
● Barrier method/s (male or female condom with or without spermicide, cervical cap with or without 
spermicide, diaphragm with or without spermicide) 
a A person of childbearing potential is defined as anyone born female who has experienced menarche and who has 
not undergone surgical sterilization (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not 
completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person born female over 
age 45 in the absence of other biological, physiological, or pharmacological causes. 
Acceptable methods for preventing secondary exposure to seminal fluid 
Subjects born male and who are sexually active with a pregnant or breastfeeding person, must use the 
contraceptives in Option 1 or 2: 
● Option 1: Male condom (with or without spermicide) and cervical cap 
● Option 2: Male condom (with or without spermicide) and diaphragm 
Unacceptable methods of contraception 
● Periodic abstinence 
● No method 
● Withdrawal 
● Rhythm 
● Spermicide only 
● Progestin-only pills 
● Concomitant use of female and male condoms 
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APPENDIX L. 
PCWG3 SUGGESTED OUTCOME MEASURES FOR CLINICAL 
TRIALS IN METASTATIC PROSTATE CANCER 
Variable 
PCWG3 (2015) 
Blood-based markers (PSA) 
● Recognize that a favorable effect on PSA may be 
delayed for ≥12 weeks, even for a cytotoxic drug 
● Monitor PSA by cycle but plan to continue through 
early rises for a minimum of 12 weeks unless other 
evidence of progression 
● Ignore early rises (before 12 weeks) in determining 
PSA response 
● For control/relieve/eliminate endpoints: 
Record the percent change from baseline (rise or fall) 
at 8–9 or 12 weeks, depending on trial design, and 
separately, the maximal change (rise or fall) at any 
time using a waterfall plot 
● Separately report the proportion of patients who have 
undergone radical prostatectomy and achieved a nadir 
less than 0.2 ng/mL; primary radiation therapy-treated 
patients who achieved a nadir less than 0.5 ng/mL 
● Describe absolute changes in PSA over time from 
baseline to best response 
● For delay/prevent end points (progression): 
After decline from baseline: record time from start of 
therapy to first PSA increase that is ≥25% and 
≥2 ng/mL above the nadir, and which is confirmed by 
a second value ≥3 weeks later (i.e., a confirmed rising 
trend); the requirement for an increase of 5 ng/mL 
was decreased to 2 ng/mL, and the requirement for a 
50% increase was reduced to 25%. 
● Recording the duration of PSA decline of little value 
● No decline from baseline: PSA progression ≥25% 
increase and ≥2 ng/mL increase from baseline beyond 
12 weeks 
● Relate to mechanism of drug and anticipated timing of 
potential favorable/unfavorable effects on PSA, if 
present 
Imaging biomarkers: nodal and visceral 
For control/relieve/eliminate endpoints: 
General 
● Record changes in lymph nodes, lung, liver, adrenal, 
and CNS sites separately 
● Record up to five lesions per site of disease 
● Use RECIST v1.1 with caveats: 
● Record changes in size using waterfall plot 
● Confirm favorable change with second scan 
● Record complete elimination of disease at any site 
separately 
Nodes 
● Only report changes in lymph nodes that were 
≥1.5 cm in the short axis 
● Record changes in pelvic (regional) nodes; extrapelvic 
(distant/metastatic) nodes separately 
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Visceral 
● Use RECIST v1.1 with caveats: 
● Record changes in liver, lung, adrenal, and CNS 
separately 
● Only report changes in lesions ≥1.0 cm in the longest 
dimension 
For delay/prevent endpoints: 
Nodal and visceral 
General: 
● Record changes in nodal and visceral (lung, liver, 
adrenal, and CNS) disease separately 
● Use RECIST v1.1 but clearly record type of 
progression (growth of existing lesions; development 
of new lesions) separately by site 
● The recommendations apply to both nmCRPC and 
mCRPC 
● Record up to 5 lesions per site of spread 
● Report the proportion who have not progressed at 
fixed time points (6 or 12 months) 
● Note that for some treatments, a lesion may increase 
in size before it decreases 
Nodal 
● Previously normal (<1.0 cm) lymph nodes must have 
grown by ≥5 mm in the short axis from baseline or 
nadir and be ≥1.0 cm in the short axis to be 
considered to have progressed 
● Nodes that have progressed to 1.0 to less than 1.5 cm 
are pathologic, subject to clinical discretion, and 
nonmeasurable 
● For existing pathologic adenopathy (≥1.5 cm), 
progression is defined per RECIST v1.1 
Imaging biomarkers: bone 
Metastatic 
For control/relieve/eliminate end points: 
● Record changes as improved or stable (no lesions), 
worse (new lesions), or resolved bone lesions 
● Changes in intensity of uptake alone do not constitute 
progression or regression 
● No new lesions: continue therapy in absence of other 
signs of progression 
● New lesions (see Progression below) 
For delay/prevent end points (progression): 
Progression: 
● Exclude pseudo progression in the absence of 
symptoms or other signs of progression 
● If at least 2 additional new lesions are seen on the 
next (confirmatory) scan, the date of progression is 
the date of the first post-treatment scan, when the first 
2 lesions were documented 
● For scans after the first post-treatment scan, at least 
2 new lesions relative to the first post-treatment scan 
confirmed on a subsequent scan 
● Date of progression is the date of the scan that first 
documents the second lesion 
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● Changes in intensity of uptake alone do not constitute 
either progression or regression 
● Report the proportion of patients who have not 
progressed at fixed time intervals (6 and 12 months) 
mCRPC=metastatic castration-resistant prostate cancer; nmCRPC=nonmetastatic castration-resistant prostate 
cancer; PCWG3=Prostate Cancer Clinical Trials Working Group 3 
Reference: (Scher 2016) 
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APPENDIX M. 
INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
 
I have read the attached protocol entitled Open-Label Phase 2 Study of Ladiratuzumab Vedotin 
(LV) for Unresectable Locally Advanced or Metastatic Solid Tumors 
I understand and agree to the provisions of the protocol, and I accept the responsibilities listed 
above in my role as principal investigator for the study. 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Investigator Name, Printed 
 
 
 
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APPENDIX N. 
DOCUMENT HISTORY 
Version 
Date 
Original 
22-April-2019 
Amendment 01 
23-March-2020 
Amendment 02 
27-August-2020 
Amendment 03 
12-October-2020 
Amendment 04 
02-November-2022 
 
 
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SUMMARY OF CHANGES IN AMENDMENT 01 
Section(s) 
Change 
Rationale 
Synopsis, 3.1, 
3.2.2, 3.2.3, 
3.2.4, 4.1, 4.2, 
5.1, 5.2.3, 
5.2.4.1, 5.2.4.2, 
5.3.1, 5.3.3, 5.5, 
6.2, 6.3, 6.6, 7.3, 
7.4, 7.6.2, 
9.3.1.9, 9.3.9, 
Appendix B, 
Appendix C  
Added a weekly LV dosing schedule for all cohorts (tumor 
types) (Part B [q1wk dosing]). The existing dosing schedule 
for LV every 3 weeks is defined as Part A (q3wk dosing). 
Wording throughout the protocol was revised to reflect Part 
A and Part B as appropriate. Affected sections include: 
● Study design 
● Rationale for study design 
● Study population 
● Treatment administered  
● Dose and administration 
● Dose modifications 
● Concomitant therapy 
● Management of hyperglycemia 
● Schedule of events for Part B 
● Determination of sample size 
● Safety assessments 
● Timing of analyses 
● Interim analyses 
● PK, ATA, and biomarker sampling time points for 
Part B 
To evaluate weekly LV 
dosing 
Synopsis, 9.1 
Sample size was revised to reflect the revised design with the 
addition of subjects to be enrolled in Part B (LV q1wk 
dosing) and a smaller number of subjects to be included in 
Part A (LV q3wk dosing) (revisions shown below for Section 
9.1): 
Up to approximately 180 264 subjects may be enrolled in the 
entire study, including up to 72 subjects in Part A (LV 
2.5 mg/kg every 3 weeks [q3wk] dosing) and up to 
192 subjects in Part B (LV every 1 week [q1wk] 
dosing).with up to 30 subjects enrolled in each cohort. In 
addition, the cohorts may be expanded to enroll additional 
subjects to better characterize LV activity. A cohort may be 
expanded to further characterize antitumor activity if the 
safety profile is acceptable, other efficacy endpoints are 
comparable to current standard of care, and the confirmed 
ORR meets cohort specific criteria. Additional cohorts may 
also be added in future protocol amendments for additional 
indications, alternative dosing schedule, biopsy/biomarker 
analysis, and LV-based combination therapy. 
Synopsis, 3.1 
Corrected timing of repeat scans for confirmed objective 
responses: 
Objective responses will be confirmed with repeat scans 
46 4–6 weeks after the first documentation of response. 
Correction 
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Section(s) 
Change 
Rationale 
4.1 
Subjects with known deficient mismatch repair (dMMR) 
and/or microsatellite instability-high (MSI-H) may have 
received prior anti-PD(L)1 therapy, unless contraindicated. 
To allow for any subject in 
Cohort 6 who meets 
criteria for receiving 
anti-PD(L)1 
4.2 
Other serious or uncontrolled underlying medical condition 
that, in the opinion of the investigator, would impair the 
subject’s ability to receive or tolerate the planned treatment 
and follow-up (eg, active cardiac disease, active systemic 
infection, chronic conditions, any psychiatric or substance 
abuse disorders), interfere with the subject’s cooperation with 
the requirements of the trial, place the subject at undue risk of 
SAE, or make the subject unable to receive sustained therapy 
To provide clarification 
5.2.3 
LV at a dose of 2.5 mg/kg (maximum dose of 250 mg per 
cycle) will be is administered on Day 1 of every 21-day cycle 
by IV infusion given over approximately 30 minutes. LV 
must not be administered as an IV push or bolus. In the 
absence of infusion-related reactions, the infusion rate for 
all patients should be calculated in order to achieve a 
30-minute infusion period. However, given the variability 
of infusion pumps from site to site, a window between –
5 minutes and +10 minutes is permitted (i.e., infusion time 
is 30 minutes –5 min/+10 min). 
To provide clarification 
regarding the infusion rate 
5.2.3.1 
Added section “Dosing Criteria” 
To provide laboratory 
criteria that must be met 
prior to dosing on Day 1 of 
each cycle 
5.2.4.2 
(Table 5-2) 
Changed “Elevated blood glucose” to “Hyperglycemia” in 
Table 5-2. 
To provide clarification 
5.3.3 
Added section “Myeloid Growth Factors” 
To provide further detail 
regarding use of myeloid 
growth factors 
5.5 
Deleted language indicating that finger stick tests for random 
blood glucose assessment are excluded and added that blood 
glucose may be measured by blood glucose meter or 
laboratory-performed blood glucose test. 
To obtain results in a 
timely manner prior to 
dosing. 
Added the following: 
Note: For AE reporting purposes, the severity of 
hyperglycemia in the NCI CTCAE, version 5, is graded 
by the medical management required to address 
hyperglycemia and not by the value of glucose 
measurement. 
To provide clarification 
6.2.1, 7.1, 
Appendix A 
Added brain CT or MRI scan to screening/baseline 
assessments for Part A. 
To assess for brain 
metastases, consistent with 
exclusion criterion #3 
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Section(s) 
Change 
Rationale 
6.6 
All subjects will be followed for survival until death or study 
closure, whichever occurs first. The first follow-up visit will 
occur 12 weeks (± 7 days) from the most recent prior 
radiographic response evaluation. Subsequent follow-up 
visits will be scheduled for 12 weeks (± 7 days) from the 
previous follow-up visit. Survival and subsequent anticancer 
therapy follow-up may be conducted with clinic visits or 
telephone calls. 
To provide correction and 
reflect current study 
practice 
6.6,  
Appendix B 
Revised timing of CT/MRI scans from every 12 weeks to 
every 6 weeks for subjects who discontinue study treatment 
for reasons other than disease progression. 
Clarification for 
consistency across sections 
7.2 
Revised language regarding guidance on use of CT or MRI. 
For subjects unable to tolerate contrast-enhanced CT 
assessments, MRI imaging is acceptable. MRI scans may are 
not be appropriate to assess lung parenchymal lesions and 
CT without contrast enhancement is acceptable in such 
situations for NSCLC subjects. 
To reflect a previous 
response to health 
authorities 
7.2 
Added reference to study imaging manual. 
To provide reference for 
further details regarding 
CT and MRI assessments 
7.3 
References to the IRIS Manual were changed to the 
Laboratory Manual for processing of samples for PK and 
immunogenicity assessments. 
To reflect current study 
practice 
7.6 
Added clarifying language regarding timing of safety 
assessments. 
The assessment of safety during the course of this study will 
consist of the surveillance and recording of AEs including 
SAEs, recording of concomitant medication, and 
measurements of protocol-specified physical examination 
findings, vital signs, pregnancy testing, and laboratory tests. 
Safety assessments will be performed at prespecified time 
points through the EOT visit and in some circumstances 
beyond the EOT visit. AEs and SAEs will be reported 
through the EOT visit or 30 days after the last study 
treatment, whichever is later (see Section 7.6.1.3). 
Clarification 
7.6.3 
Description of the CBC test was clarified to indicate that the 
standard differential includes, but is not limited to, 
neutrophils, lymphocytes, and monocytes. 
Clarification 
9.1 
Added language and table to describe rationale for 12-subject 
safety run-in for Part B.  
In Part B, the initial 12 subjects enrolled across the tumor 
cohorts per dose level will be evaluated for safety after the 
12th patient completes the first cycle of treatment. The 
sample size of 12 allows for a reasonable likelihood of 
observing a given AE in at least 1 subject even when the 
incidence of the specific AE is low. 
To provide rationale for 
design of Part B. 
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Section(s) 
Change 
Rationale 
The table below shows the probability of observing an AE 
in at least 1 subject out of 12 subjects for different 
underlying incidence of AEs. 
Underlying AE 
Incidence 
Probability of Observing the  
AE in 1 or More Subjects  
Out of 12 Subjects 
1% 
11% 
5% 
46% 
10% 
72% 
Appendix I 
Updated guidance on contraception. 
To comply with Clinical 
Trial Facilitation Group 
(CTFG) guidelines 
Multiple sections 
Minor editorial corrections and clarifications made in some 
sections of the protocol. 
Corrections and 
clarifications 
 
 
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SUMMARY OF CHANGES IN AMENDMENT 02 
Section(s) 
Change 
Rationale 
Page 1 
Added EudraCT Number to Title page 
Added per protocol 
template requirement 
List of 
Abbreviations 
Added castration-resistant prostate cancer (CRPC), 
computed tomography/magnetic resonance imaging 
(CT/MRI), Prostate Cancer Clinical Trials Working Group 
3 (PCWG3), and prostate-specific antigen (PSA) 
New acronyms defined 
Synopsis, 3.1, 
Figure 2, 4.1, 9.1 
Added tumor types: Cohort 7: castration-resistant prostate 
cancer and Cohort 8: melanoma. Wording throughout the 
protocol was revised to reflect the addition of Cohort 7 and 
Cohort 8 as appropriate. Affected sections include: 
Study population 
Number of planned subjects 
Summary of Study Design 
Study Design and Cohorts – Part A and Part B 
Primary and secondary objectives 
Inclusion criteria 
Determination of Sample Size 
Statistical methods 
Efficacy assessments 
Appendix A 
Appendix C 
To evaluate LV in 
prostate cancer and 
melanoma subjects 
Synopsis, 3.1 
Subjects with the following advanced solid tumors will be 
enrolled: 
 
Cohort 1: SCLC 
 
Cohort 2: NSCLC-squamous 
 
Cohort 3: NSCLC-nonsquamous 
 
Cohort 4: HNSCC 
 
Cohort 5: esophageal squamous cell carcinoma 
(esophageal-squamous) 
 
Cohort 6: gastric and gastroesophageal junction 
(GEJ) adenocarcinoma  
 
Cohort 7: CRPC (Part B only) 
 
Cohort 8: melanoma (Part B only) 
To reflect the addition 
of 2 subject cohorts to 
study design 
Synopsis, 3.1 
The study consists of: 
● Part A (LV every 3 weeks [q3wk]; Cohorts 1A 
through 6A): LV administered by IV infusion at 
a dose of 2.5 mg/kg on Day 1 of each 21-day 
cycle (see Section 5.1).  
● Part B (LV q1wk; Cohorts 1B-1.0 mg/kg 
through 6B-1.0 mg/kg and 1B-1.25 mg/kg 
through 8B-1.25 mg/kg; starting with Protocol 
Amendment 1): LV administered by IV infusion 
To reflect the addition 
of 2 subject cohorts to 
study design and to 
specify dose level 
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Section(s) 
Change 
Rationale 
at a dose of 1.0 mg/kg or 1.25 mg/kg on Day 1, 
Day 8, and Day 15 of each 21-day cycle (see 
Section 5.1). 
1.2.4.3, Table 1-3 
Added section “Safety data of LV q1wk” 
To expand the LV 
safety profile with 
recently acquired q1wk 
safety data from the 
SGNLVA-001 ongoing 
study 
Synopsis, 2 
Added Primary Objective: 
● 
For prostate cancer, investigator-determined PSA 
response by Prostate Cancer Clinical Trials Working Group 
3 (PCWG3) criteria in addition to ORR 
Added Secondary Objectives:  
● 
For prostate cancer, investigator determined 
PSA-DOR 
● 
For prostate cancer, investigator determined 
PSA-PFS 
To reflect addition of 
prostate cancer cohort 
Figure 2 
Added Cohort 7: Prostate cancer and Cohort 8: melanoma 
to Figure 2 
To reflect the addition 
of 2 subject cohorts 
Figure 3, 
Appendix B, 
Appendix C 
Changed “Every 12 weeks” to “Every 6 or 12 weeks” for 
Follow-up in Figure 3: Study Schema Overview and in 
Appendix B: Schedule of Events for Treatment (Part A) and 
Appendix C: Schedule of Events for Treatment (Part B) 
Clarification for 
consistency across 
sections 
3.1 
Added tumor assessment for prostate cancer subjects: 
For prostate cancer subjects (Part B, Cohort 7), 
prostate-specific antigen (PSA) will be assessed every 
3 weeks (±3 days). Bone scans will be performed every 
8 weeks (±7 days) for the first 24 weeks, then every 
12 weeks (±7 days) thereafter. In addition to PSA and bone 
scans, prostate cancer subjects with measurable tumor 
lesions will undergo soft tissue tumor assessment CT/MRI 
(CT or MRI scan) every 8 weeks (±7 days) for the first 
24 weeks, then every 12 weeks (±7 days) thereafter 
according to the Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3) criteria. 
To provide plan for 
tumor assessment in 
prostate cancer subjects 
3.2.3 
Updated rationale for selection of q1wk LV doses. 
To provide most up to 
date safety information 
for LV q1wk dosing 
4.1 
Added inclusion criteria for Cohort 7, CRPC and for 
Cohort 8, melanoma. 
To provide criteria that 
must be met for 
prostate cancer and 
melanoma subjects to 
be enrolled 
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Section(s) 
Change 
Rationale 
Synopsis, 5.1, 
5.2.3 
For Part B (q1wk dosing), added language to state that the 
maximum dose of LV is 200 mg per infusion 
To align with current 
guidelines for LV 
5.2.4.2, Table 5-4 
Provided clarification on allowed concomitant therapy and 
myeloid growth factors to manage Grade 3 and Grade 4 
hematologic and febrile neutropenia toxicities with LV 
q1wk dosing. 
Clarification for 
consistency across 
sections 
5.3.1 
In Part B, primary prophylactic G-CSF is not required but is 
allowed (see Sections 5.3.2 Allowed Concomitant Therapy 
and 5.3.3. Myeloid Growth Factors). 
Added to ensure 
consistency with 
Table 5-4 
5.5 
Revised wording added: 
● 
Part B: random blood glucose should be checked 
prior to dosing on Day 1, 8, and 15 of the first 2 cycles. 
For Cycle 3 and later, blood glucose should be checked 
on Day 1 of each cycle, and may be checked on Day 8 
and/or Day 15 if clinically indicated for subjects at risk of 
hyperglycemia. 
To clarify random 
blood glucose testing in 
Part B (weekly dosing) 
6.3.1, 6.3.3, 
Appendix C  
For Part B (q1wk dosing), added multiple study activities to 
Screening and Treatment Cycle visits. Clarified that CBC 
with differential, serum chemistry panel and liver function 
tests, and random blood glucose assessments are only 
required in Cycle 1 and Cycle 2 
Added for prostate 
cancer subject 
screening and 
assessments 
6.4, 6.5, 6.6, 
Appendix C  
Added response assessment criteria for prostate cancer 
subjects (Cohort 7) 
To identify prostate 
cancer subject response 
assessments 
7.2 
Added: 
For prostate cancer subjects, PSA response is defined as a 
reduction from baseline PSA level of at least 50%, 
maintained for at least 3 weeks. The duration of PSA 
response is defined as the time between the first evaluation 
at which the response criteria are met and the first 
documentation of PSA progression. Early increase in PSA 
within 12 weeks, when followed by subsequent decline, is 
ignored in determining this endpoint. 
To define prostate 
cancer subject 
response/efficacy 
assessments 
Table 7-1 and 
Table 7-2 
Removed PBMC1 and PBMC2 columns 
The probability of 
using these samples for 
analysis is low and 
doesn’t justify the cost 
for continued sample 
collection 
Synopsis, 9.1 
Sample size was revised to reflect the additional subjects 
planned to be enrolled in Cohort 7 and Cohort 8 (revisions 
shown below for Section 9.1): 
Up to approximately 264324 subjects may be enrolled in 
the study, including up to 72 subjects in Part A (q3wk 
dosing), and up to 192252 subjects in Part B (q1wk dosing). 
To reflect the addition 
of 2 subject cohorts 
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Section(s) 
Change 
Rationale 
9.2.2, 9.2.4, 9.2.7 
Confirmed PSA Response Rate: 
Confirmed PSA response rate is defined as the proportion 
of subjects with a reduction from baseline PSA level of at 
least 50%, measured twice ≥3 weeks apart. 
PSA Duration of Response: 
PSA-DOR is defined as the time from the first 
documentation of PSA response (subsequently confirmed at 
least 3 weeks apart) to the first documentation of PSA 
progression or death due to any cause, whichever comes 
first. 
Prostate-Specific Antigen Progression-Free Survival: 
PSA PFS is defined as the time from the start of study 
treatment to first occurrence of PSA progression or death, 
whichever comes first. 
New definitions added  
9.3.1.7 
The PSA evaluable analysis set includes subjects in the 
prostate cancer cohort who received any amount of study 
drug and had both baseline and at least one evaluable post 
baseline PSA measurements. 
Definition added 
9.3.5.1 
For prostate cancer, confirmed PSA response per 
investigator assessment is another primary endpoint. The 
confirmed PSA response is defined as a reduction from 
baseline PSA level of at least 50%, measured twice 
≥3 weeks apart. The confirmed PSA response rate and its 
exact 2 sided 90% CI using the Clopper Pearson method 
(Clopper 1934) will be calculated. 
Primary Efficacy 
Analysis for prostate 
cancer subjects added 
Appendix F 
Edits made in Part A and Part B for G-CSF 
recommendations 
To align with dose 
modifications tables 
and Section 5.3 
Appendix J 
New appendix added as reference 
PCWG3 suggested 
outcome measures for 
clinical trials in 
metastatic prostate 
cancer 
Multiple sections 
Minor editorial corrections and clarifications made in some 
sections of the protocol. 
Corrections and 
clarifications 
 
 
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SUMMARY OF SUBSTANTIVE CHANGES IN AMENDMENT 03 
Document concerned: SGNLVA-005 Protocol Amendment 03 
N° and date of the previous version: 2 dated 27-August-2020 
N° and date of the new version: 3 dated 12-October-2020 
Note: not all of the changes are reproduced in this table, reference is made to the redlined 
amendment 3 of the protocol. 
Initial Wording 
Amended or New Wording 
Reason/Justification for 
Change 
Reason of 
Substantiality 
Section concerned: Table 12 
Withhold until toxicity is 
≤ Grade 2 or baselined,e, then 
reduce dose to the next 
lower dose level (see Table 
11) and resume treatment or 
discontinue at the discretion 
of the investigator.b,c If dose 
held >48 hours, may omit 
and resume dosing at next 
scheduled dosing day. 
Revised wording added: 
Withhold until toxicity resolves to 
≤ Grade 2 or baselined,e, then 
reduce dose to the next lower dose 
level (see Table 11) if treatment is 
resumedb,c. If the dose is held 
>48 hours, the dose may be omitted 
and dosing may resume on the next 
scheduled dosing day. If Grade 4 
neutropenia recurs, reduce dose to 
the next lower dose level (see 
Table 11) if treatment is resumed, 
or discontinue at the discretion of 
the investigator. 
Clarification. The revision 
aims to improve the 
clarity of instructions in 
the management of 
neutropenia and febrile 
neutropenia. 
Safety related  
Section concerned: 7.6.1.5  
The sponsor will report all 
SAEs to regulatory 
authorities as required per 
local legislation or 
regulatory reporting 
requirements. 
Revised wording added: 
The sponsor will report all SAEs, 
including SUSARs, to regulatory 
authorities as required per local 
legislation or regulatory reporting 
requirements. 
Updating language to the 
most current protocol 
template text and to align 
with regulatory guidance. 
Safety related 
Section concerned: 7.6.3 
Results of all clinical 
laboratory tests except 
pregnancy and PSA tests are 
to be submitted to iRIS. 
Revised wording added: 
Results of all clinical laboratory 
tests except pregnancy and PSA 
tests are to be submitted to iRIS. 
Process update. PSA test 
will not be submitted to 
iRIS (collected in CRF 
only). 
Process 
related 
 
 
 
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SUMMARY OF CHANGES IN AMENDMENT 04 
Section(s) 
Change 
Rationale 
Title page 
Added Study Director  information 
Administrative change 
Title page 
Changed Brief Title to “A Study of Ladiratuzumab Vedotin 
in Advanced Solid Tumors” 
Updated to replace the 
abbreviation of the drug 
with the full 
nonproprietary drug 
name and to match 
Brief Title used on 
clinicaltrials.gov 
Protocol Synopsis,  
Section 9.1  
Revised the total number of patients up to approximately 
414 subjects 
Revised number of 
patients to reflect 
addition of Part C 
Section 1.2.3  
Added additional language on non-clinical toxicology 
findings including toxicities in testes and ovarian follicles. 
Updated to include key 
toxicology findings 
since last amendment 
Section 1.2.4  
Updated SGNLVA-001 study information to include Part F 
 
Updated SGNLVA-001 safety and efficacy information to 
align with the LV IB V09 
Part F added to 
SGNLVA-001 protocol 
amendment 15 
 
Updated SGNLVA-001 
safety and efficacy 
information to establish 
rationale for 2q3wk 
dosing (Section 3.2.5)  
Protocol Synopsis, 
Sections 1.4, 2, 
3.1, 3.2.5, 3.2.6, 
3.2.7, 4.1, 4.2, 5, 
6.4, 7.2, 7.3, 
7.6.1.3, 7.6.1.6, 
7.6.2, 7.6.3, 7.7, 
9.1, 9.3.1.1, 
Appendix A, 
Appendix D, 
Appendix G, 
Appendix I 
Addition of Part C, LV monotherapy and LV + 
pembrolizumab combination. Part C includes new study 
arms that apply to Cohort 8 (melanoma) only: 
Arm 1: LV 1.5 mg/kg 2q3wk monotherapy 
Arm 2: LV 1.5 mg/kg 2q3wk + 200 mg pembrolizumab 
q3wk 
Arm 3: LV 1.25 mg/kg q1wk + 200 mg pembrolizumab 
q3wk 
 
Updated Figure 2 and Figure 3 with new study design. 
 
Added new Sections 3.2.5 and 3.2.6 to provide a rationale 
for Part C and new 2q3wk schedule in Arm 1 and Arm 2. 
Updated Sections 3.2.5 and 3.2.6 to reflect Part C addition. 
 
Added new Section 6.4 and Appendix D to outline study 
activities for Part C. 
 
Updated Appendix A and Appendix G to include Part C. 
 
Part C of 
SGNLVA-005 is 
testing the safety and 
efficacy of LV 
monotherapy and LV + 
pembrolizumab 
combination therapy in 
Cohort 8 (melanoma) 
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Study SGNLVA-005 
Clinical Protocol 
Amendment 04; 02-Nov-2022  
Ladiratuzumab vedotin  
Seagen Inc. - Confidential 
Page 162 of 162 
Section(s) 
Change 
Rationale 
Updated Section 7 and Section 9 to include study 
assessments and changes to statistical methods including 
continuous monitoring of the benefit-risk profile for Part C. 
 
Added Appendix I. Response assessments for Arm 2 and 
Arm 3 will use iRECIST criteria in addition to RECIST 
v1.1 to guide treatment decision-making. 
Sections 1.3, 3.2.7, 
5.3, 5.4.4.1, 
5.5.1.2, 5.5.1.3, 
5.5.2.2, 5.5.3, 
5.5.4  
Addition of pembrolizumab drug information: 
 
Added Section 1.3 which includes background for 
pembrolizumab 
 
Added Section 3.2.7 as rationale for pembrolizumab dose. 
 
Updated Section 4 to include inclusion/exclusion criteria 
for Part C pembrolizumab arms. 
 
Added Section 5.3 to include pembrolizumab drug 
information, administration, dose modification, and other 
safety information. Updated Section 5.4 to include 
concomitant therapy information for pembrolizumab. 
Update Section 5.5 to include AE information for 
pembrolizumab. 
Added for Part C 
pembrolizumab 
combination therapy 
(Arm 2 and Arm 3) 
Sections 7.4, 7.4.1  
Added additional detail on biomarkers to be assessed from 
blood samples 
Additional details 
added to more 
accurately convey 
biomarker assessments 
that will be performed 
Section 7.6.1.2  
Updated time period for reporting pregnancy to the Drug 
Safety Department from “within 48 hours” to “within 
24 hours” 
Update to match 
current Seagen Inc. 
policy 
Throughout 
protocol 
Minor editorial corrections and clarifications made in some 
sections of the protocol. 
Corrections and 
clarifications 
 
090177e1a13637f5\Approved\Approved On: 07-Nov-2022 21:36 (GMT)