Conditions: Merkel Cell Carcinoma Small Cell Lung Cancer
Keywords: MCC SCLC
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 4
Healthy volunteers: no

Brief summary:
This is a Phase 1b/2, multiple-dose study designed to describe safety and efficacy, and to assess PK and immunogenicity of XmAb18087 monotherapy and in combination with pembrolizumab in participants with metastatic Merkel cell (MCC) or locoregional MCC that has recurred after locoregional therapy with surgery and/or radiation therapy, and mAb18087 monotherapy in participants with extensive-stage small cell lung cancer (SCLC) that has progressed after standard therapies.

This study was terminated by the sponsor. No participants enrolled in Part B.

Detailed description:

Arms:
arm 1: Part A, will enroll participants with previously treated advanced MCC, consists of safety-run in cohorts followed by an expansion cohort. arm 2: Part B, will enroll participants with advanced MCC not previously treated with anti-programmed cell death 1 (PD1) or anti-programmed cell death ligand 1 (PDL1) agents, consists of safety run-in cohorts followed by an expansion cohort. arm 3: Part C will enroll participants with previously treated extensive-stage SCLC and consists of safety-run in cohorts followed by an expansion cohort.

Interventions: intervention 1: XmAb18087 intervention 2: XmAb18087 ± Pembrolizumab
Intervention descriptions: intervention 1: Monoclonal bispecific antibody intervention 2: XmAb18087 ± Pembrolizumab

Protocol document:
Prot_000.pdf: 
Xencor, Inc 
CONFIDENTIAL 
18 August 2020 
Protocol XmAb18087-02 
Version 1.0 
Page 1 of 145 
CLINICAL STUDY PROTOCOL 
A Phase 1b/2 Multiple-Dose Study to Evaluate the Safety and 
Efficacy of XmAb18087 ± Pembrolizumab in Subjects with 
Advanced Merkel Cell Carcinoma or Extensive-stage Small Cell 
Lung Cancer (DUET-1-02) 
Protocol No.: 
XmAb18087-02  
IND No.: 
IND 136250 
Test Product: 
XmAb®18087 
Indications: 
Advanced Merkel Cell Carcinoma, Extensive-Stage Small Cell 
Lung Cancer 
Sponsor: 
Xencor, Inc. 
111 West Lemon Avenue 
Monrovia, CA 91016 
Development Phase: 
Phase 1b/2 
Sponsor Medical Expert: 
 
 
Telephone: 
 
Email: 
 
Version and Date: 
Version 1.0 (18 August 2020) 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator, potential 
Investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee and/or Institutional Review Board. It is understood that the information will not be 
disclosed to others without written authorization from Xencor, Inc. except to the extent necessary 
to obtain informed consent from those persons to whom the drug may be administered. 
NCT #: NCT04590781


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Protocol XmAb18087-02 
 
 
 
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SIGNATURE PAGES 
 
Declaration of Sponsor or Responsible Medical Expert 
 
PROTOCOL TITLE: A Phase 1b/2 Multiple-Dose Study to Evaluate the Safety and 
Efficacy of XmAb18087 ± Pembrolizumab in Subjects with Advanced Merkel Cell 
Carcinoma or Extensive-stage Small Cell Lung Cancer (DUET-1-02) 
 
PROTOCOL NUMBER: XmAb18087-02 
Xencor, Inc. 
 
This clinical study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational medicinal product 
(IMP), as well as with the moral, ethical and scientific principles governing clinical research as set 
out in the Declaration of Helsinki (Version 2013), and the current guidelines on good clinical 
practices (GCP) applicable to this clinical study. 
 
 
{See appended electronic signature page at the end of the document} 
 
Xencor, Inc. 


Xencor, Inc 
CONFIDENTIAL  
18 August 2020 
Protocol XmAb18087-02 
 
 
 
Version 1.0 
 
Page 3 of 145  
 
SIGNATURE PAGE 
 
Declaration of the Principal Investigator 
 
PROTOCOL TITLE: A Phase 1b/2 Multiple-Dose Study to Evaluate the Safety and 
Efficacy of XmAb18087 ± Pembrolizumab in Subjects with Advanced Merkel Cell 
Carcinoma or Extensive-stage Small Cell Lung Cancer (DUET-1-02) 
 
This clinical study protocol was subjected to critical review and has been released by the Sponsor. 
I have read this protocol and agree that the information it contains is consistent with current risk 
and benefit evaluation of the IMP, as well as with the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki (Version 2013), and the current 
guidelines on GCP applicable to this clinical study. 
I will provide copies of the protocol and of the clinical and preclinical information on the 
investigational product, which was furnished to me by the Sponsor, to all members of the study 
team responsible to me who participate in the study. I will discuss this material with them to assure 
that they are fully informed regarding the study drug and the conduct of the study. 
I will perform the study according to specifications outlined in the protocol and agree to implement 
protocol requirements only after this protocol version and the subject information/informed 
consent forms (ICF) have been approved by the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC). I will not modify this protocol without obtaining the prior approval of the 
Sponsor and of the IRB/IEC. I will submit any protocol modifications (amendments) and/or any 
ICF modifications to the Sponsor and the IRB/IEC, and approval will be obtained before any 
modifications are implemented. 
I understand that the information presented in this study protocol is confidential, and I hereby 
assure that no information based on the conduct of the study will be released without prior consent 
from the Sponsor, Xencor, Inc., unless this requirement is superseded by a regulatory authority, 
eg, United States (US) Food and Drug Administration (FDA). 
I agree to conduct the study as outlined in this clinical study protocol dated 18 August 2020. Any 
modification of the clinical study protocol must be agreed upon by the Sponsor and the 
Investigator(s) and must be documented in writing. 
Principal Investigator 
 
 
Name, Title 
 
Date 
(Day/Month/2020) 
 


Xencor, Inc 
CONFIDENTIAL  
18 August 2020 
Protocol XmAb18087-02 
 
 
 
Version 1.0 
 
Page 4 of 145  
 
GENERAL INFORMATION 
Protocol Title: 
A Phase 1b/2 Multiple-Dose Study to Evaluate the Safety and Efficacy of 
XmAb18087 ± Pembrolizumab in Subjects with Advanced Merkel Cell 
Carcinoma or Extensive-stage Small Cell Lung Cancer (DUET-1-02) 
Protocol No.: 
XmAb18087-02 
Protocol Date: 
Version 1.0, Original (18 August 2020) 
Sponsor: 
Xencor, Inc 
111 West Lemon Avenue 
Monrovia, CA 91016 
Sponsor Medical Monitor: 
 
 
Telephone: 
 
Email: 
 
Adverse Event Reporting: 
 
ICON Clinical Research 
Emergency phone number: 
 (Toll free for US) 
 
 (Toll number for US and outside 
of US) 
E-mail:
 (Americas) 
 (Europe) 
Clinical Research 
Organization: 
ICON Clinical Research Ltd  
South County Business Park 
Leopardstown 
Ireland 
Clinical Laboratories: 
ICON Laboratory Services 
123 Smith Street 
Farmingdale, NY 11735 
Bioanalytical Laboratory 
(PK): 
See Laboratory Manual for contact information. 
Cytokine Laboratory: 
See Laboratory Manual for contact information. 
Immunogenicity (ADA) 
Assessment Laboratory: 
See Laboratory Manual for contact information. 
Flow Cytometry, B Cell, 
NK Cell T Cell Assessment, 
and Immunohistochemistry 
Laboratory 
See Laboratory Manual for contact information. 
Merkel cell polyoma virus 
antibody assay and 
Immunohistochemistry 
Laboratory 
See Laboratory Manual for contact information. 
 


Xencor, Inc 
CONFIDENTIAL  
18 August 2020 
Protocol XmAb18087-02 
 
 
 
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Page 5 of 145  
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Xencor, Inc. 
Name of Investigational Product: 
XmAb®18087 
Name of Active Ingredient: 
XmAb18087 
Protocol Number: XmAb18087-02 
Phase: 1b/2 
Country: United States  
Title of Study:  
A Phase 1b/2 Multiple-Dose Study to Evaluate the Safety and Efficacy of XmAb18087 ± Pembrolizumab in 
Subjects with Advanced Merkel Cell Carcinoma or Extensive-stage Small Cell Lung Cancer (DUET-1-02) 
Study Center(s):  
It is planned that up to 25 study centers will be initiated for this study in the United States. 
Publications: 
None 
Planned Study Period: 
Estimated date first subject enrolled: 31 March 2021 
Estimated date last subject completed: 30 June 2024 
Development Phase: 
Phase 1b/2 
Objectives:  
Primary Objectives: 
The primary objectives of the study are as follows: 
1. To determine the safety and efficacy (by overall response rate [ORR], complete response [CR], and partial 
response [PR] per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria) of XmAb18087 
monotherapy in subjects with advanced Merkel cell carcinoma (MCC) that has progressed after treatment 
with standard therapies 
2. To determine the safety and efficacy (by ORR, CR, and PR per RECIST 1.1 criteria) of XmAb18087 in 
combination with pembrolizumab in subjects with advanced MCC who have not received prior 
anti-programmed cell death 1 (PD1) or anti-programmed cell death ligand 1 (PDL1) therapies, and for whom 
pembrolizumab as a single agent is indicated 
3. To determine the safety and efficacy (by ORR, CR, and PR per RECIST 1.1 criteria) of XmAb18087 
monotherapy in subjects with extensive-stage small cell lung cancer (SCLC) that has progressed after 
treatment with standard therapies 
Secondary Objectives: 
The secondary objectives of the study are as follows: 
1. To assess antitumor activity of XmAb18087 by progression-free survival (PFS) per RECIST 1.1 criteria, as 
well as overall survival (OS) and duration of response, when administered with and without pembrolizumab 
in subjects with advanced MCC, and as monotherapy in subjects with extensive-stage SCLC 
2. To characterize the pharmacokinetics (PK) and immunogenicity of XmAb18087 administered with and 
without pembrolizumab in subjects with advanced MCC, and as monotherapy in subjects with extensive-stage 
SCLC 
3. To assess the PK profile (maximum observed serum concentration [Cmax] and Cmin[trough]) of pembrolizumab 
when co-administered with XmAb18087 
Exploratory Objectives: 
The exploratory objectives of the study are as follows: 


Xencor, Inc 
CONFIDENTIAL  
18 August 2020 
Protocol XmAb18087-02 
 
 
 
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Page 6 of 145  
 
1. To assess the incidence, timing, and severity of cytokine release syndrome (CRS) by the following: 
a. CRS-related adverse events (AEs), incidence and grade of AEs and incidence of serious adverse events 
[SAEs]) 
b. Biomarkers of CRS 
2. To characterize the response to administration of XmAb18087 with and without pembrolizumab by 
assessment of cell surface markers on selected immune system cells in peripheral blood, including changes in 
lymphocyte subsets and in T-cell activation/exhaustion by flow cytometry and similar bioanalytical methods 
3. To characterize pharmacodynamics (PD) by correlation of response with NETSPOT® (gallium 68 dotatate) 
positron emission tomography/computed tomography (PET/CT) scan results after XmAb18087 
administration with and without pembrolizumab 
4. To evaluate by immunohistochemistry tumor-cell expression of somatostatin receptor 2 (SSTR2) and PDL1 
on tumor cells and tumor-infiltrating T cells for expression of proliferation markers and PD1/PDL1 after 
XmAb18087 administration with and without pembrolizumab, as well as changes in other immune cell subsets 
5.  To characterize the pharmacodynamic changes in the intratumoral inflammatory response using 
immunostaining of immune cells and analysis of RNA signatures 
6. To correlate response in MCC subjects to Merkel cell polyomavirus (MCPyV) status as determined by 
serology and immunohistochemistry 
Methodology:  
This is a Phase 1b/2, multiple-dose study designed to describe safety and efficacy, and to assess PK and 
immunogenicity of XmAb18087 monotherapy and in combination with pembrolizumab in subjects with 
metastatic MCC or locoregional MCC that has recurred after locoregional therapy with surgery and/or radiation 
therapy, and XmAb18087 monotherapy in subjects with extensive-stage SCLC that has progressed after standard 
therapies. 
Part A of the study will enroll safety run-in cohorts of subjects with advanced MCC that has progressed after 
treatment with standard therapies to confirm the safety and tolerability of the XmAb18087 monotherapy 
administered intravenously (IV) with weekly step-up dosing for 42-day cycles. Additional subjects will be 
enrolled into an expansion cohort and will receive XmAb18087 monotherapy using the recommended dose (RD) 
identified following the safety run-in. 
Part B of the study will enroll safety run-in cohorts of subjects with advanced MCC not previously treated with 
anti-PD1 or anti-PDL1 agents, and for whom pembrolizumab as a single agent is indicated, to confirm the safety 
and tolerability of XmAb18087 in combination with pembrolizumab. Subjects will receive step-up IV dosing of 
XmAb18087 on Days 1, 8, 22, 29, and 36, and IV dosing of pembrolizumab on Day 15 of each 42-day cycle. 
Additional subjects will be enrolled into an expansion cohort and will receive XmAb18087 plus pembrolizumab 
combination therapy using the RD identified following the safety run-in. 
Enrollment into the first safety run-in cohort of Part B (Cohort 1B) may begin after the first safety run-in cohort 
in Part A (Cohort 1A, one dose level higher than Cohort 1B) has completed the first cycle and the regimen has 
been demonstrated to be tolerable. 
Part C of the study will enroll safety run-in cohorts of subjects with extensive-stage SCLC that has progressed 
after treatment with standard therapies to confirm the safety and tolerability the same XmAb18087 monotherapy. 
The safety run-in will follow the same cohort schema as described for Part A to identify a RD for expansion in 
SCLC. Additional subjects will be enrolled into an expansion cohort and will receive XmAb18087 monotherapy 
using the RD identified following the safety run-in. 
Enrollment into Part C may begin concurrently with Part A. 
Termination of Study 
If the Investigator or the Sponsor becomes aware of conditions or events that suggest a possible hazard to subjects 
should the clinical study continue, the clinical study may be terminated after appropriate consultation among the 
involved parties. The clinical study also may be terminated at the Sponsor’s discretion, also in the absence of such 
a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
•  The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in the clinical study. 


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18 August 2020 
Protocol XmAb18087-02 
 
 
 
Version 1.0 
 
Page 7 of 145  
 
•  Failure to enroll subjects at the required rate. 
•  A decision of the Sponsor to suspend or discontinue development of the investigational medicinal product 
(IMP). 
Should the study be terminated and/or the site closed for whatever reason, all documentation pertaining to the 
study and IMP must be returned to the Sponsor. Any actions required for assessing or maintaining subject safety 
will continue as required, despite termination of the study by the Sponsor. 
Treatment Plan: 
Part A, which will enroll subjects with previously treated advanced MCC, consists of safety-run in cohorts 
followed by an expansion cohort. For the first safety run-in cohort (Cohort 1A), 3 to 6 subjects will be enrolled 
and will receive step-up dosing as follows: 0.3 µg/kg on Day 1, followed by 1.0 µg/kg on Days 8, 15, 22, 29, and 
36 of the first cycle, and Days 1, 8, 15, 22, 29, and 36 of all subsequent cycles. If the Cohort 1A regimen is not 
tolerated, lower dose levels may be explored. If the Cohort 1A regimen is tolerated, 3 to 6 subjects will be enrolled 
in Cohort 2A and will receive step-up dosing as follows: 0.3 µg/kg on Day 1, 1.0 µg/kg on Day 8, and 2.0 µg/kg 
on Days 15, 22, 29, and 36 of the first cycle and Days 1, 8, 15, 22, 29, and 36 of all subsequent cycles. If this 
regimen is tolerated, 3 to 6 subjects will be enrolled in Cohort 3A and will receive step-up dosing as follows: 
0.3 µg/kg on Day 1, 1.0 µg/kg on Day 8, 2.0 µg/kg on Day 15, and 4.0 µg/kg on Days 22, 29, and 36 of the first 
cycle and Days 1, 8, 15, 22, 29, and 36 of all subsequent cycles. See Cohort Table A. 
Based on assessments of tolerability, safety, and PK data from all the safety run-in cohorts in Part A, an RD 
regimen for expansion will be selected. Up to 9 subjects will be enrolled at the RD. If at least 1 subject shows a 
response by RECIST 1.1 criteria, then enrollment will continue up to a total of 22 subjects to evaluate efficacy. 
Part B, which will enroll subjects with advanced MCC not previously treated with anti-PD1 or anti-PDL1 agents, 
consists of safety run-in cohorts followed by an expansion cohort. Safety run-in Cohort 1B (one dose level below 
Cohort 1A) will begin enrolling after Cohort 1A is completed and the dosing regimen is deemed tolerable. For all 
Part B cohorts, 400 mg pembrolizumab will be administered IV on Day 15 of each 42-day cycle. Three to 
6 subjects will be enrolled in Cohort 1B and will receive XmAb18087 administered IV as follows: 0.3 µg/kg on 
Days 1, 8, 22, 29, and 36 of all cycles. If this regimen is tolerated, 3 to 6 additional safety run-in subjects will be 
enrolled in Cohort 2B and will receive step-up IV dosing of XmAb18087 as follows: 0.3 µg/kg on Day 1, then 
1.0 µg/kg on Days 8, 22, 29, and 36 of the first cycle and Days 1, 8, 22, 29, and 36 of all subsequent cycles. If 
this regimen is tolerated, 3 to 6 subjects will be enrolled in Cohort 3B and will receive step-up IV dosing of 
XmAb18087 as follows: 0.3 µg/kg on Day 1, 1.0 µg/kg on Days 8 and 22, then 2.0 µg/kg on Days 29 and 36 of 
the first cycle and Days 1, 8, 22, 29, and 36 of all subsequent cycles. If this regimen is tolerated, 3 to 6 subjects 
will be enrolled in Cohort 4B and will receive step-up IV dosing of XmAb18087 as follows: 0.3 µg/kg on Day 1, 
1.0 µg/kg on Days 8 and 22, 2.0 µg/kg on Days 29 and 36 of the first cycle and Day 1 of all subsequent cycles, 
and 4.0 µg/kg and Days 1, 8, 22, 29, and 36 of all cycles after the first cycle. See Cohort Table B. 
Based on assessments of tolerability, safety, and PK data from all the safety run-in cohorts in Part B, an RD for 
expansion will be selected. Up to 12 subjects will be enrolled at the RD. If at least 4 subjects show a response by 
RECIST 1.1 criteria, enrollment will continue up to a total of 30 subjects to evaluate efficacy. 
Part C will enroll subjects with previously treated extensive-stage SCLC and consists of safety-run in cohorts 
followed by an expansion cohort. Part C will follow the same safety run-in schema as described for Part A. See 
Cohort Table C. 
Based on assessments of tolerability, safety, and PK data from all the safety run-in cohorts in Part C, an RD for 
expansion will be selected. Up to 9 subjects will be enrolled at the RD. If at least 1 subject shows a response by 
RECIST 1.1 criteria, then enrollment will continue up to a total of 30 subjects to evaluate efficacy. Throughout 
the study, SSTR2 expression levels and prevalence will be assessed histologically using tumor biopsies from 
enrolled subjects; a higher number of subjects may be enrolled in the Part C expansion cohort based on these 
assessments.  
Parts A, B, and C: The decision to advance to higher dose levels after each safety run-in cohort will be made by 
a Safety Review Committee (SRC) based on review of the aggregate safety data for all subjects in that cohort as 
well as cumulative safety data for the study overall. The SRC will be allowed to make adaptations to the dosing 
schema, if needed, in accordance with evolving trial safety and tolerability findings, as long as adaptations do not 
significantly increase subject risk. Any such adaptations would require a protocol amendment and Institutional 
Review Board (IRB) approval. 


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Schema: 
MCC = Merkel cell carcinoma; PD1 = programmed cell death protein 1; PDL1 = programmed cell death ligand 1; 
SCLC = small cell lung cancer. 
Number of Subjects:  
Up to 142 subjects will be enrolled. 
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Inclusion Criteria for All Cohorts 
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
•
Able to provide written informed consent
•
Adult subjects ≥ 18 years
•
Disease measurable by RECIST 1.1 criteria using either CT or magnetic resonance imaging (MRI) scan
•
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
•
All subjects must have adequate archival tumor sample (slides or archival formalin-fixed paraffin-embedded
[FFPE] block[s] containing tumor that has not been previously irradiated; FFPE blocks are preferred to slides,
and newly obtained biopsies are preferred to archived tissue. Refer to the laboratory manual for further
instructions). Excepted are subjects who consent to having a fresh tumor biopsy to provide a fresh tumor
sample instead of the archival tumor sample.
•
Female subjects of childbearing potential must agree to use a highly effective method of birth control during
and for 4 weeks after completion of study. Women are considered to be of childbearing potential unless it is
documented that they are over the age of 60 OR postmenopausal by history with no menses for 1 year and
confirmed by follicle-stimulating hormone (FSH; using local reference ranges) OR have a history of
hysterectomy and/or bilateral oophorectomy OR have a history of bilateral tubal ligation. Highly effective
methods of birth control include combined hormonal birth control (oral, intravaginal, or transdermal), or
progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or
intrauterine), intrauterine devices (IUDs), intrauterine hormone-releasing system, bilateral tubal occlusion,
vasectomized partner (provided partner is the sole sexual partner and there has been a medical assessment of
surgical success), or sexual abstinence as defined in Section 8.9.1.
•
Fertile male subjects must be willing to practice a highly effective method of birth control for the duration of
the study and continuing for 4 weeks after the last dose of XmAb18087 or pembrolizumab (when applicable).


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Highly effective methods of birth control include vasectomy or a condom in combination with double-barrier 
methods, spermicide, hormonal birth control, or IUD (nonhormonal) used by the woman. 
 • Able and willing to complete the entire study according to the study schedule 
 
Additional Inclusion Criteria for Part A and Part B Cohorts:  
In addition to the inclusion criteria above, the following criteria are required for Parts A and B safety run-in and 
expansion cohorts: 
• 
Histologically or cytologically confirmed metastatic MCC or locoregional MCC that has recurred following 
standard locoregional therapy with surgery and/or radiation therapy 
Additional Inclusion Criteria for Part A Cohorts:  
In addition to the inclusion criteria above, the following criteria are required for Part A safety run-in and expansion 
cohorts: 
• 
Subjects must have progressed on or been ineligible for treatment with anti-PD1 or anti PDL1 therapy. 
Additional Inclusion Criteria for Part B Cohorts: 
In addition to the inclusion criteria above, the following criteria are required for Part B safety run in and expansion 
cohorts: 
• 
Subjects must be eligible to receive pembrolizumab as standard of care. 
Additional Inclusion Criteria for Part C Cohorts:  
In addition to the inclusion criteria above, the following criteria are required for Part C safety run-in and expansion 
cohorts: 
•  Histologically or cytologically confirmed extensive-stage SCLC that has progressed following standard 
therapies 
Exclusion Criteria for All Cohorts 
Subjects who meet any of the following criteria will be excluded from the study: 
• 
History of prior organ or bone marrow transplant 
• 
History of chronic lymphocytic leukemia 
• 
Subjects currently receiving anticancer therapies 
• 
Subjects who have received anticancer therapies within 2 weeks of the start of study drug (including 
chemotherapy, radiation therapy, immunotherapy, etc.) 
• 
Prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA4, OX40, 
CD137) AND were permanently discontinued from that treatment due to an immune-related adverse event 
(IRAE) 
• 
Failure to recover from any IRAE from prior cancer therapy to ≤ Grade 1 (participants with ≤ Grade 2 
neuropathy or endocrinopathies controlled by hormone replacement are eligible) 
 • Failure to recover from any other toxicity (other than immune-related toxicity) from previous anticancer 
treatment to ≤ Grade 2 
• 
Known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously 
treated brain metastases may participate provided they are stable (without evidence of progression by imaging 
for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 28 days 
prior to trial treatment. 
• 
Have a history of (noninfectious) pneumonitis that required steroids or have current pneumonitis (history of 
radiographically visible but asymptomatic radiation pneumonitis is allowed) 
• 
Platelet count < 50 × 109/L 
• 
Absolute neutrophil count < 1.0 × 109/L 
•  Aspartate aminotransferase (AST) ≥ 3 × upper limit of normal (ULN), or if subject has known liver 
metastases, AST ≥ 7 × ULN 
•  Alanine aminotransferase (ALT) ≥ 3 × ULN, or if subject has known liver metastases, ALT ≥ 7 × ULN 


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•  Estimated creatinine clearance < 50 mL/min calculated by the Cockcroft Gault or Modification of Diet in 
Renal Disease formulas at screening 
•  Treatment with immunosuppressive therapy within 28 days of first dose of study drug 
•  History or evidence of any other clinically unstable/uncontrolled disorder, condition, or disease (including, 
but not limited to, cardiopulmonary, renal, metabolic, hematologic, or psychiatric) other than their primary 
malignancy that in the opinion of the Investigator would pose a risk to subject safety or interfere with the 
study evaluation, procedures, or completion 
•  Treatment for any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to 
study entry 
• 
Active known or suspected COVID-19 disease 
• 
Active known or suspected autoimmune disease (except that subjects are permitted to enroll if they have 
vitiligo; type 1 diabetes mellitus; residual hypothyroidism due to an autoimmune condition that is treatable 
with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition 
that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral 
acetaminophen and nonsteroidal anti-inflammatory drugs [NSAIDS]) 
•  Positive test for human immunodeficiency virus (HIV) or hepatitis C antibodies 
•  Positive test for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb; a subject whose 
HBsAg is negative and HBcAb is positive may be enrolled if a hepatitis B virus [HBV] DNA test is negative 
and either the subject is treated with potent antiviral therapy or is retested for HBsAg and HBV DNA every 
month) 
•  Subject is pregnant or breastfeeding, planning to become pregnant, or expecting to conceive or father children 
while enrolled in the study, up to the end of study (EOS) visit. 
•  Positive serum pregnancy test (ie, urine human chorionic gonadotropin) at screening 
Additional Exclusion Criteria for Part B Cohorts:  
In addition to the exclusion criteria above, subjects will be excluded from Part B cohorts administered 
XmAb18087 in combination with pembrolizumab if they meet the following criteria: 
• 
Prior treatment with therapeutics directed at anti-programmed cell death 1 (anti-PD1) or anti-programmed 
cell death ligand 1 (anti-PDL1) 
• 
Have severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients 
Test Product, Dose, and Mode of Administration: 
XmAb18087 is a humanized bispecific antibody (bsAb) that binds both the tumor antigen SSTR2 and CD3 
antigen to recruit cytotoxic T cells for killing of SSTR2+ tumor cells.
 
 
 
  
The cohorts and dose levels to be administered in this clinical trial are shown below. 
 
 


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Cohorts 
Cohort Table A: Part A (MCC) Monotherapy Safety Run-in and Expansion Cohorts 
  
Cycle 
and Day 
Cycle 1 
Cycle 2+ 
Subjects 
D1 
D8 D15 D22 D29 D36 
D40 
 ± 2 
D1 
D8  D15 D22 D29 
D36  
D40  
± 2 
Drug 
XmAb18087 
(μg/kg) 
EA 
XmAb18087  
(μg/kg) 
EA 
Study 
Day 
1 
8 
15 
22 
29 
36 
40 
43 
50 
57 
64 
71 
78 
82 
Part A 
(Safety 
Run-in) 
1A 
0.3 1.0 
1.0 
1.0 
1.0 
1.0 
--- 
1.0 
1.0 
1.0 
1.0 
1.0 
1.0 
--- 
3 – 6 
2A 
0.3 1.0 
2.0 
2.0 
2.0 
2.0 
--- 
2.0 
2.0 
2.0 
2.0 
2.0 
2.0 
--- 
3 - 6 
3A 
0.3 1.0 
2.0 
4.0 
4.0 
4.0 
--- 
4.0 
4.0 
4.0 
4.0 
4.0 
4.0 
--- 
3 - 6 
Part A 
(Expansion) 
Expansion 
A 
At RD cohort 
Up to 22 
D = day; EA = efficacy assessment (no drug administered). Maximum escalated dose for each cohort in bold. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Cohort Table B: Part B (MCC) Combination Therapy Safety Run-in and Expansion Cohorts 
  
Cycle 
and Day 
Cycle 1 
Cycle 2+ 
Subjects 
D1 
D8 
D15 
D22 D29 
D36 
D40 
± 2 
D1 
D8 
D15 
D22 
D29 
D36 
 
D40 
± 2  
Drug 
XmAb18087 
(μg/kg) 
Pem 
(mg) 
XmAb18087 
(μg/kg) 
EA 
XmAb18087 
(μg/kg) 
Pem 
(mg) 
XmAb18087 
(μg/kg) 
EA 
Study 
Day 
1 
8 
15 
22 
29 
36 
40 
43 
50 
57 
64 
71 
78 
82 
Part B 
(Safety 
Run-in) 
1B 
0.3 
0.3 
400 
0.3 
0.3 
0.3 
--- 
0.3 
0.3 
400 
0.3 
0.3 
0.3 
--- 
3 – 6 
2B 
0.3 
1.0 
400 
1.0 
1.0 
1.0 
--- 
1.0 
1.0 
400 
1.0 
1.0 
1.0 
--- 
3 – 6 
3B 
0.3 
1.0 
400 
1.0 
2.0 
2.0 
--- 
2.0 
2.0 
400 
2.0 
2.0 
2.0 
--- 
3 – 6 
4B 
0.3 
1.0 
400 
1.0 
2.0 
2.0 
--- 
2.0 
4.0 
400 
4.0 
4.0 
4.0 
--- 
3 – 6 
Part B 
(Expansion) 
Expansion 
B 
At RD cohort 
Up to 30 
D = day; EA = efficacy assessment (no drug administered); Pem = pembrolizumab. Maximum escalated dose for each cohort in bold. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Cohort Table C: Part C (SCLC) Monotherapy Safety Run-in and Expansion Cohorts 
  
Cycle 
and Day 
Cycle 1 
Cycle 2+ 
Subjects 
D1 
D8 D15 D22 D29 D36 
D40 
 ± 2 
D1 
D8  D15 D22 D29 
D36  
D40  
± 2 
Drug 
XmAb18087 
(μg/kg) 
EA 
XmAb18087  
(μg/kg) 
EA 
Study 
Day 
1 
8 
15 
22 
29 
36 
40 
43 
50 
57 
64 
71 
78 
82 
Part C 
(Safety 
Run-in) 
1C 
0.3 1.0 
1.0 
1.0 
1.0 
1.0 
--- 
1.0 
1.0 
1.0 
1.0 
1.0 
1.0 
--- 
3 - 6 
2C 
0.3 1.0 
2.0 
2.0 
2.0 
2.0 
--- 
2.0 
2.0 
2.0 
2.0 
2.0 
2.0 
--- 
3 – 6 
3C 
0.3 1.0 
2.0 
4.0 
4.0 
4.0 
--- 
4.0 
4.0 
4.0 
4.0 
4.0 
4.0 
--- 
3 - 6 
Part C 
(Expansion) 
Expansion 
C 
At RD cohort 
Up to 30 
D = day; EA = efficacy assessment (no drug administered). Maximum escalated dose for each cohort in bold. 
 


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Reference Therapy, Dosage, and Mode of Administration:  
None 
Duration of Treatment:  
Each treatment cycle (Parts A, B, and C) is 42 days long. In Parts A and C, each cycle will consist of 6 weekly 
doses of XmAb18087 (on Days 1, 8, 15, 22, 29, and 36). In Part B, each cycle will consist of 6 weekly doses of 
either XmAb18087 or pembrolizumab: 5 doses of XmAb18087 (on Days 1, 8, 22, 29, and 36) and 1 dose of 
pembrolizumab (on Day 15). 
Criteria for Evaluation: 
Safety: 
As assessed by AEs, vital signs, physical examination (PE) findings, clinical laboratory safety assessments, and 
electrocardiogram (ECG) parameters: 
•  Incidence of treatment-emergent AEs (TEAEs), treatment-emergent serious adverse events (TESAEs), 
treatment-related TEAEs and TESAEs, TEAEs by severity as defined in the National Cancer Institute’s (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and TEAEs resulting in the 
permanent discontinuation of XmAb18087 or pembrolizumab. 
Efficacy: 
Antitumor activity of XmAb18087 as assessed by response rates (ORR, CR rate, PR rate), duration of response, 
PFS, and OS. 
Pharmacokinetics: 
Pharmacokinetic parameters including Cmax, time to reach maximum concentration (tmax), half-life (t1/2), area 
under the serum concentration-time curve from time zero to infinity (AUC0-∞), clearance (CL), volume of 
distribution (Vd), and volume of distribution at steady state (Vdss) will be estimated using either 
noncompartmental or compartmental methods, whichever best describes the observed data. Pharmacokinetic 
parameters for XmAb18087 will be compared with and without pembrolizumab administration. 
Pharmacodynamics: 
Baseline and serial assessment of B-cell, NK-cell, and T-cell numbers and T-cell activation will be assessed in 
peripheral venous blood. 
Endpoints: 
Primary Endpoints: 
The primary endpoints are as follows:  
• Safety of (1) XmAb18087 monotherapy in MCC and SCLC, and (2) XmAb18087 and pembrolizumab 
combination therapy in MCC, as assessed by the following: 
- 
Incidence of TEAEs 
- 
Incidence of clinically significant changes in safety laboratory tests, PE findings, vital signs, and ECGs 
- 
Incidence and severity of CRS 
• Efficacy of (1) XmAb18087 monotherapy in MCC and SCLC, and (2) XmAb18087 and pembrolizumab 
combination therapy in MCC using RECIST 1.1 assessment of CT/MRI imaging, as well as aggregate data, 
for the following: 
- 
ORR 
- 
CR rate 
- 
PR rate 
Secondary Endpoints: 
The secondary endpoints are as follows: 
• Efficacy of (1) XmAb18087 monotherapy in MCC and SCLC, and (2) XmAb18087 and pembrolizumab 
combination therapy in MCC using RECIST 1.1 assessment of CT/MRI imaging, as well as aggregate data, 
for the following: 
- 
Duration of response 


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- 
PFS 
- 
OS 
• PK characterization of XmAb18087, when administered as monotherapy and in combination with 
pembrolizumab, based on the parameters of Cmax, tmax, t1/2, AUC0-∞, CL, Vd, and Vdss. Further details will be 
defined in a PK analysis plan. 
• Assessment of immunogenicity by incidence of anti-XmAb18087 antibodies and qualitative assessment of 
safety outcomes 
• PK characterization of pembrolizumab, when administered in combination with XmAb18087, based on 
parameters similar to those for XmAb18087, with further details to be provided in a PK analysis plan. 
Exploratory Endpoints: 
The exploratory endpoints are as follows: 
• Assessment of peripheral blood for cell surface markers by flow cytometry and similar bioanalytical methods 
that evaluate the response of selected immune system cells following administration of XmAb18087 as a 
monotherapy and in combination with pembrolizumab, including changes in lymphocyte subsets and in T-cell 
activation and exhaustion markers 
• PD characterized by NETSPOT (gallium 68 dotatate) PET/CT results and by tumor cell expression of SSTR2 
and PDL1 and tumor-infiltrating immune-cell expression of PD1/PDL1 and other markers by 
immunohistochemistry, in response to administration of XmAb18087 monotherapy and in combination with 
pembrolizumab 
• PD: immunohistochemistry (IHC) SSTR2 panel 
• PD: MCC and SCLC IHC panels 
• Correlation of clinical/radiographic response with MCPyV serology (MCC subjects only) 
• Additional exploratory genetic, cellular, and/or serum markers of potential future interest. If evidence of 
therapeutic activity is seen with XmAb18087, biobanked samples may be assessed for genetic and 
immunologic factors that might predict response or nonresponse (optional part of study and may be reported 
separately from the clinical study report). Samples will not be retained for more than 15 years. 
Statistical Methods: 
Analysis Populations: 
The populations defined below will be used for analysis: 
• Safety population: All subjects who are enrolled and receive at least 1 infusion of XmAb18087.  
• Evaluable population: All subjects who are enrolled, receive at least 1 cycle (Parts A and C: 6 doses 
XmAb18087, Part B: 5 doses XmAb18087 and 1 dose pembrolizumab) of XmAb18087 and have at least 
1 postbaseline RECIST 1.1 assessment of tumor imaging available.  
• PD population: All subjects who are enrolled, receive at least 1 dose of XmAb18087 (and 1 infusion of 
pembrolizumab, when relevant for a particular PD assessment), and have at least 1 preinfusion and 
1 postinfusion set of biomarker data available for analysis.  
• PK populations: All subjects who are enrolled and receive at least 1 dose of XmAb18087 (ie, the XmAb18087 
PK population) or 1 infusion of pembrolizumab, (ie, the pembrolizumab PK population), and have at least 1 
set of postinfusion PK data available for analysis. 
Continuous data will be presented using descriptive statistics: number of subjects (N), mean, standard deviation, 
median, minimum, and maximum. Categorical data will be summarized by the number and percentage, where the 
percentage is presented in brackets to 1 decimal place. Safety and efficacy summaries will be provided for the 
monotherapy and combination therapy arms separately, as well as for the combined arms. 
Date of the Protocol: 18 August 2020 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
SIGNATURE PAGES .....................................................................................................................2 
GENERAL INFORMATION ..........................................................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
LIST OF TABLES .........................................................................................................................21 
LIST OF FIGURES .......................................................................................................................22 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................23 
5. 
INTRODUCTION ......................................................................................................27 
5.1. 
Background .................................................................................................................27 
5.1.1. 
Somatostatin and Somatostatin Receptors ..................................................................27 
5.1.2. 
Merkel Cell Carcinoma ...............................................................................................27 
5.1.3. 
Small Cell Lung Cancer..............................................................................................29 
5.1.4. 
Therapeutic Bispecific Antibodies .............................................................................29 
5.1.5. 
XmAb18087 Product Description ..............................................................................29 
5.1.6. 
Preclinical Studies ......................................................................................................30 
5.1.6.1. 
Pharmacology .............................................................................................................30 
5.1.6.2. 
Pharmacokinetics and Toxicokinetics ........................................................................33 
5.1.6.3. 
Toxicology ..................................................................................................................34 
5.1.7. 
Human Experience with XmAb18087 and Related Molecules ..................................36 
5.2. 
Pembrolizumab ...........................................................................................................37 
5.2.1. 
Pharmaceutical and Therapeutic Background ............................................................37 
5.2.2. 
Nonclinical Studies .....................................................................................................38 
5.2.3. 
Justification for Pembrolizumab Dose ........................................................................38 
5.3. 
Rationale for Dose Selection of XmAb18087-01 FIH, XmAb18087-02, and 
Study Design ...............................................................................................................38 
6. 
STUDY OBJECTIVES ..............................................................................................40 
6.1. 
Primary Objectives .....................................................................................................40 
6.2. 
Secondary Objectives .................................................................................................40 


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6.3. 
Exploratory Objectives ...............................................................................................40 
7. 
INVESTIGATIONAL PLAN .....................................................................................42 
7.1. 
Overall Study Design and Plan ...................................................................................42 
7.2. 
Study Flowcharts ........................................................................................................44 
7.3. 
Dosing Schedule .........................................................................................................44 
7.4. 
Continuation/Discontinuation of Therapy ..................................................................49 
7.4.1. 
Continuation Prior to Progression ..............................................................................49 
7.4.2. 
Continuation/Discontinuation at Progression .............................................................49 
7.4.3. 
Intrasubject Dose Escalation .......................................................................................50 
7.5. 
Number of Subjects ....................................................................................................50 
7.6. 
Treatment Assignment ................................................................................................50 
7.7. 
Safety Run-in Cohorts ................................................................................................51 
7.8. 
Criteria for Adverse Events of Specific Concern and Dose Adjustment ....................51 
7.8.1. 
Replacement of Subjects .............................................................................................52 
7.8.2. 
Criteria for Study Termination ...................................................................................52 
7.9. 
Study Assessments......................................................................................................53 
7.9.1. 
Pretreatment Evaluations ............................................................................................60 
7.9.1.1. 
Screening Period (Day -28 to -2) ................................................................................60 
7.9.1.2. 
Baseline Assessments (Day -1 or 1) ...........................................................................61 
7.9.2. 
Subject Enrollment .....................................................................................................62 
7.9.3. 
Treatment Cycle Assessments ....................................................................................62 
7.9.3.1. 
Clinical Assessments ..................................................................................................62 
7.9.3.2. 
Laboratory Assessments .............................................................................................63 
7.9.3.3. 
End-of-Treatment Visit ...............................................................................................64 
7.9.4. 
Post-treatment Follow-up Period (2 Weeks and 4 Weeks After EOT).......................64 
7.9.5. 
Long-Term Follow-up Period (6 and 12 Months After EOT) ....................................64 
7.10. 
Discussion of Study Design ........................................................................................64 
7.10.1. 
Risk/Benefit and Ethical Assessment .........................................................................65 
7.10.2. 
Termination of Study ..................................................................................................65 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................66 
8.1. 
Inclusion Criteria for All Cohorts ...............................................................................66 
8.2. 
Additional Inclusion Criteria for Part A and Part B Cohorts: ....................................66 
8.3. 
Additional Inclusion Criteria for Part A Cohorts: ......................................................67 


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8.4. 
Additional Inclusion Criteria for Part B Cohorts:.......................................................67 
8.5. 
Additional Inclusion Criteria for Part C Cohorts:.......................................................67 
8.6. 
Exclusion Criteria for All Cohorts ..............................................................................67 
8.7. 
Additional Exclusion Criteria for Part B Cohorts: XmAb18087 in 
Combination with Pembrolizumab .............................................................................69 
8.8. 
Withdrawal of Subjects...............................................................................................69 
8.9. 
Other Subject Restrictions ..........................................................................................70 
8.9.1. 
Avoidance of Pregnancy .............................................................................................70 
8.9.2. 
Use in Nursing Women ..............................................................................................70 
9. 
TREATMENT OF SUBJECTS ..................................................................................71 
9.1. 
Identity of Study Treatments ......................................................................................71 
9.2. 
Concomitant Therapy .................................................................................................71 
9.2.1. 
Permitted Medications ................................................................................................71 
9.2.2. 
Excluded Medications ................................................................................................72 
9.3. 
Subject Compliance ....................................................................................................72 
9.4. 
Blinding and Randomization of Study Treatment ......................................................72 
9.5. 
Procedure for Breaking the Randomization Code ......................................................72 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................73 
10.1. 
XmAb18087 ...............................................................................................................73 
10.1.1. 
Pretreatment of XmAb18087 ......................................................................................73 
10.1.2. 
Prophylaxis of Nausea and Vomiting .........................................................................73 
10.1.3. 
Prophylaxis of Infusion Reactions/Cytokine Release Syndrome: ..............................73 
10.1.4. 
Administration of XmAb18087 ..................................................................................74 
10.2. 
Pembrolizumab (Keytruda®) ......................................................................................74 
10.2.1. 
Administration of Pembrolizumab .............................................................................74 
10.2.2. 
Treatment of Overdose ...............................................................................................75 
10.3. 
Safety Criteria for Dose Adjustment or Stopping Dose .............................................75 
10.3.1. 
Criteria for Adjustment or Stopping Dose of XmAb18087 ........................................75 
10.3.2. 
Criteria for Adjustment or Stopping Dose of Pembrolizumab ...................................76 
10.4. 
Study Treatment Packaging and Labelling .................................................................76 
10.4.1. 
Packaging and Labelling of XmAb18087 ..................................................................76 
10.4.2. 
Storage of XmAb18087 ..............................................................................................76 
10.4.3. 
Preparation of XmAb18087 ........................................................................................76 


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10.4.4. 
Packaging and Labeling of Pembrolizumab ...............................................................76 
10.4.5. 
Storage of Pembrolizumab .........................................................................................77 
10.5. 
Study Treatment Accountability, Handling, and Disposal .........................................77 
11. 
ASSESSMENT OF SAFETY.....................................................................................78 
11.1. 
Adverse Events ...........................................................................................................78 
11.1.1. 
Definitions ..................................................................................................................78 
11.1.2. 
Recording of Adverse Events .....................................................................................80 
11.1.2.1. 
Intensity ......................................................................................................................80 
11.1.2.2. 
Causality .....................................................................................................................81 
11.1.2.3. 
Action Taken with Study Treatment ...........................................................................82 
11.1.2.4. 
Outcome ......................................................................................................................82 
11.1.3. 
Preidentified Immune-Mediated Adverse Events .......................................................83 
11.1.4. 
Adverse Events of Special Interest .............................................................................83 
11.1.4.1. 
Deaths .........................................................................................................................83 
11.1.4.2. 
Pregnancy ...................................................................................................................83 
11.1.5. 
Reporting Serious Adverse Events .............................................................................84 
11.1.6. 
Follow-up of Adverse Events .....................................................................................85 
11.1.7. 
Treatment/Reporting of Overdose ..............................................................................85 
11.2. 
Investigational New Drug Safety Reports ..................................................................86 
11.3. 
Guidelines for Prophylaxis and Management of Hypersensitivity Reactions, 
Cytokine Release Syndrome, and Neurological Toxicity Attributed to 
XmAb18087 ...............................................................................................................86 
11.3.1. 
Introduction and Grading ............................................................................................86 
11.3.2. 
Cytokine Release Syndrome Versus Allergic or Hypersensitivity Reactions ............87 
11.3.3. 
Treatment Guidelines for Cytokine Release Syndrome .............................................88 
11.3.3.1. 
Use of Tocilizumab for Cytokine Release Syndrome ................................................88 
11.3.3.2. 
Fluid Management ......................................................................................................89 
11.3.3.3. 
Cytokine Release Syndrome Treatment Guidelines by Grade ...................................89 
11.3.3.4. 
Neurotoxicity ..............................................................................................................91 
11.4. 
Guidelines for Prophylaxis and Management of Infusion Reactions 
Attributed to Pembrolizumab .....................................................................................94 
11.5. 
Laboratory Assessments .............................................................................................94 
11.6. 
Electrocardiogram Assessments .................................................................................95 


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11.7. 
Physical Examination .................................................................................................95 
11.8. 
Vital Signs ..................................................................................................................95 
12. 
ASSESSMENT OF EFFICACY ................................................................................97 
13. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ......................97 
13.1. 
Serum Sampling for Pharmacokinetic Analyses, Anti-drug Antibodies, 
Cytokines, and Inflammatory Factors .........................................................................97 
13.2. 
Pharmacokinetics ........................................................................................................97 
13.3. 
Pharmacodynamics .....................................................................................................97 
13.4. 
Biobanking Samples ...................................................................................................98 
14. 
STATISTICAL EVALUATION ................................................................................99 
14.1. 
Sample Size and Power ..............................................................................................99 
14.2. 
Statistical Methods......................................................................................................99 
14.3. 
Study Endpoints ..........................................................................................................99 
14.3.1. 
Primary Endpoints ......................................................................................................99 
14.3.2. 
Secondary Endpoints ................................................................................................100 
14.3.3. 
Exploratory Endpoints ..............................................................................................100 
14.4. 
Analysis Populations ................................................................................................101 
14.5. 
Subject Characteristics and Disposition ...................................................................101 
14.6. 
Safety Assessment ....................................................................................................102 
14.7. 
Efficacy Assessment .................................................................................................103 
14.8. 
Pharmacokinetic Analysis ........................................................................................104 
14.9. 
Immunogenicity Assays............................................................................................104 
15. 
DIRECT ACCESS TO SOURCE DATA/NOTES ...................................................105 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................106 
16.1. 
Conduct of the Study ................................................................................................106 
16.2. 
Study Monitoring ......................................................................................................106 
17. 
ETHICS ....................................................................................................................108 
17.1. 
Institutional Review Board/Independent Ethics Committee ....................................108 
17.2. 
Good Clinical Practice ..............................................................................................108 
17.3. 
Written Informed Consent ........................................................................................108 
17.4. 
Protocol Approval and Amendment(s) .....................................................................109 
17.5. 
Subject Confidentiality .............................................................................................109 
18. 
DATA HANDLING AND RECORD KEEPING ....................................................109 


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18.1. 
Case Report Forms/Source Data Handling ...............................................................109 
18.2. 
Retention of Essential Documents ............................................................................110 
18.3. 
Principal Investigator’s Record Requirements .........................................................110 
19. 
PUBLICATION POLICY ........................................................................................111 
20. 
LIST OF REFERENCES ..........................................................................................112 
APPENDIX A. RECIST GUIDELINES ...................................................................................117 
APPENDIX B. ECOG PERFORMANCE SCALE ..................................................................120 
APPENDIX C. PROPHYLAXIS AND MANAGEMENT OF NAUSEA AND 
VOMITING AND HYPERSENSITIVITY REACTIONS, CYTOKINE 
RELEASE SYNDROME, AND NEUROLOGICAL TOXICITY ..........................121 
APPENDIX D. DOSE MODIFICATION AND TOXICITY MANAGEMENT FOR 
IMMUNE-RELATED ADVERSE EVENTS ..........................................................130 
APPENDIX E. NATIONAL COMPREHENSIVE CANCER NETWORK AND 
AMERICAN SOCIETY OF CLINICAL ONCOLOGY: MANAGEMENT 
OF IMMUNOTHERAPY-RELATED TOXICITIES (IMMUNE 
CHECKPOINT INHIBITOR-RELATED TOXICITIES) ........................................133 
 
LIST OF TABLES 
Table 1:  
Mean Results of Noncompartmental Analysis of XmAm18087 after Multiple 
IV Dose Administration in Cynomolgus Monkey (Good Laboratory 
Practice) ......................................................................................................................34 
Table 2:  
Part A (MCC) Monotherapy Safety Run-in and Expansion Cohorts .........................46 
Table 3: 
Part B (MCC) Combination Therapy Safety Run-in and Expansion Cohorts ............47 
Table 4: 
Part C (SCLC) Monotherapy Safety Run-in and Expansion Cohorts ........................48 
Table 5:  
Boundaries for AESC Incidence: Cohort A ................................................................53 
Table 6: 
Boundaries for AESC Incidence: Cohorts B and C ....................................................53 
Table 7:  
Schedule of Assessments ............................................................................................54 
Table 8: 
Severity Grading Scale ...............................................................................................81 
Table 9:  
Causality Grading Scale .............................................................................................82 
Table 10: American Society for Transplantation and Cellular Therapy Cytokine 
Release Syndrome Consensus Grading ......................................................................87 
Table 11: Immune Effector Cell-associated Encephalopathy Scoring .......................................92 
Table 12: American Society for Transplantation and Cellular Therapy Immune 
Effector Cell-associated Neurotoxicity Syndrome Consensus Toxicity 
Grading for Adults ......................................................................................................93 


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Table 13: Assessment of Overall Response in Subjects with Target (± Nontarget 
Disease).....................................................................................................................119 
Table 14:  ECOG Performance Scale ........................................................................................120 
Table 15.  American Society for Transplantation and Cellular Therapy Cytokine 
Release Syndrome Consensus Grading ....................................................................122 
Table 16: Immune Effector Cell-associated Encephalopathy Scoring .....................................127 
Table 17: American Society for Transplantation and Cellular Therapy Immune 
Effector Cell-associated Neurotoxicity Syndrome Consensus Toxicity 
Grading for Adults ....................................................................................................128 
Table 18: Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events in Patients Receiving Pembrolizumab ................131 
 
LIST OF FIGURES 
Figure 1.  Molecular Domain Format of XmAb18087 ...............................................................30 
Figure 2.  Antitumor Activity in a Mouse Xenograft Model ......................................................32 
Figure 3.  XmAb18087 Mean Serum Concentration Versus Time in Cynomolgus 
Monkeys (Good Laboratory Practice) ........................................................................33 
Figure 4:  Study Design ...............................................................................................................42 
Figure 5: 
Part A and Part C: XmAb18087 Monotherapy Treatment .........................................44 
Figure 6: 
Part B: XmAb18087/Pembrolizumab Combination Therapy Treatment ...................44 
 
 
 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
anti-drug antibody 
AE(s) 
adverse event(s) 
AESC 
adverse event of specific concern 
AI 
accumulation index 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
AUC0-∞ 
area under the serum concentration-time curve from time zero to infinity 
AUC0-7 
area under the serum concentration-time curve from time zero to seven days postdose 
AUCt 
area under the serum concentration-time curve during a dosing interval (t) 
β-hCG 
beta human chorionic gonadotropin 
bpm 
beats per minute 
bsAb 
bispecific antibody 
CAR-T 
chimeric antigen receptor T cell 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL 
Clearance 
Cmax  
maximum observed serum concentration 
Cmin,ss 
minimum steady-state concentration 
Cmin[trough] 
predose or trough concentration 
Css 
steady-state concentration 
Ctrough 
trough concentration at predose 
CR 
complete response 
CRF 
case report form 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DERC 
Dose Escalation Review Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOI 
end of infusion 
EOS 
end of study 


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EOT 
end of treatment 
Fab 
antigen-binding fragment of an antibody 
FACS 
fluorescence-activated cell sorting 
Fc 
fragment, crystallizable  
FcγR 
Fc gamma receptor 
FDA 
US Food and Drug Administration 
FFPE 
formalin-fixed paraffin embedded 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GGT 
gamma glutamyl transferase 
GIST 
gastrointestinal stromal tumor 
GLP 
good laboratory practice 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HbA1C 
glycated hemoglobin 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
FSH 
follicle-stimulating hormone 
ICANS 
immune effector cell-associated neurotoxicity syndrome 
ICE 
Immune Effector Cell-Associated Encephalopathy 
ICF 
informed consent from 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon-gamma 
Ig 
immunoglobulin  
IgE 
immunoglobulin E 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IMP(s) 
investigational medicinal product(s) 
IND 
Investigational New Drug Application 
IRAE 
immune-related adverse event 
IRB 
Institutional Review Board 


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IUD 
intrauterine device 
IV 
Intravenous 
mAb 
monoclonal antibody 
MCC 
Merkel cell carcinoma 
MCPyV 
Merkel cell polyomavirus 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-mental State Examination 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
US National Cancer Institute 
NET(s) 
neuroendocrine tumor(s) 
NETSPOT 
Ga-68 DOTATATE PET gallium scanning 
NOAEL 
no-observed-adverse-effect-level 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PBS 
phosphate-buffered saline 
PD 
pharmacodynamics; progressive disease 
PD1 
programmed cell death protein 1 
PDL1 
programmed cell death ligand 1 
PDL2 
programmed cell death ligand 2 
PE 
physical examination 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PO 
Orally 
PR 
partial response 
Q6W 
every 6 weeks 
RBC 
red blood cell 
RD 
recommended dose 
RedFlu 
red fluorescent protein 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE(s) 
serious adverse event(s) 


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SAP 
statistical analysis plan 
scFv 
single-chain variable fragment (immunoglobulin fusion protein) 
SCLC 
small cell lung cancer 
SOC 
System Organ Class 
SOP(s) 
standard operating procedure(s) 
SRC 
Safety Review Committee 
SST 
Somatostatin 
SSTR 
somatostatin receptor 
t1/2  
half-life 
TEAE(s) 
treatment-emergent AE(s) 
TESAE(s) 
treatment-emergent SAE(s) 
TNF-α 
tumor necrosis factor α 
tmax  
time to reach maximum concentration 
tmin 
time of minimum concentration 
ULN 
upper limit of normal 
US 
United States 
UV 
Ultraviolet 
Vd 
volume of distribution 
Vdss , Vss 
steady-state volume of distribution 
WBC 
white blood cell 
%Fluct 
steady-state fluctuation in concentrations 


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5. 
INTRODUCTION 
5.1. 
Background 
5.1.1. 
Somatostatin and Somatostatin Receptors 
Somatostatin (SST), a peptide hormone that is secreted by endocrine and other cells throughout 
the body, has largely inhibitory effects that are mediated through 5 SST receptor (SSTR) subtypes 
(1-5). The specific effects of SSTR subtypes are largely due to different distributions and levels of 
expression within tissues (Barbieri, 2013). SSTR2 is widely expressed in normal tissues and 
upregulated in many types of tumors (Bronstein-Sitton, 2006; Taniyama, 2005). Like other 
neuroendocrine tumors, a high proportion of Merkel cell carcinomas (MCC) possesses receptors 
for somatostatin. In one series of 105 MCC tissue samples from 98 patients, SSTR2a and SSTR5 
were expressed in 58 cases (59.2%) and 44 cases (44.9%), respectively. Overall, at least one SSTR 
subtype was expressed in 75 tumors (76.5%). Expression of SSTR2A, but not SSTR5, was 
associated with Merkel cell polyomavirus (MCPyV) positivity (Gardair, 2015).  
Small cell lung cancer (SCLC), like MCC, often expresses SSTR2, with expression detected by 
immunohistochemistry (IHC) in patient tumor samples at varying frequencies. Among three 
different studies, SSTR2 IHC positivity was reported in 11/18 cases (61%; Reubi, 2000), 6/19 
cases (32%; Lapa, 2016), and 47/98 cases (48%; Lehman, 2019). 
These receptors can also be demonstrated in vivo in both MCC and SCLC by somatostatin 
receptor-based diagnostic imaging techniques, such as indium-111 pentetreotide single-photon 
emission computed tomography (SPECT; OctreoScan) or Ga-68 DOTATATE positron emission 
tomography (PET) gallium scanning (NETSPOT) (Kritikos, 2015; Epstude, 2013; Reisinger, 
1998; Lapa, 2016; NETSPOT Package Insert, 2018). 
Small series and some case reports have demonstrated success with therapeutic targeting of the 
SSTR in patients with MCC. This includes radionuclide therapy with yttrium-90-DOTATOC (a 
somatostatin analog containing the active octapeptide of somatostatin (Meier, 2004); peptide 
receptor radionuclide therapy with lutetium-177 isotope (Salavati, 2012), the somatostatin analogs 
lanreotide and octreotide (di Bartolomeo, 1996). Somatostatin analog therapy has also been tested 
in a limited number of SCLC patients with mixed results (Tartarone, 2016). 
5.1.2. 
Merkel Cell Carcinoma  
MCC is a rare, aggressive cutaneous malignancy that predominantly affects older adults and is 
more common in Caucasians compared with other ethnicities. Risk factors for the disease include 
ultraviolet exposure and advancing age. Immunosuppression, such as that associated with organ 
transplant, lymphoproliferative malignancies, or HIV, is also a risk factor for the diagnosis.  
The tumor has a propensity for local recurrence and early regional lymph node metastasis. In 2013, 
the MCC incidence rate was 0.7 cases per 100,000 person-years, corresponding to 2488 cases per 
year. The incidence increased exponentially with age, from 0.1 to 1.0 to 9.8 (per 100,000 
person-years) among age groups 40 to 44 years, 60 to 64 years, and ≥ 85 years, respectively 
(Paulson, 2018). 


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MCC pathogenesis is associated with either the presence of MCPyV or chronic exposure to 
ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. In 
areas with high UV exposure, UV-mediated carcinogenesis is predominant; by contrast, in areas 
with lower UV exposure, the majority of MCC cases are of viral etiology. The 2 etiologies share 
similar clinical, histopathological, and prognostic characteristics. Ultraviolet light exposure is 
suspected to be involved in viral-mediated and non-viral-mediated carcinogenesis, by contributing 
to immunosuppression or DNA damage, respectively (Becker, 2017). 
Approximately 30% of patients have locoregional metastases at the time of initial diagnosis. In an 
analysis of over 9000 MCC cases from the National Cancer Database between 1998 and 2012, 
patients presented with local disease in 65% of cases, while 26% had regional lymph node 
involvement and 8% had distant metastases (Harms, 2016).  
Excision of the primary tumor is the first-line therapy for locoregional disease, and surgery is 
frequently combined with radiation therapy to improve locoregional control. However, recurrences 
of MCC are frequent, even after definitive local and regional therapy, and are associated with a 
relatively poor prognosis (Eng, 2004). 
In general, the management of patients with distant metastases must be individually tailored. While 
systemic therapy and radiation therapy have until recently been the primary treatment options, 
surgery may be beneficial in highly selective circumstances for resection of oligometastasis or 
symptomatic lesions (NCCN Guidelines, 2019). 
Until recently, systemic therapy for metastatic MCC consisted of various regimens of cytotoxic 
chemotherapy, but these treatments have been met with limited success. While a response rate of 
55% was observed to a first-line chemotherapeutic regimen (most commonly platinum plus 
etoposide), the responses were typically not durable, and the median progression-free survival 
(PFS) was only 3 months (Iyer, 2016; NCCN Guidelines, 2019). 
In contrast, immunotherapy with checkpoint inhibitors has shown promise in treating metastatic 
MCC. Avelumab, an anti-programmed cell death ligand 1 (PDL1)-targeted monoclonal antibody, 
is approved in the United States to treat patients with metastatic MCC, irrespective of prior therapy. 
In the JAVELIN Merkel 200 trial, Part A, 88 patients who had received prior cytotoxic 
chemotherapy were treated with avelumab. With a median follow-up of 2 years, there was a 33% 
overall response rate (ORR), including 10 complete responses (Kaufman, 2016; Kaufman, 2018; 
Nghiem, 2018). The 2-year PFS rate was 26%, and the 2-year overall survival rate was 36%. In 
addition, 2 anti-programmed cell death protein 1 (PD1) monoclonal antibodies, pembrolizumab 
and nivolumab, have shown evidence of activity in patients with metastatic MCC (Nghiem, 2019; 
Topalian, 2017). 
There are no FDA approved therapies or standard treatments if anti PD1 or anti PDL1 checkpoint 
inhibitor therapy fails. MCC is an aggressive tumor with high rates of locoregional recurrence and 
metastatic spread; thus, development of novel therapeutic agents is a significant unmet medical 
need. XmAb18087 is a bispecific antibody that simultaneously targets a highly expressed 
somatostatin receptor and CD3, a T cell identifier, bringing together tumor cells and immune 
effector cells with the idea of activating the immune system to kill tumor cells. Given the medical 
need and the previous success of immunotherapy in this indication, XmAb18087 should be 
investigated for treatment of MCC.  


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5.1.3. 
Small Cell Lung Cancer 
Small cell lung cancer shares several biological and clinical characteristics with MCC that 
warrant the investigation of XmAb18087 in this indication as well, including SSTR2 expression, 
responsiveness to immunotherapy, rapid progression, and poor prognosis. Accounting for 15% of 
all lung cancers, SCLC is, like MCC, a high-grade neuroendocrine tumor with poor clinical 
outcome. The estimated yearly incidence of small cell lung cancer in 2017 was approximately 
30,000 cases in the United States; almost all cases are associated with a history of cigarette 
smoking (NCCN Guidelines, 2018).  
Around 70% of patients with SCLC present with extensive stage, metastatic disease, for which 
treatment options are palliative. The standard of care for extensive stage SCLC remains 
combination chemotherapy with various regimens, with a platinum agent plus etoposide being 
the most commonly used (NCCN Guidelines, 2018, Früh, 2013). Most patients initially benefit 
from chemotherapy, with response rates of 60 to 70%, but then quickly relapse; the median PFS 
in this patient population is less than 6 months (Früh, 2013).  
Recently, immune checkpoint inhibitors have shown activity in SCLC. Atezolizumab and 
durvalumab each received FDA approval in combination with chemotherapy for first line 
treatment of extensive stage SCLC; pembrolizumab and nivolumab are each approved in the US 
as single agents in the third-line setting. Still, improvements in clinical outcomes have been 
modest. For example, in the IMpower133 trial, patients who received atezolizumab plus 
chemotherapy had a median PFS of 5.2 months, compared to 4.3 months for those receiving 
chemotherapy alone (Horn, 2018). Thus, despite recent advances in the field, there remains a 
substantial need for better treatment options for extensive-stage SCLC. This high unmet clinical 
need coupled with the biological features of SCLC warrant investigation of XmAb18087 in this 
indication.  
5.1.4. 
Therapeutic Bispecific Antibodies  
The concept of recombinant antibodies that would allow for simultaneous engagement with 
2 targets was first developed in the late 1990s. Bispecific antibodies (bsAbs), it was theorized, 
could potentially increase binding specificity, providing simultaneous dual activation or blockade 
of 2 disease mediators, or in the case of cancer therapy, simultaneous binding of cytotoxic T cells 
and tumor antigens, thus promoting T-cell activation and killing of tumor cells. Although technical 
obstacles in production initially slowed development of bsAbs, recent advances in protein biology 
and recombinant expression techniques have resulted in several more easily producible formats 
for bsAbs, each of which has different properties (Spiess, 2015).While small format bispecific 
constructs are rapidly excreted and have short half-lives that require continuous infusion for 
maintenance of efficacious concentrations, XmAb18087 is built on a construct that includes a full 
fragment, crystallizable (Fc) region, which is designed to yield pharmacokinetics (PK) similar to 
humanized antibodies and should allow intermittent administration on a weekly or biweekly 
schedule (Przepiorka, 2015). 
5.1.5. 
XmAb18087 Product Description 
XmAb18087 is a humanized bsAb that binds both the tumor antigen SSTR2 and CD3 antigen to 
recruit cytotoxic T cells for killing of SSTR2+ tumor cells. 
 
 


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Figure 1.  
Molecular Domain Format of XmAb18087 
 
Fc = fragment, crystallizable; scFv = single-chain variable fragment (immunoglobulin fusion protein); 
SSTR = somatostatin receptor. 
5.1.6. 
Preclinical Studies 
5.1.6.1. 
Pharmacology 
XmAb18087 is a humanized and affinity-optimized bsAb that engages both SSTR2 on tumor cells 
as well as CD3 on T cells to recruit cytotoxic T cells to kill SSTR2+ tumor cells. XmAb18087 has 
been designed to maintain full-length humanized monospecific antibody properties in a bispecific 
antibody, thus enabling the design of stable molecules with favorable in vivo half-life and allowing 
for standard antibody production methods.  
In preclinical in vitro studies, XmAb18087 stimulated robust redirected T-cell–mediated 
cytotoxicity against SSTR2+ cell lines 
 
 
 
 
 
 
 
 
 
Anti-SSTR2 Fab domain 


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Figure 2.  
Antitumor Activity in a Mouse Xenograft Model 
0
2
4
6
8
1 0
1 2
1 4
1 6
1 8
2 0
0
2 ×1 0 1 0
4 ×1 0 1 0
6 ×1 0 1 0
8 ×1 0 1 0
1 ×1 0 1 1
D a y s  P o s t h u P B M C /D o s e  # 1
T o ta l F lu x  (p /s )
PBS
0 .0 3  m g /k g
0 .1  m g /k g
0 .3  m g /k g
1 .0  m g /k g
    *  P  <  0 .0 0 0 1
   * *  P  <  0 .0 0 2
 * * *  P  =  0 .0 0 5 3
* * *
*
*
*
*
* *
*
*
*
X m A b 1 8 0 8 7
0
2
4
6
8
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1 2
1 4
1 6
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1 5 0
2 0 0
2 5 0
D a y s  P o s t h u P B M C /D o s e  # 1
M ean  T u m o r V o lu m e (m m
3)
P B S
0 .0 3  m g /k g
0 .1  m g /k g
0 .3  m g /k g
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    *  P  <  0 .0 0 0 1
   * *  P  =  0 .0 0 0 1
 * **  P  =  0 .0 0 4
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X m A b 1 8 0 8 7
A .
B .
 
huPBMCs = human peripheral blood mononuclear cells; NSG = NOD SCID gamma; PBS = phosphate-buffered 
saline; FLuc = Firefly Luciferase. 
On Study Day 0, young NSG mice received a subcutaneous injection of 1x106 A549 Red-FLuc cells from a human 
non-small cell lung tumor cell line that had been modified to express a red-shifted luciferase transgene for in vivo 
imaging. Seven days later, mice were engrafted intraperitoneally with 10 × 106 huPBMCs and treated with either 
vehicle (PBS), or 0.03, 0.1, 0.3 , or 1.0 mg/kg of XmAb18087 once a week for 3 consecutive weeks. (A) Tumor burden 
was monitored by in vivo imaging using total flux (p/s) captured by In Vivo Imaging System. (B) Tumor volumes 
were determined using physical caliper measurements. 


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In summary, the results in human cells, in human xenograft in mice, and in cynomolgus monkeys 
indicate activity of XmAb18087 against SSTR2+ cells and supports clinical assessment of 
XmAb18087 in SSTR2+ cancers, including neuroendocrine tumors (NET) and gastrointestinal 
stromal tumor (GIST.) 
5.1.6.2. 
Pharmacokinetics and Toxicokinetics 
In a good laboratory practice (GLP) toxicology study, 
 
 
 
  
Figure 3.  
XmAb18087 Mean Serum Concentration Versus Time in Cynomolgus 
Monkeys (Good Laboratory Practice) 
 
 
The mean results of a noncompartmental analysis of this study are shown in Table 1. 
0
2
4
6
8
10
12
14
1
10
100
2229364350
Day 1
Day 8
Days 22-50
Time (days)
Concentration (ng/mL)


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5.1.6.3. 
Toxicology 
The toxicology of XmAb18087 was also explored in this GLP toxicology study and in 3 non-GLP 
pharmacology studies. 
In the GLP toxicology study,
 
 
 
  
All doses and regimens of XmAb18087 were well tolerated, with no observed effects on food 
consumption, electrocardiography, body temperature, ophthalmic examinations, or urinalysis 


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parameters. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.1.7. 
Human Experience with XmAb18087 and Related Molecules 
Two bsAb products have previously been approved by FDA. In 2014, accelerated approval was 
granted to blinatumomab (Blincyto® PI, 2018) for the treatment of Philadelphia 
chromosome-negative, relapsed or refractory precursor B-cell acute lymphoblastic leukemia 
(Przepiorka, 2015). It has since also received approval for treatment of relapsed or refractory B-cell 
precursor acute lymphoblastic leukemia. Blinatumomab is an anti-CD19/anti-CD3 bsAb, 
constructed as a small-format recombinant protein that, due to its small size, is rapidly cleared and 
given as a continuous infusion. Cytokine release syndrome and neurologic events were the drug’s 
primary toxicities (Spiess, 2015). In 2017, approval was granted to emicizumab-kxwh (Hemlibra), 
a bispecific factor IXa- and factor X-directed antibody for prophylaxis to prevent or reduce the 
frequency of bleeding episodes in adult and pediatric patients with hemophilia A. 
Emicizumab-kxwh is administered by subcutaneous injection. In contrast to blinatumomab, 
emicizumab-kxwh is not designed to engage T-cells; thus, cytokine release syndrome is not a 
significant risk with this drug (HEMLIBRA® Package Insert, 2018).  
Although the receptor target of XmAb18087 and its distribution are different from those of 
blinatumomab, the 2 drugs’ common mechanism of T-cell engagement and redirection, in addition 
to the results of Xencor’s toxicology studies with XmAb18087 and the company’s experience with 
2 other CD3-directed bsAb products now in the clinic, indicate that CRS is expected to be a toxicity 
of the drug, principally after the first dose. 


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The first-in-human (FIH) Phase 1 clinical study of XmAb18087 in advanced low to intermediate 
grade NETs and advanced GISTs (XmAb18087-01) has thus far borne out this expectation, with 
mostly low-grade CRS events being observed. The maximum tolerated dose (MTD)-determining 
toxicities in the NET arm of the trial were nausea and vomiting. The trial now includes a CRS 
prophylactic regimen and an antiemetic prophylactic regimen for at least the first 
 
; these prophylactic regimens decreased the incidence of CRS and the incidence and 
severity of nausea and vomiting. See also Section 5.3. 
5.2. 
Pembrolizumab 
Pembrolizumab (MK-3475; Keytruda®) is a potent humanized immunoglobulin G4 monoclonal 
antibody (mAb) with high specificity of binding to the PD1 receptor, thus inhibiting its interaction 
with PDL1 and programmed cell death ligand 2 (PDL2). Pembrolizumab has high affinity and 
potent receptor blocking activity for PD1. Pembrolizumab is in clinical development as an IV 
immunotherapy for advanced malignancies. Pembrolizumab is indicated for the treatment of 
patients across several indications, including MCC. For more details on these specific indications, 
refer to the approved product labeling for detailed background information (Keytruda® Package 
Insert, 2020). 
The clinical responses to pembrolizumab highlight the utility of immunotherapeutic agents for 
treating cancer. However, some patients either fail to respond to pembrolizumab or relapse after 
an initial response. Such patients could potentially benefit from the addition of an additional 
immune-targeted agent with a distinct mechanism of action. This general rationale has spurred the 
investigation of several T-cell bispecific antibodies in combination with anti-PD1 agents, and 
supports the proposed combination of XmAb18087 with pembrolizumab in MCC, an indication 
for which the latter is already FDA-approved (Kobold, 2018; Keytruda® Package Insert, 2020). 
5.2.1. 
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 
ex vivo and reinfused, inducing durable objective tumor responses in cancers such as melanoma 
(Dudley, 2005; Hunder, 2008). 
The PD1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to CD28 and CTLA4 that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PDL1 and/or PDL2; Greenwald, 2005; Okazaki, 2001). 
The structure of murine PD1 has been resolved (Zhang, 2004). PD1 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 


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tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following T-cell 
stimulation, PD1 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 (CD3ζ), protein kinase C-theta (PKCθ), and 
zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling 
cascade (Okazaki, 2001; Chemnitz, 2004; Sheppard, 2004; Riley, 2009). As a consequence, the 
PD1/PDL1 pathway is an attractive target for therapeutic intervention in a number of neoplastic 
diseases. 
5.2.2. 
Nonclinical Studies 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD1/PDL1 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 
(Blank, 2004; Curran, 2010; Hirano, 2005; Pilon-Thomas, 2010; Strome, 2003; Spranger, 2014; 
Weber, 2010). Antimouse PD1 or antimouse PDL1 antibodies have demonstrated antitumor 
responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, acute myeloid 
leukemia, and colorectal carcinoma (Curran, 2010; Nomi, 2007; Pilon-Thomas, 2010; Strome, 
2003; Zhang, 2004). 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 PD1 checkpoint inhibition involved local infiltration and activation of 
effector T-cell function in vivo (Curran, 2010). Experiments have confirmed the in vivo efficacy 
of antimouse PD1 antibody as a monotherapy, as well as in combination with chemotherapy, in 
syngeneic mouse tumor models. 
5.2.3. 
Justification for Pembrolizumab Dose 
The planned dose of pembrolizumab for this study is 400 mg every 6 weeks (Q6W), which is a 
current FDA-approved dose for adults with recurrent locally advanced or metastatic MCC 
(Keytruda® Package Insert, 2020).  
5.3. 
Rationale for Dose Selection of XmAb18087-01 FIH, XmAb18087-02, 
and Study Design 
 
 
 
 
 
 
 
 
  
 
 
 


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objectives 
The primary objectives of the study are as follows: 
1. To determine the safety and efficacy (by ORR, complete response [CR], and partial 
response [PR] per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) of 
XmAb18087 monotherapy in subjects with advanced MCC that has progressed after 
treatment with standard therapies 
2. To determine the safety and efficacy (by ORR, CR, and PR per RECIST 1.1 criteria) of 
XmAb18087 in combination with pembrolizumab in subjects with advanced MCC who 
have not received prior anti-PD1 or anti-PDL1 therapies, and for whom pembrolizumab as 
a single agent is indicated 
3. To determine the safety and efficacy (by ORR, CR, and PR per RECIST 1.1 criteria) of 
XmAb18087 monotherapy in subjects with extensive-stage SCLC that has progressed after 
treatment with standard therapies 
6.2. 
Secondary Objectives 
The secondary objectives of the study are as follows: 
1. To assess antitumor activity of XmAb18087 by PFS per RECIST 1.1 criteria, as well as 
overall survival (OS) and duration of response, when administered with and without 
pembrolizumab in subjects with advanced MCC, and as monotherapy in subjects with 
extensive-stage SCLC 
2. To characterize the PK and immunogenicity of XmAb18087 administered with and without 
pembrolizumab in subjects with advanced MCC, and as monotherapy in subjects with 
extensive-stage SCLC 
3. To assess the PK profile (Cmax and trough concentration, Cmin[trough]) of pembrolizumab 
when co-administered with XmAb18087 
6.3. 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
1. To assess the incidence, timing, and severity of CRS by the following: 
a. CRS-related AEs (incidence and grade of AEs and incidence of serious adverse events 
[SAEs]) 
b. Biomarkers of CRS 
2. To characterize the biological activity associated with administration of XmAb18087 with 
and without pembrolizumab by assessment of cell surface markers on selected immune 
system cells in peripheral blood, including changes in lymphocyte subsets and in T-cell 
activation/exhaustion by flow cytometry and similar bioanalytical methods 


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3. To characterize PD by correlation of clinical response with NETSPOT® (gallium 68 
dotatate) positron emission tomography/computed tomography (PET/CT) scan results after 
XmAb18087 administration with and without pembrolizumab 
4. To evaluate by immunohistochemistry tumor-cell expression of SSTR2 and PDL1 and 
tumor-infiltrating T cells expression of proliferation markers and PD1/PDL1 after 
XmAb18087 administration with and without pembrolizumab, as well as changes in other 
immune cell subsets  
5. To characterize the pharmacodynamic (PD) changes in the intratumoral inflammatory 
response using immunostaining of immune cells and analysis of RNA signatures 
6. To correlate clinical response in MCC subjects to MCPyV status as determined by serology 
and immunohistochemistry 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a Phase 1b/2, multiple-dose study of XmAb18087, both as a monotherapy and in 
combination with pembrolizumab in MCC subjects, and as monotherapy only in SCLC subjects. 
The study is designed in 3 parts, Part A, Part B, and Part C shown in Figure 4. 
Figure 4:  
Study Design 
 
MCC = Merkel cell carcinoma; PD1 = programmed cell death protein 1; PDL1 = programmed cell death ligand 1; 
SCLC = small cell lung cancer. 
 
Part A is designed to describe safety and efficacy, and to assess PK and immunogenicity of 
XmAb18087 monotherapy in subjects with advanced MCC. All eligible subjects will have 
relapsed or refractory disease that has previously been treated with all standard therapies for which 
they are eligible. 
Part A will enroll safety run-in cohorts to confirm the safety and tolerability of XmAb18087 
monotherapy administered IV with weekly step-up dosing for 42-day cycles. Additional subjects 
will then be enrolled into an expansion cohort and will receive XmAb18087 monotherapy using 
the recommended dose (RD) identified following the safety run-in cohorts.  
Part B is designed to describe safety and efficacy, and to assess PK and immunogenicity of 
XmAb18087 in combination with pembrolizumab in subjects with advanced MCC. All eligible 
subjects may be treatment naïve or have relapsed or refractory disease after prior treatment; 
however, subjects who have received prior treatment with anti-PD1 or anti-PDL1 therapeutics will 
not be eligible to participate in Part B. 
Part B will enroll additional safety run-in cohorts to confirm the safety and tolerability of 
XmAb18087 in combination with pembrolizumab. Subjects will receive step-up IV dosing of 
XmAb18087 (except for Cohort 1B, in which subjects will receive the same dose level on each 


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dosing day) on Days 1, 8, 22, 29, and 36, and IV dosing of pembrolizumab on Day 15 of each 
42-day cycle. Additional subjects will be enrolled into an expansion cohort and will receive 
XmAb18087 plus pembrolizumab combination therapy using the RD identified following the 
safety run-in. 
Enrollment into Part B safety run-in cohorts (starting with Cohort 1B) may begin after the first 
safety run-in cohort in Part A (Cohort 1A, one dose level higher than Cohort 1B) has completed 
the first cycle and the regimen has been demonstrated to be tolerable.  
Part C is designed to describe safety and efficacy, and to assess PK and immunogenicity of 
XmAb18087 monotherapy in subjects with extensive-stage SCLC. All eligible subjects will have 
relapsed or refractory disease that has previously been treated with all standard therapies for which 
they are eligible. 
Part C of the study will enroll additional safety run-in cohorts to confirm the safety and tolerability 
of XmAb18087 monotherapy in this indication. The safety run-in will follow the same cohort 
schema as described for Part A to identify a RD for expansion in SCLC. Additional subjects will 
be enrolled into an expansion cohort and will receive XmAb18087 monotherapy using the RD 
identified following the safety run-in. 
Enrollment into Part C may begin concurrently with Part A. 
Part A, Part B, and Part C: The decision to advance to higher dose levels after each safety run-in 
cohort will be made by an SRC based on review of the aggregate safety data for all subjects in that 
cohort as well as cumulative safety data for the study overall. The SRC will be allowed to make 
adaptations to the dosing schema, if needed, in accordance with evolving trial safety and 
tolerability findings, as long as adaptations do not significantly increase subject risk. Any such 
adaptations would require a protocol amendment and IRB approval.  
In each safety run-in cohort, no more than 1 subject will receive the first infusion of XmAb18087 
on any given day. 
Subjects may be admitted and monitored on Day -1 (hospitalization is optional), and will be 
admitted on study days 1, 2, and 3 for their first dose of XmAb18087 and for at least 48 hours 
following the second dose. In addition, any subject who has shown symptoms of CRS during 
inpatient admission will continue to be monitored as an inpatient for at least 24 hours after the 
symptoms have subsided. 
The Schedules of Assessments is provided in Section 7.9, Table 7. 
 
 


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7.2. 
Study Flowcharts 
Figure 5 shows the dosing schedule for each 42-day cycle in the Part A and Part C monotherapy 
portions of the trial, while Figure 6 shows Part B combination therapy portions of the trial. 
Inpatient stays are only required in Cycle 1.  
Figure 5: 
Part A and Part C: XmAb18087 Monotherapy Treatment 
 
Figure 6: 
Part B: XmAb18087/Pembrolizumab Combination Therapy Treatment 
 
7.3. 
Dosing Schedule 
Each subject will be administered XmAb18087 IV at a constant infusion rate over 
 
. 


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The initial treatment period for each subject in this study is 1 cycle. Each cycle is 42 days long. In 
Part A and Part C, each cycle will consist of 6 weekly doses of XmAb18087 (on Days 1, 8, 15, 22, 
29, and 36). 
In Part B, each cycle will consist of 5 XmAb18087 doses on Days 1, 8, 22, 29, and 36. 
Pembrolizumab will be administered as 1 dose during each 42-day cycle, on Day 15.  
Part A dose levels are defined in Table 2. Part B dose levels are defined in Table 3. Part C dose 
levels are defined in Table 4.  
The dose is based on the subject’s actual baseline weight measurement in kilograms (rounded to 
the nearest integer) on Day -1. Following the first dose at any dose level, the weight used for 
calculation of subsequent doses will be modified only if the subject’s weight changes by more than 
10% from the baseline weight, at which point the dose will be recalculated using the current weight 
(rounded to the nearest integer). 


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Table 2:  
Part A (MCC) Monotherapy Safety Run-in and Expansion Cohorts  
  
Cycle 
and Day 
Cycle 1 
Cycle 2+ 
Subjects 
D1 
D8 
D15 
D22 D29 
D36 
D40 
 ± 2 
D1 
D8  
D15 
D22 
D29 
D36  
D40  
± 2 
Drug 
XmAb18087 
(μg/kg) 
EA 
XmAb18087  
(μg/kg) 
EA 
Study 
Day 
1 
8 
15 
22 
29 
36 
40 
43 
50 
57 
64 
71 
78 
82 
Part A 
(Safety 
Run-in) 
1A 
0.3 
1.0 
1.0 
1.0 
1.0 
1.0 
--- 
1.0 
1.0 
1.0 
1.0 
1.0 
1.0 
--- 
3 - 6 
2A 
0.3 
1.0 
2.0 
2.0 
2.0 
2.0 
--- 
2.0 
2.0 
2.0 
2.0 
2.0 
2.0 
--- 
3 - 6 
3A 
0.3 
1.0 
2.0 
4.0 
4.0 
4.0 
--- 
4.0 
4.0 
4.0 
4.0 
4.0 
4.0 
--- 
3 - 6 
Part A 
(Expansion) 
Expansion 
A 
At RD cohort 
Up to 22 
D = day; EA = efficacy assessment (no drug administered); MCC = Merkel cell carcinoma; RD = recommended dose. Maximum escalated dose for each cohort 
in bold. 
 
 


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Table 3: 
Part B (MCC) Combination Therapy Safety Run-in and Expansion Cohorts 
  
Cycle 
and Day 
Cycle 1 
Cycle 2+ 
Subjects 
D1 
D8 
D15 
D22 D29 
D36 
D40 
± 2 
D1 
D8 
D15 
D22 D29 
D36 
 
D40 
± 2  
Drug 
XmAb18087 
(μg/kg) 
Pem 
(mg) 
XmAb18087 
(μg/kg) 
EA 
XmAb18087 
(μg/kg) 
Pem 
(mg) 
XmAb18087 
(μg/kg) 
EA 
Study 
Day 
1 
8 
15 
22 
29 
36 
40 
43 
50 
57 
64 
71 
78 
82 
Part B 
(Safety 
Run-in) 
1B 
0.3 
0.3 
400 
0.3 
0.3 
0.3 
--- 
0.3 
0.3 
400 
0.3 
0.3 
0.3 
--- 
3 - 6 
2B 
0.3 
1.0 
400 
1.0 
1.0 
1.0 
--- 
1.0 
1.0 
400 
1.0 
1.0 
1.0 
--- 
3 - 6 
3B 
0.3 
1.0 
400 
1.0 
2.0 
2.0 
--- 
2.0 
2.0 
400 
2.0 
2.0 
2.0 
--- 
3 - 6 
4B 
0.3 
1.0 
400 
1.0 
2.0 
2.0 
--- 
2.0 
4.0 
400 
4.0 
4.0 
4.0 
--- 
3 - 6 
Part B 
(Expansion) 
Expansion 
B 
At RD cohort 
Up to 30 
D = day; EA = efficacy assessment (no drug administered); MCC = Merkel cell carcinoma; Pem = pembrolizumab; RD = recommended dose. Maximum 
escalated dose for each cohort in bold. 
 
 
 
 
 


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Table 4: 
Part C (SCLC) Monotherapy Safety Run-in and Expansion Cohorts 
  
Cycle 
and Day 
Cycle 1 
Cycle 2+ 
Subjects 
D1 
D8 
D15 
D22 D29 
D36 
D40 
 ± 2 
D1 
D8  
D15 
D22 
D29 
D36  
D40  
± 2 
Drug 
XmAb18087 
(μg/kg) 
EA 
XmAb18087  
(μg/kg) 
EA 
Study 
Day 
1 
8 
15 
22 
29 
36 
40 
43 
50 
57 
64 
71 
78 
82 
Part C 
(Safety 
Run-in) 
1C 
0.3 
1.0 
1.0 
1.0 
1.0 
1.0 
--- 
1.0 
1.0 
1.0 
1.0 
1.0 
1.0 
--- 
3 - 6 
2C 
0.3 
1.0 
2.0 
2.0 
2.0 
2.0 
--- 
2.0 
2.0 
2.0 
2.0 
2.0 
2.0 
--- 
3 - 6 
3C 
0.3 
1.0 
2.0 
4.0 
4.0 
4.0 
--- 
4.0 
4.0 
4.0 
4.0 
4.0 
4.0 
--- 
3 - 6 
Part C 
(Expansion) 
Expansion 
C 
At RD cohort 
Up to 30 
D = day; EA = efficacy assessment (no drug administered); RD = recommended dose; SCLC = small cell lung cancer. Maximum escalated dose for each cohort 
in bold. 
 


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7.4. 
Continuation/Discontinuation of Therapy 
There will be a pretreatment tumor assessment, followed by a reassessment after each treatment 
cycle (Table 7).  
7.4.1. 
Continuation Prior to Progression 
Subjects who appear to benefit from XmAb18087 or XmAb18087/pembrolizumab combination 
therapy may continue to receive additional drug treatment until unacceptable toxicity develops, 
progression occurs, or the Investigator thinks there is no longer clinical benefit to the subject.  
To receive study drug past the first cycle, a subject in Part A or Part C must also satisfy the 
following criteria: 
• Does not meet any criteria for stopping dosing (Section 7.8 and Section 10.3) 
• Has recovered from any toxicity to ≤ Grade 2 or to baseline 
• Has experienced clinical benefit, as assessed by the Investigator  
To receive combination therapy past the first cycle, a subject in Part B must satisfy all continuation 
criteria for Part A and Part C, and, in addition, must have recovered sufficiently from any 
immune-related adverse event so that he/she is eligible for continuation/re-initiation of study 
treatment. Refer to Section 7.4 and the pembrolizumab label (Keytruda® Package Insert, 2020) for 
dose modification and toxicity management guidelines. 
For subjects who continue to receive XmAb18087 or XmAb18087 and pembrolizumab 
combination therapy past the first cycle, tumor assessments will be repeated after every cycle of 
therapy. 
7.4.2. 
Continuation/Discontinuation at Progression 
Treatment with XmAb18087 as monotherapy (in Part A and Part C) or as part of the combination 
regimen (in Part B) will be discontinued upon assessment of progressive disease (PD) per 
RECIST 1.1 (Appendix A). 
A subject on combination therapy who is assessed as having PD per RECIST 1.1 may choose to 
continue pembrolizumab monotherapy in this clinical trial until confirmatory RECIST 1.1 
assessment not less than one month and not more than six weeks after the initial determination of 
PD if he/she 
• Meets all the criteria for continuation of dosing listed above in Section 7.4.1  
• Has not experienced a decline in Eastern Cooperative Oncology Group (ECOG) 
performance status since the baseline assessment 
• Does not have signs or symptoms of unequivocal PD or PD at disease sites that pose a 
medical risk to the subject. 
Subjects who are assessed as having initial RECIST 1.1 PD but who wish to continue receiving 
pembrolizumab monotherapy until confirmatory RECIST 1.1 assessment will be reconsented with 
a separate consent form to ensure they are aware of all treatment options and therapies that they 
may be foregoing. 


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If PD is confirmed on follow-up RECIST 1.1 assessment, the subject must discontinue receiving 
pembrolizumab in this clinical trial. 
If PD is not confirmed by follow-up RECIST 1.1 assessment, the subject must discontinue 
receiving pembrolizumab in this clinical trial but will continue to be followed for progression and 
survival. 
Subjects will be followed as per Table 7, or until death or the initiation of other anticancer therapy 
(whichever comes first). Information regarding disease status will be collected by the 
investigational sites for up to an additional 12 months, or until death or disease progression 
requiring other anticancer therapy (whichever comes first). 
7.4.3. 
Intrasubject Dose Escalation 
Intrasubject dose escalation of XmAb18087 is permitted in the study. The subject must meet the 
following criteria in order to be eligible for treatment at the higher dose level: 
• The subject tolerates his/her dose level of XmAb18087 
• The subject meets criteria for continuation of therapy prior to progression 
(Section 7.4.1) 
• All subjects in the safety run-in cohort at the next higher dose level have completed the 
first cycle of treatment, and the SRC has made the decision that the higher dose level 
is tolerable 
No dose escalation will be permitted for pembrolizumab. 
For MCC subjects, crossover from monotherapy (Part A) to combination therapy (Part B) is not 
permitted. Subjects in Part B may not escalate more than once. 
7.5. 
Number of Subjects 
Up to 142 subjects will be enrolled; the total number required will depend on the number of safety 
run-in cohorts required to define each RD for expansion in Part A, Part B, and Part C. Up to 
25 clinical investigation sites in the US will enroll subjects in this study. 
7.6. 
Treatment Assignment 
Subject Screening Number: Subjects who consent for the study will be assigned a Subject 
Screening Number. 
Subject Enrollment Number: Subjects eligible to receive study treatment will be assigned a Subject 
Enrollment Number. 
Enrolled subjects will be assigned to a cohort as follows: 
• Subjects with advanced MCC who have received prior treatment with or are ineligible for 
treatment with anti-PD1 and/or anti-PDL1 will be assigned to a monotherapy cohort in 
Part A.  
• Subjects with advanced MCC who are anti-PD1 and anti-PDL1 therapy naïve and who do 
not have a contraindication to anti-PD1 therapy will be assigned to a combination therapy 
cohort in Part B. 


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• Subjects with extensive stage SCLC who have received prior treatment with standard 
therapies will be assigned to a monotherapy cohort in Part C.  
7.7. 
Safety Run-in Cohorts 
In each safety run-in cohort, no more than 1 subject will be initiated on treatment with 
XmAb18087 on any given day.  
The planned initial XmAb18087 dose for all cohorts is 0.3 μg/kg. Subsequent doses will then be 
escalated in steps (except for Cohort 1B, which will use 0.3 μg/kg for all doses) as indicated in 
Table 2, Table 3, and Table 4 in an effort to reduce the incidence and severity of CRS.  
For all safety run-in cohorts in Part A, Part B, and Part C, the SRC will decide whether to advance 
to the next higher dose level cohort based on review of all available safety data. For each cohort, 
3 subjects will be initially enrolled. If no subject experiences an adverse event of specific concern 
(AESC, as defined in Section 7.8 below), the SRC will be convened after all 3 subjects have 
completed one treatment cycle or discontinued treatment, whichever comes first. If 1 of the initial 
3 subjects experiences an AESC, 3 additional subjects will be enrolled in that cohort (up to a total 
of 6 subjects) prior to convening the SRC. If 2 subjects experience an AESC, no additional subjects 
will be enrolled until the SRC has convened and made a recommendation based on the available 
safety data. Based on the type and severity of toxicities observed, the SRC may modify the safety 
run-in scheme (eg, decreases in dose level, smaller escalation steps, or other changes in the 
regimen), as long as the changes do not significantly affect the risk profile of the study. 
If a subject discontinues treatment prior to completion of the first cycle due to an AE, that subject 
will not be replaced. If a subject discontinues treatment prior to completion of the first cycle for 
any other reason, an additional subject may be enrolled as a replacement.  
Part A will begin by enrolling 3 to 6 subjects in Cohort 1A. After Cohort 1A dosing is demonstrated 
to be tolerable and is approved by the SRC, Part B will begin by enrolling Cohort 1B, which is one 
dose level lower than Cohort 1A.  
Part C may begin concurrently with Part A. 
The safety run-in portion will continue until establishment of an RD for expansion or until the 
repeated dose level reaches the highest dose planned in this study. 
Enrolling additional subjects beyond 142 will require a protocol amendment. 
7.8. 
Criteria for Adverse Events of Specific Concern and Dose Adjustment 
The National Cancer Institute’s (NCI’s) Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.0, will be used for grading toxicities, except for CRS, which will be graded 
using the CRS revised grading system (Section 11.2 or Appendix C; Lee, 2014). 
An AESC is defined as an AE or clinically significant abnormal laboratory value (unless clearly 
attributable to underlying malignancy or concurrent disease) occurring after the initiation of dosing 
and meeting the criteria listed below: 
For Parts A, B, and C: 
1. Any Grade 5 toxicity 


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2. Grade ≥ 3 thrombocytopenia lasting ≥ 7 days or ≥ Grade 3 thrombocytopenia of any 
duration if associated with ≥ Grade 3 bleeding 
3. Grade 4 neutropenia or Grade 3 febrile neutropenia lasting ≥ 7 days, or Grade 4 febrile 
neutropenia  
4. Any ≥ Grade 3 nonhematological toxicity, except: 
a. Grade 3 fatigue, asthenia, fever, anorexia, or constipation 
b. Grade 3 nausea, vomiting, diarrhea, or abdominal pain controlled by medical 
management that decreases to ≤ Grade 2 within ≤ 7 days 
c. Grade 3 alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) that 
decrease to ≤ Grade 2 within ≤ 5 days  
d. Grade ≥ 3 gamma glutamyl transferase (GGT), unless it occurs with AST, ALT, and/or 
total bilirubin values that meet AESC criteria 
e. Grade 3 electrolyte abnormalities that are clinically insignificant, or treatable, and that 
resolve, with or without intervention, to < Grade 2 in < 72 hours 
f. Grade 3 or 4 lipase values that are not accompanied by ≥ Grade 3 amylase values or 
clinical symptoms or radiographic evidence of pancreatitis 
Additional Criterion for Part B (combination therapy) only: 
1. Any immune related adverse event (IRAE) that requires permanent discontinuation of 
study drug according to the guidelines in Table 18  
Subjects who experience any toxicity should be followed until the toxicity stabilizes or has 
returned to their baseline level, or until the commencement of a new anticancer treatment. 
Refer to Section 10.3 for safety criteria for adjustment or stopping XmAb18087 and 
pembrolizumab. 
7.8.1. 
Replacement of Subjects 
A subject enrolled in a safety run-in cohort who withdraws from study before completing the first 
cycle for reasons other than an AE will be considered to have inadequate data for evaluation by 
the SRC. In such cases, a replacement subject may be enrolled to receive the same dose of 
XmAb18087 (and pembrolizumab, when applicable) as the subject who withdrew prematurely. 
Subjects enrolled in the safety run-in cohorts who are discontinued from the study for any reason 
after the first cycle will not be replaced. 
7.8.2. 
Criteria for Study Termination 
Sequential boundaries will be used to monitor AESC rates over the monotherapy expansion 
cohorts and combination therapy expansion cohorts, separately. If excessive numbers of AESC are 
seen; that is, if the number of AESC that occur in either expansion cohort is equal to or exceeds a 
boundary, bn, out of n subjects (n = all safety-evaluable subjects in the disease-specific expansion 
cohort [Table 5]), then enrollment will be suspended until the SRC has met.  


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Table 5:  
Boundaries for AESC Incidence: Cohort A 
Subjects, n 
of 22 
1 2 3 4 5 6 7 8 9 10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
Boundary, bn - 
- 
3 3 3 4 5 5 6 
6 
6 
7 
7 
7 
8 
8 
8 
8 
9 
9 
9 
10 
AESC = adverse event of specific concern. 
This is a Pocock-type stopping boundary that yields the probability of crossing the boundary of at most 7.5% when 
the rate of AESC is equal to the acceptable rate of 20% (Ivanova, 2005). If instead the rate of AESC is an excessive 
40%, then on average only 14 of the 22 patients will complete the toxicity follow up period before the boundary is 
crossed. 
Table 6: 
Boundaries for AESC Incidence: Cohorts B and C 
Subjects, n 
of 30 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Boundary, 
bn 
- 
- 
3 
3 
3 
4 
5 
5 
6 
6 
6 
7 
7 
7 
8 
8 
8 
6 
9 
9 
Subjects, n 
of 30 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
 
 
 
 
 
 
 
 
 
 
Boundary, 
bn 
9 
10 
10 
10 
11 
11 
11 
11 
12 
12 
AESC = adverse event of specific concern. 
This is a Pocock-type stopping boundary that yields the probability of crossing the boundary of at most 8% when the 
rate of AESC is equal to the acceptable rate of 20% (Ivanova, 2005). If instead the rate of AESC is an excessive 40%, 
then on average only 17 of the 30 patients will complete the toxicity follow up period before the boundary is crossed. 
If the enrollment of a disease-specific expansion cohort has been suspended in accordance with 
this section, it may not be reopened until the SRC has met, considered the available data, and made 
a decision to continue, with or without modifications to the trial. 
7.9. 
Study Assessments 
The Schedule of Assessments is shown in Table 7. Pretreatment, treatment, and follow-up 
procedures are detailed in Sections 7.9.1 through 7.9.5. 


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Table 7:  
Schedule of Assessments  
Evaluation or Procedure 
Pretreatment 
Cycle 1 
Study Day 
Screen 
(-28 to 
-2) 
Day 
-1 
1 
2 
3 
8 
9 
10 
15 
22 
29 
36 
37 
38 
39 
40 
± 2 
Informed consent 
X 
NETSPOT Gallium 68 dotatate PET/CT 
scana,b 
X 
X 
Review of inclusion/exclusion criteria 
X 
Collection of FFPE tumor sample/slides  
X 
Record tumor genetic information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient statusc,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XmAb18087 administratione,f 
X 
X 
X 
X 
X 
X 
Pembrolizumab administrationf 
X 
Medical historyg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
Physical examinationg,h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologic examinationi 
X 
Vital signsc,j,k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
ECOG performance statush 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
12-lead electrocardiogram (supine)l,m 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
CBC w/ differential (absolute and 
percentage), platelet counth 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panelh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation panelh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg, HBcAb, HCV, HIV 
X 


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Table 7:  
Schedule of Assessments (Continued) 
Evaluation or Procedure 
Pretreatment 
Cycle 1 
Study Day 
Screen 
(-28 to 
-2) 
Day 
-1 
1 
2 
3 
8 
9 
10 
15 
22 
29 
36 
37 
38 
39 
40 
± 2 
Serum β–hCG (females of childbearing 
potential) FSH (postmenopausal)n 
X 
X 
X 
Flow cytometry (blood)o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cytokine/inflammation panelp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Polyoma virus assay (serum)q 
X 
Biobanking sample (blood)r,s 
X 
X 
X 
X 
PK blood samplingt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity (ADA) blood samplingu 
X 
X 
X 
X 
X 
X 
X 
RECIST 1.1 tumor assessmentv 
X 
X 
Monitor/record adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fresh tumor biopsy (optional)s,w 
X 
X 
 
 
 


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Table 7:  
Schedule of Assessments (Continued) 
Evaluation or Procedure 
Cycle 2 and Higher 
Study Day 
1 
8 
15 
22 
29 
36 
40 ± 2 
NETSPOT Gallium 68 dotatate PET/CT scana,b 
 
 
 
 
 
 
X 
XmAb18087 administratione,f 
X 
X 
X 
X 
X 
X 
Pembrolizumab administrationf 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
 
Vital signsj, k 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
ECOG performance statush 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram (supine) l,m 
X 
X 
X 
X 
X 
X 
 
CBC w/ differential (absolute and percentage), platelet counth 
X 
X 
X 
X 
X 
X 
Chemistry panelh 
X 
X 
X 
X 
X 
X 
Coagulation panelhl 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
X 
 
 
 
Serum β–hCG (females of childbearing potential) FSH (postmenopausal)n 
X 
X 
Flow cytometry (blood)o 
X 
X 
Cytokine/inflammation panelp 
X 
 
 
X 
 
 
 
PK blood samplingt 
X 
X 
Immunogenicity (ADA) blood samplingu,x 
X 
X 
X 
X 
RECIST 1.1 tumor assessmentv 
X 
Monitor/record adverse events 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
 
 


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Table 7:  
Schedule of Assessments (Continued) 
Evaluation or Procedure 
Post-treatment 
Study Day 
EOT 
14 d post-EOT 
28 d post-EOT 
Long-term Follow-up (6 & 12 
mo after EOT) 
NETSPOT Gallium 68 dotatate PET/CT scana,b 
X 
 
 
 
Medical history 
X 
Physical examination 
X 
X 
X 
Vital signsj, k 
X 
X 
X 
 
Weight 
X 
X 
X 
 
ECOG performance statush 
X 
X 
X 
12-lead electrocardiogram (supine) l,m 
X 
CBC w/ differential (absolute and percentage), platelet counth 
X 
X 
X 
 
Chemistry panelh 
X 
X 
X 
Coagulation panelh 
X 
X 
X 
Urinalysis 
X 
X 
X 
HBsAg, HBcAb, HCV, HIV 
X 
 
 
 
Serum β–hCG (females of childbearing potential) FSH 
(postmenopausal)n 
X 
X 
Flow cytometry (blood)o 
X 
X 
X 
Cytokine/inflammation panelp 
Polyoma virus assay (serum)q 
X 
 
X 
 
PK blood samplingt 
X 
X 
X 
Immunogenicity (ADA) blood samplingu,x 
X 
X 
X 
RECIST 1.1 tumor assessmentv 
X 
Monitor/record adverse events 
X 
X 
X 
Concomitant medications 
X 
X 
X 
Phone/email/mail contact for progression 
X 
 


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Abbreviations: ADA = anti-drug antibody; β–hCG = beta unit of human chorionic gonadotrophin; CBC = complete blood counts; CT = computed tomography; 
EOI = end of infusion. EOT = end of treatment; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FACS = fluorescence-activated cell 
sorting; FFPE = fresh frozen paraffin-embedded; FSH = follicle-stimulating hormone; HBsAg = hepatitis B surface antigen; HBcAb = hepatitis B core antibody; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; mo = month; MRI = magnetic resonance imaging; NET = neuroendocrine tumors; PE = physical 
examination; PET = positron emission tomography; PK = pharmacokinetic; RECIST = Response Evaluation Criteria In Solid Tumors; SSTR2 = somatostatin 
receptor 2. 
a 
If subject has undergone NETSPOT gallium 68 dotatate PET/CT scan within 6 weeks prior to enrollment and the images and a report of results are available 
for collection, the scan need not be repeated at baseline. If SSTR2 radionuclide scanning and RECIST 1.1 tumor assessment by CT/MRI are planned within 
2 days of each other, RECIST imaging should be conducted first. 
b NETSPOT gallium 68 dotatate PET/CT scan will be performed on Day 40 ± 2 of Cycle 1 and of every second cycle thereafter; that is, at the end of Cycle 3, 
Cycle 5, etc. The EOT scan will be performed only if the subject has not undergone scan within the past 2 months. 
c 
On Day -1, hospitalization is optional. Hospitalization on Days 36 through 39 in Cycle 1 is optional if PK sampling cannot be accommodated as an outpatient. 
Vital sign assessments on Days 36 through 39 in Cycle 1 will be performed only if the subject is hospitalized. 
d Any subject who has shown symptoms of CRS during a required inpatient hospitalization will be monitored as an inpatient for at least 24 hours after the 
symptoms have subsided. 
e 
XmAb18087 will be administered as 
. Subjects will 
be observed as inpatients for the first 2 doses. For all other infusions of XmAb18087, the subject will be observed for at least 4 hours following subsequent 
infusions, except that the observation period may be decreased to 2 hours if no infusion reactions have occurred for at least 3 consecutive infusions and the 
subject has completed 4 infusions at the highest dose for that subject. 
f  XmAb18087 is administered on Day 15 in Parts A and C only. Pembrolizumab is administered on Day 15 of each cycle in Part B only. XmAb18087 is NOT 
to be administered on Day 15 in Part B. Pembrolizumab will be provided by sites as standard of care. 
g Complete medical history and PE is to be performed at Screening. For all the other time points, only an abbreviated, symptom-directed PE is to be performed. 
h 
May be performed up to 24 hours prior to infusion. The following procedures that are completed on Day -1 within 24 hours of Cycle 1 Day 1 dosing do not 
need to be repeated on Cycle 1 Day 1: PE, ECOG, and local safety laboratories (eg, CBC with differential and platelets, chemistry panel, coagulation panel, 
and urinalysis). These safety laboratory assessments will be performed by the central laboratory and should also be performed by local clinical site laboratories 
so that clinical site personnel can review results before administering XmAb18087.  
i 
Baseline neurologic examination to be performed on Day -1. If a subject appears to be experiencing neurologic toxicity, the neurologic examination should be 
repeated as necessary to evaluate the subject’s condition. Guidelines on management of neurologic toxicity are included in both Section 11.3.3.4 and 
Appendix C. 
j 
Supine blood pressure and pulse rate, body temperature, respiratory rate, and blood oxygen saturation by pulse oximetry. On days of XmAb18087 infusions, 
vital signs should be taken within 60 minutes of predose; 15, 30, and 60 minutes after start of infusion (± 5 minutes for each time point); immediately (within 5 
minutes) before EOI; 15, 30, and 60 minutes after EOI (± 5 minutes for each time point); and then hourly (± 5 minutes) for 3 hours. When possible, vitals 
should be measured before blood sampling. Oxygen saturation levels will be captured with each vital sign collection; however, pulse oximetry monitoring 
must be maintained continuously throughout the entire admission or observation period for each administration of XmAb18087. For information on 
management of oxygen saturation of 90% or lower, see Section 11.3.3.1. All vital signs during infusion should be taken with the subject in the same position. 
On nondosing days, vitals should be measured before blood sampling.  
k 
On days of pembrolizumab infusions, vital signs should be taken immediately prior (within 10 minutes before blood sampling) to the start of infusion; during 
the infusion at 5 and 15 minutes (± 2 minutes); immediately (within 2 minutes) before the EOI; and at 15 minutes (± 2 minutes) after EOI. 
l 
On days when XmAb18087 is infused, electrocardiograms should be taken prior to infusion, 2 to 4 hours after EOI, and if clinically indicated. 
m Part B only: ECGs are not performed on days when pembrolizumab is administered.  
n Once postmenopausal status has been established by FSH, this test need not be repeated during the clinical trial. 
o In Cycle 1, whole blood for flow cytometry (FACS) analysis will be obtained predose on Day 1 (± 1 hour); on Day 2 (24 hours post-EOI ± 3 hours); on 
Day 3 (48 hours post-EOI ± 3 hours); predose on Day 8 ± 1 hour; on Day 9 (24 hours post-EOI ± 3 hours); on Day 10 (48 hours post-EOI ± 3 hours); predose 
on Day 15 ± 1 hour; predose on Day 22 ± 1 hour; predose on Day 29 ± 1 hour; predose on Day 36 ± 1 hour; on Day 37 (24 hours post-EOI ± 3 hours); on 


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Day 38 (48 hours post-EOI ± 3 hours); and on Day 39 (72 hours post-EOI ± 3 hours). In Cycles 2 and higher, whole blood for FACS will be obtained predose 
on Day 22 ± 2 days and on Day 36 ± 2 days. Upon discontinuation from the study, whole blood for FACS analysis should be obtained at EOT (± 2 days), 
at 14 days post-EOT (± 2 days), and at the 28 days post-EOT visit(± 2 days.) 
p 
In Cycle 1, serum for cytokine profile analysis will be obtained predose on Day 1, 8, and 36 and at 5 minutes (± 1 minute), 1 hour (± 10 minutes), 2 hours 
(± 10 minutes), 4 hours (± 10 minutes), 7 hours (± 10 minutes), and 10 hours (± 10 minutes) post-EOI; on Days 2, 9, and 37 (24 hours post-EOI ± 3 hours), 
Day 3, 10, and 38 (48 hours post-EOI ± 3 hours), and on Day 39 (72 hours post-EOI ± 3 hours). Additionally, samples will be collected predose on Days 15, 
22, and 29 and at 5 minutes (± 1 minute), 1 hour (± 10 minutes), 2 hours (± 10 minutes), 4 hours (± 10 minutes), and 7 hours (± 10 minutes) post EOI. In 
Cycle 2 and higher, serum for cytokine profile analysis will be obtained on Day 1 and Day 22 (± 2 days) of each cycle predose and at 1 hour (± 10 minutes), 
2 hours (± 10 minutes), and 4 hours (± 10 minutes) post EOI. Serum should also be drawn at any time there is clinical suspicion of cytokine release syndrome 
and repeated 4 hours later. 
q Polyoma virus assay serum collection is for Part A and Part B only. 
r 
Including serum, peripheral blood, and nucleic acid samples. 
s 
Optional; by specific subject consent. 
t 
In Cycle 1, serum for PK analysis will be obtained at Day -1; on Days 1 and 36 predose and at 5 minutes (± 1 minute), 1 hour (± 10 minutes), 2 hours 
(± 10 minutes), 4 hours (± 10 minutes), 7 hours (± 10 minutes), and 10 hours post-EOI (± 10 minutes, Day 1 only); on Days 2 and 37 (24 hours post-EOI 
± 3 hours), and Days 3 and 38 (48 hours post-EOI ± 3 hours), and Day 39 (72 hours post-EOI ± 3 hours); on Day 8 predose and at 5 minutes (± 1 minute) 
post-EOI; on Day 10 (48 hours post-EOI); and on Days 15, 22, and 29 predose and at 5 minutes post-EOI (± 1 minute). In Cycles 2 and higher, serum for PK 
analysis will be collected on the first day of each cycle (± 2 days) predose and 5 minutes (± 1 minute) post-EOI (all subjects). Subjects in Part B only 
(combination therapy) will also have serum collected for PK analysis on Day 15 at predose and 5 minutes (± 1 minute) post-EOI. Upon discontinuation from 
the study, serum for PK analysis should be obtained at the EOT visit (± 2 days), the 14-day post-EOT visit (± 2 days), and the 28 day post-EOT visit (± 2 days). 
u 
In Cycle 1, serum for ADA will be collected on Day -1 and predose (± 1 hour) on Days 1, 8, 15, 22, 29, and 36. In Cycles 2 and higher, serum for ADA 
analysis will be collected predose on Days 1, 15, 22 and 36 (± 2 days). Upon discontinuation from the study, serum for ADA will be collected at EOT 
(± 2 days), at 14 days post-EOT (± 2 days), and at 28 days post-EOT (± 2 days). 
v 
Radiographic tumor evaluation will be performed by CT/MRI at baseline and at all other disease assessment time points. All studies for the baseline RECIST 
assessment should be performed within 14 days prior to the first dose of drug. The EOT tumor assessment will not be performed if the subject has had an assessment 
within the past 30 days. 
w The post-treatment fresh tumor biopsy should be performed between 12 and 21 days after first dose of XmAb18087. 
x Subjects with a positive ADA at termination will be followed every 28 days (± 3 days) until ADA reverts to baseline or until the next intervening treatment. 
 
 


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7.9.1. 
Pretreatment Evaluations 
Only those subjects who meet all inclusion (Sections 8.1 and 8.2) and no exclusion (Sections 8.6 
and 8.7) criteria specified may be enrolled into this study. Prior to the initiation of any on-study 
testing, including screening testing, the subject must have signed the ICF and received a Subject 
Screening Number (Section 7.6). The pretreatment period lasts for up to 28 days and includes 
screening evaluations (Day -28 to -2) and baseline assessments (defined as the assessment 
immediately prior to the first dose).  
Prior to administration of XmAb18087, each subject must have completed all screening activities 
and received approval via the eligibility checklist from the Medical Monitor. 
7.9.1.1. 
Screening Period (Day -28 to -2) 
Subjects will undergo a Screening Visit 2 to 28 days prior to the planned first day of study 
treatment. Screening assessments are as follows: 
• Obtain signed informed consent (Section 17.3) 
• Review inclusion and exclusion criteria (Sections 8.1, 8.2, 8.6, and 8.7) 
• Medical history 
• Demographics 
• Physical examination (PE; Section 11.7) 
• Collect formalin-fixed paraffin embedded (FFPE) tumor sample or slides for 
immunohistochemical assessment of MCPyV status (MCC subjects only), tumor cell 
SSTR2 expression and immune cell expression of proliferation and exhaustion markers 
• Perform tumor assessment by CT/magnetic resonance imaging (MRI) per RECIST 1.1 
criteria and guidelines (Appendix A) within 14 days prior to the first dose of drug 
• Perform NETSPOT gallium 68 dotatate PET/CT if not performed within 3 months 
prior to enrollment (refer to study manual for details on performing NETSPOT gallium 
68 dotatate PET/CT). If the subject has undergone NETSPOT gallium 68 dotatate 
PET/CT scan within 3 months prior to enrollment and the images and reports of results 
are available, the scan need not be repeated at baseline; however, a copy of images and 
the report of scan results must be collected.  
• Record any available genetic information on the tumor, including sequencing data 
• ECOG performance status (Appendix B) 
• Vital signs (Section 11.8) 
• Electrocardiogram (ECG) standard 12-lead, supine position (Section 11.6) 
• Complete blood count (CBC; Section 11.5) 
• Chemistry panel (Section 11.5)  
• Coagulation panel (Section 11.5) 


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• Screening test for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody 
(HBcAb; a subject whose HBsAg is negative and HBcAb is positive may be enrolled 
if a hepatitis B virus [HBV] DNA test is negative and either the subject is treated with 
potent antiviral therapy or is retested for HBsAg and HBV DNA every month while on 
study drug treatment). 
• Screening tests for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) 
• Serum beta human chorionic gonadotropin (β-hCG) pregnancy test for women of 
childbearing potential or follicle-stimulating hormone (FSH) for postmenopausal 
women (Section 11.5) 
• Urinalysis (Section 11.5) 
• Record concomitant medications (Section 9.2) 
• Record adverse events (using CTCAE and CRS revised grading system for grading; 
Section 11.1) 
• Pretreatment fresh tumor biopsy (optional; by specific subject consent) to be examined 
by fluorescent immunohistochemical assay for tumor-cell expression of SSTR2 and 
tumor and immune-cell expression of proliferation and exhaustion markers, and by 
Nanostring analysis of nucleic acid and protein content 
7.9.1.2. 
Baseline Assessments (Day -1 or 1) 
If a test or assessment is performed on both Day -1 and Day 1, the Day 1 (predose) test is 
considered the baseline: 
• Medical history 
• Abbreviated PE (Section 11.7) 
• Neurological examination 
• ECOG performance status (Appendix B) 
• Vital signs (Section 11.8) 
• Height, weight 
• ECG: standard 12-lead, supine position (Section 11.6) 
• CBC (Section 11.5) 
• Chemistry panel (Section 11.5) 
• Coagulation panel (Section 11.5) 
• Urinalysis (Section 11.5) 
• Urine β-hCG pregnancy test for women of childbearing potential (Section 11.5) 
• Blood for cell surface markers by flow cytometry or other similar bioanalytical 
methods (Section 13.3) 
• Serum for MCPyV assay (Part A and Part B only) 


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• PK, cytokine/inflammation panel blood sample (Section 13.1) 
• Immunogenicity (ADA) blood sample (Section 13.1) 
• Blood for biobanking (Section 13.4) 
• Record concomitant medications (Section 9.2) and AEs  
7.9.2. 
Subject Enrollment 
Subjects who have completed screening activities and whose eligibility has been confirmed by the 
Medical Monitor will be considered enrolled in the study. 
7.9.3. 
Treatment Cycle Assessments 
The schedule of required procedures and clinical site study days for each cycle are detailed in the 
Schedule of Assessments (Table 7). The day prior to Cycle 1 Day 1 is Day -1. 
Subjects will be followed for PFS and overall survival at 6 and 12 months after end of treatment 
(EOT) by telephone, email, or mail contact from the clinical site (Section 7.9.5). 
Procedures during the treatment cycles to 4 weeks after EOT are detailed in Sections 7.9.3.1 to 
7.9.3.2. Study days for required procedures are specified in the Schedule of Assessments (Table 7). 
7.9.3.1. 
Clinical Assessments 
PEs and laboratory evaluations may be performed within 24 hours prior to XmAb18087 infusion: 
• Record concomitant medications and AEs (CTCAE and CRS revised grading system, 
Section 11.1). 
• Abbreviated, symptom-directed PE, including weight 
• ECOG performance status (Appendix B) 
• Vital signs (Section 11.8): 
− On infusion days, time points include: within 60 minutes of predose; approximately 
15, 30, and 60 minutes after start of infusion (± 5 minutes for each time point); 
immediately (within 5 minutes) before end of infusion (EOI; if different than 
60 minutes from start of infusion); approximately 15, 30, and 60 minutes after EOI 
(± 5 minutes for each time point); and then hourly (± 5 minutes) for 3 hours. The 
pulse oximetry for blood oxygen saturation level needs to be captured with each 
vital sign collection; however, pulse oximetry monitoring must be maintained 
continuously throughout the entire admission or observation period for each 
administration of XmAb18087. For information on management of oxygen 
saturation of 90% or lower, see Section 11.3.3.1.  
− On non-dosing days, vitals should be measured before blood is drawn. 
− For subjects who tolerate 3 XmAb18087 consecutive infusions without an infusion 
reaction during the infusion or postinfusion observation period and who have 
completed 4 infusions at the highest dose for that subject, the postinfusion 


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observation period and vital signs assessment may be reduced from 4 hours to 
2 hours. 
7.9.3.2. 
Laboratory Assessments 
Unless otherwise specified, assessments during Cycle 1, Days 1, 8, 15, 22, 29, and 36 should be 
completed ± 1 hour of the scheduled time; for other days during Cycle 1, ± 3 hours; and for 
subsequent cycles and disease assessments, ± 2 days. Details for laboratory assessments are 
provided in Section 11.5 and Section 11.6; details for PK, PD, flow cytometry, and biobanking are 
provided in Section 13. 
Laboratory assessments include the following: 
• CBC 
• Chemistry panel 
• Coagulation panel 
• Urinalysis 
• Serum pregnancy test for women of childbearing potential  
• Blood for cell surface markers by flow cytometry or similar bioanalytical methods (see 
the Laboratory Manual for detailed instructions) 
• PK (see the Laboratory Manual for detailed instructions) 
• Cytokine/inflammation panel (see the Laboratory Manual for detailed instructions) 
• ADA blood sample (see the Laboratory Manual for detailed instructions) 
• Biobanking blood sample (optional; by specific subject consent) 
• ECG, standard 12-lead 
• RECIST 1.1 tumor assessment by CT/MRI (See Appendix A) 
• Post-treatment fresh tumor biopsy (optional; by specific subject consent) to be 
examined by various immunohistochemistry assays for tumor-cell expression of 
SSTR2 and tumor- and immune-cell expression of proliferation and exhaustion 
markers, and transcriptomic analysis by Nanostring. The optional post-treatment fresh 
tumor biopsy should be performed between 12 and 21 days after the first dose of 
XmAb18087. 
• NETSPOT gallium 68 dotatate PET/CT after the first cycle of treatment and, for 
subjects continuing to receive study drug, after every second cycle thereafter 
NETSPOT gallium 68 dotatate PET/CT should be performed after RECIST tumor 
assessment by CT/MRI has been completed. Refer to study manual for details on 
performing NETSPOT gallium 68 dotatate PET/CT. 


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7.9.3.3. 
End-of-Treatment Visit 
Subjects will have their EOT visit at the end of the last cycle of treatment. If a subject terminates 
before the end of a cycle, the EOT assessments (Table 7, Schedule of Assessments) will be 
performed on the day of study termination. 
Subjects with a positive ADA at study termination will be followed every 28 days (± 3 days), if feasible, 
until administration of another anticancer therapy, or until ADA levels return to baseline if results are 
available. 
7.9.4. 
Post-treatment Follow-up Period (2 Weeks and 4 Weeks After EOT) 
Subjects will have visits 14 days post-EOT and 28 days post-EOT. Assessments are as indicated 
in Table 7. Once these two visits have been completed, the subject will be considered as having 
completed participation in the clinical trial. If a subject enrolls into another trial or requires 
treatment before either of these scheduled visits, the visits may be performed earlier. If a subject 
is unable to return for any scheduled visits after the end of treatment, he/she will be considered as 
having completed study requirements at the end of treatment. 
7.9.5. 
Long-Term Follow-up Period (6 and 12 Months After EOT) 
Subjects will be contacted by site staff by telephone, email, or mail at 6 and 12 months after their 
active participation in the study ends to gather information about disease progression and survival. 
Completion of the long-term follow-up period is not required for a subject to be considered as 
having completed the clinical trial.  
7.10. 
Discussion of Study Design 
This is a Phase 1b/2, multiple-dose study designed to describe safety and efficacy, and to assess 
PK and immunogenicity of XmAb18087 monotherapy and in combination with pembrolizumab 
in subjects with metastatic MCC or locoregional MCC that has recurred after locoregional therapy 
with surgery and/or radiation therapy, and XmAb18087 monotherapy in subjects with 
extensive-stage SCLC that has progressed after standard therapies. 
Part A of the study will enroll safety run-in cohorts of subjects with advanced MCC that has 
progressed after treatment with standard therapies to confirm the safety and tolerability of 
XmAb18087 monotherapy administered IV with weekly step-up dosing for 42-day cycles. 
Additional subjects will be enrolled into an expansion cohort and will receive XmAb18087 
monotherapy using the RD identified following the safety run-in. 
Part B of the study will enroll safety run-in cohorts of subjects with advanced MCC not previously 
treated with anti-PD1 or anti-PDL1 agents, and for whom pembrolizumab as a single agent is 
indicated, to confirm the safety and tolerability of XmAb18087 in combination with 
pembrolizumab. Subjects will receive step-up IV dosing of XmAb18087 on Days 1, 8, 22, 29, and 
36, and IV dosing of pembrolizumab on Day 15 of each 42-day cycle. Additional subjects will be 
enrolled into an expansion cohort and will receive XmAb18087 plus pembrolizumab combination 
therapy using the RD identified following the safety run-in. 
Enrollment into the first safety run-in cohort of Part B (Cohort 1B) may begin after the first safety 
run-in cohort in Part A (Cohort 1A, one dose level higher than Cohort 1B) has completed the first 
cycle and the regimen has been demonstrated to be tolerable. 


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Part C of the study will enroll safety run-in cohorts of subjects with extensive-stage SCLC that has 
progressed after treatment with standard therapies to confirm the safety and tolerability 
XmAb18087 monotherapy. The safety run-in will follow the same cohort schema as described for 
Part A to identify a RD for expansion in SCLC. Additional subjects will be enrolled into an 
expansion cohort and will receive XmAb18087 monotherapy using the RD identified following 
the safety run-in. 
Enrollment into Part C may begin concurrently with Part A. 
7.10.1. 
Risk/Benefit and Ethical Assessment 
XmAb18087 has been characterized through an extensive program of in vitro and in vivo testing 
which demonstrates that the drug binds CD3 and SSTR2 and is active against SSTR2+ cells and 
tumors. The pharmacology and toxicology of the drug have also been studied in numerous 
experiments using cynomolgus monkeys, the relevant species for a CD3-directed bsAb. 
Pharmacology results show that XmAb18087 activates T cells, and toxicology results, as well as 
results from the first 42 subjects dosed in the XmAb18087-01 trial, indicate that the drug can be 
administered safely within the careful program of prophylactic medication, frequent subject 
assessment, and close observation that the XmAb18087-02 clinical trial protocol describes. Given 
that Part A and Part C of the XmAb18087-02 trial are being conducted in subjects with advanced 
cancer for which there is no effective available therapy, the sponsor believes that the administration 
of monotherapy under the auspices of this clinical study is ethical.  
Pembrolizumab (Keytruda) is approved for the treatment of adult and pediatric patients with 
recurrent locally advanced or metastatic MCC. Given that the combination of XmAb18087 and 
pembrolizumab will be administered to this patient population within a careful program of frequent 
subject assessment and close observation, the Sponsor believes that the proposed combination 
therapy portion of the clinical study is ethical. 
7.10.2. 
Termination of Study 
If the Investigator or the Sponsor becomes aware of conditions or events that suggest a possible 
hazard to subjects should the clinical study continue, the clinical study may be terminated after 
appropriate consultation among the involved parties. The clinical study also may be terminated at 
the Sponsor’s discretion, also in the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
• The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled 
in the clinical study. 
• Failure to enroll subjects at the required rate. 
• A decision of the Sponsor to suspend or discontinue development of the IMP. 
Should the study be terminated and/or the site closed for whatever reason, all documentation 
pertaining to the study and IMP must be returned to the Sponsor. Any actions required for assessing 
or maintaining study-subject safety will continue as required, despite termination of the study by 
the Sponsor. 
Details for study termination due to AESC are provided in Section 7.8.2. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Inclusion Criteria for All Cohorts 
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
• Able to provide written informed consent 
• Adult subjects ≥ 18 years 
• Disease measurable by RECIST 1.1 criteria using either CT or MRI scan 
• ECOG performance status of 0 or 1 
• All subjects must have adequate archival tumor sample (slides or archival FFPE 
block[s] containing tumor that has not been previously irradiated; FFPE blocks are 
preferred to slides, and newly obtained biopsies are preferred to archived tissue. Refer 
to the laboratory manual for further instructions). Excepted are subjects who consent 
to having a fresh tumor biopsy to provide a fresh tumor sample instead of the archival 
tumor sample. 
• Female subjects of childbearing potential must agree to use a highly effective method 
of birth control during and for 4 weeks after completion of study. Women are 
considered to be of childbearing potential unless it is documented that they are over the 
age of 60 OR postmenopausal by history with no menses for 1 year and confirmed by 
FSH (using local reference ranges) OR have a history of hysterectomy and/or bilateral 
oophorectomy OR have a history of bilateral tubal ligation. Highly effective methods 
of birth control include combined hormonal birth control (oral, intravaginal, or 
transdermal), or progestogen-only hormonal contraception associated with inhibition 
of ovulation (oral, injectable, or intrauterine), intrauterine devices (IUDs), intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomized partner (provided 
partner is the sole sexual partner and there has been a medical assessment of surgical 
success), or sexual abstinence as defined in Section 8.9.1. 
• Fertile male subjects must be willing to practice a highly effective method of birth 
control for the duration of the study and continuing for 4 weeks after the last dose of 
XmAb18087 or pembrolizumab (when applicable). Highly effective methods of birth 
control include vasectomy or a condom in combination with double-barrier methods, 
spermicide, hormonal birth control, or IUD (nonhormonal) used by the woman. 
• Able and willing to complete the entire study according to the study schedule 
8.2. 
Additional Inclusion Criteria for Part A and Part B Cohorts:  
In addition to the inclusion criteria above, the following criteria are required for Parts A and B 
safety run-in and expansion cohorts: 
• Histologically or cytologically confirmed metastatic MCC or locoregional MCC that 
has recurred following standard locoregional therapy with surgery and/or radiation 
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8.3. 
Additional Inclusion Criteria for Part A Cohorts: 
In addition to the inclusion criteria above, the following criteria are required for Part A safety 
run-in and expansion cohorts: 
• Subjects must have progressed on or been ineligible for treatment with anti-PD1 or 
anti-PDL1 therapy. 
8.4. 
Additional Inclusion Criteria for Part B Cohorts: 
In addition to the inclusion criteria above, the following criteria are required for Part B safety 
run-in and expansion cohorts: 
• Subjects must be eligible to receive pembrolizumab as standard of care. 
8.5. 
Additional Inclusion Criteria for Part C Cohorts: 
In addition to the inclusion criteria above, the following criteria are required for Part C safety 
run-in and expansion cohorts: 
• Histologically or cytologically confirmed extensive-stage SCLC that has progressed 
following standard therapies 
8.6. 
Exclusion Criteria for All Cohorts 
Subjects who meet any of the following criteria will be excluded from the study: 
• History of prior organ or bone marrow transplant 
• History of chronic lymphocytic leukemia 
• Subjects currently receiving anticancer therapies 
• Subjects who have received anticancer therapies within 2 weeks of the start of study 
drug (including chemotherapy, radiation therapy, immunotherapy, etc.) 
• Prior therapy with an agent directed to another stimulatory or coinhibitory T-cell 
receptor (eg, CTLA4, OX40, CD137) AND were permanently discontinued from that 
treatment due to an IRAE 
• Failure to recover from any IRAE from prior cancer therapy to ≤ Grade 1 (participants 
with ≤ Grade 2 neuropathy or endocrinopathies controlled by hormone replacement are 
eligible) 
• Failure to recover from any other toxicity (other than immune-related toxicity) from 
previous anticancer treatment to ≤ Grade 2 
• Known active central nervous system metastases and/or carcinomatous meningitis. 
Subjects with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging for at least 4 weeks prior to the first 
dose of trial treatment and any neurologic symptoms have returned to baseline), have 
no evidence of new or enlarging brain metastases, and are not using steroids for at least 
28 days prior to trial treatment. 


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• Have a history of (noninfectious) pneumonitis that required steroids or have current 
pneumonitis (history of radiographically visible but asymptomatic radiation 
pneumonitis is allowed) 
• Platelet count < 50 × 109/L 
• Absolute neutrophil count < 1.0 x 109/L 
• AST ≥ 3 × upper limit of normal (ULN), or if subject has known liver metastases, AST 
≥ 7 × ULN 
• ALT ≥ 3 × ULN, or if subject has known liver metastases, ALT ≥ 7 × ULN 
• Estimated creatinine clearance < 50 mL/min calculated by the Cockcroft Gault or 
Modification of Diet in Renal Disease formulas at screening 
• Treatment with immunosuppressive therapy within 28 days of first dose of study drug 
• History or evidence of any other clinically unstable/uncontrolled disorder, condition, 
or disease (including, but not limited to, cardiopulmonary, renal, metabolic, 
hematologic, or psychiatric) other than their primary malignancy that in the opinion of 
the Investigator would pose a risk to subject safety or interfere with the study 
evaluation, procedures, or completion 
• Treatment for any serious bacterial, viral, parasitic, or systemic fungal infections within 
the 30 days prior to study entry 
• Active known or suspected COVID-19 disease 
• Active known or suspected autoimmune disease (except that subjects are permitted to 
enroll if they have vitiligo; type 1 diabetes mellitus; residual hypothyroidism due to an 
autoimmune condition that is treatable with hormone replacement therapy only; 
psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed 
without systemic therapy; or arthritis that is managed without systemic therapy beyond 
oral acetaminophen and nonsteroidal anti-inflammatory drugs [NSAIDS]) 
• Positive test for HIV or hepatitis C antibodies 
• Positive test for HBsAg or HBcAb (a subject whose HBsAg is negative and HBcAb is 
positive may be enrolled if an HBV DNA test is negative and either the subject is 
treated with potent antiviral therapy or is retested for HBsAg and HBV DNA every 
month) 
• Subject is pregnant or breastfeeding, planning to become pregnant, or expecting to 
conceive or father children while enrolled in the study, up to the end of study (EOS) 
visit. 
• Positive serum pregnancy test (ie, urine human chorionic gonadotropin) at screening  


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8.7. 
Additional Exclusion Criteria for Part B Cohorts: XmAb18087 in 
Combination with Pembrolizumab 
In addition to the exclusion criteria in Section 8.6, subjects will be excluded from Part B safety 
run-in and expansion cohorts administered XmAb18087 in combination with pembrolizumab if 
they meet the following criteria: 
• Prior treatment with therapeutics directed at anti-programmed cell death 1 (anti-PD1) 
or anti-programmed cell death ligand 1 (anti-PDL1) 
• Have severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients 
8.8. 
Withdrawal of Subjects 
Subjects must be withdrawn if the β-HCG pregnancy test is consistent with pregnancy. Before 
permanent discontinuation, the treatment may be interrupted to confirm the positive pregnancy 
test. Pregnancy should be reported as described in Section 11.1.4.2. 
The Principal Investigator (PI) also has the right to withdraw subjects from the study at his/her 
discretion for any of the following reasons: 
• Disease progression 
• Occurrence of an unacceptable serious or non-serious AE 
• Failure to return for follow-up 
• Uncontrolled intercurrent illness unrelated to the disease under study that renders 
continuing treatment with XmAb18087 unsafe or regular study visits impossible 
• Investigator decision 
• Subject decision 
• Death 
• Administrative reasons 
Subjects will be considered to have completed/ended participation in the study at the time that a 
subsequent anticancer therapy is administered. 
Whenever possible, the Sponsor must be notified within 24 hours if a subject is withdrawn from 
the study. The reason(s) for a subject’s discontinuation from the study are to be recorded in the 
source documents and the subject’s electronic case report form (eCRF). 
The EOT eCRF must be completed for all subjects who discontinue XmAb18087 permanently. 
For subjects who discontinue prematurely, all assessments described for the EOT visit should be 
performed at the scheduled visit date, if at all possible. If this is not possible, all assessments should 
be performed as close to the scheduled dates as is practicable. Post-treatment evaluations should 
be completed no later than 4 weeks after the final administration of XmAb18087 and prior to 
initiation of a new treatment for malignancy. 
Subjects who are withdrawn for any reason may not reenter this study. The Study Sponsor, Xencor, 
reserves the right to terminate this clinical study at any time and for any reason. 


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8.9. 
Other Subject Restrictions 
8.9.1. 
Avoidance of Pregnancy 
Women are considered to be of childbearing potential unless there is a documented reason (ie, 
postmenopausal by history with no menses for 1 year and confirmed by FSH [using local reference 
ranges], OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral 
oophorectomy). 
Women of childbearing potential must have a negative pregnancy test during screening and at 
Day 1 prior to study drug infusion and must use 1 highly effective method of birth control during 
the study and for 4 weeks following last dose of XmAb18087 or pembrolizumab (when 
applicable). Highly effective methods of birth control include combined hormonal birth control 
(oral, intravaginal, or transdermal), or progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, or intrauterine), IUDs, intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomized partner (provided partner is the sole sexual partner 
and there has been a medical assessment of surgical success), or sexual abstinence. Sexual 
abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. Total abstinence 
is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. The Investigator is responsible for evaluating the reliability 
of the subject’s ability to maintain sexual abstinence throughout the duration of the clinical trial. 
Fertile male subjects must be willing to practice a highly effective method of birth control for the 
duration of the study and continuing for 4 weeks after the last dose of XmAb18087 or 
pembrolizumab (when applicable). Highly effective methods of birth control include vasectomy 
or a condom in combination with double-barrier methods, spermicide, hormonal birth control, or 
IUD (nonhormonal) used by the woman. 
8.9.2. 
Use in Nursing Women 
It is unknown whether XmAb18087 or pembrolizumab are excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Identity of Study Treatments 
XmAb18087 is a humanized bsAb that binds both CD3 and the tumor antigen SSTR2 to recruit 
cytotoxic T cells that will kill SSTR2+ tumor cells. Intravenous Stabilization Solution is a 
concentrated form of the XmAb18087 buffer that minimizes protein binding to the administration 
equipment. 
XmAb18087 drug product is a sterile liquid supplied in single-use glass vials. 
 
 
  
 
 
 
 
 
 
Prior to dilution, the vial containing parenteral drug product should be inspected visually. 
If particulate matter and/or discoloration are noted, drug should not be administered, and 
the Sponsor should be notified. 
Pembrolizumab (Keytruda®) is an approved humanized mAb targeting the cell surface antigen 
PD1. It will be administered at the dose and schedule of 400 mg IV over 30 minutes every 6 weeks. 
It is supplied as a 100 mg per 4 mL (25 mg/mL) solution in a single-dose vial. Pembrolizumab is 
provided by sites as standard of care for advanced MCC. 
9.2. 
Concomitant Therapy 
All medications (including over-the-counter medications and herbals) and blood products that are 
administered within the 30 days prior to start of study treatment and throughout a subject’s 
participation in the study until the post-treatment follow-up visit must be recorded in the source 
document and on the eCRF. Concomitant medications for other medical conditions are permitted 
as clinically indicated, subject to the specific requirements outlined in Section 7.9.1 and 7.9.2. 
9.2.1. 
Permitted Medications 
Subjects who experience CRS should receive aggressive intervention and supportive measures as 
indicated. These may include, but are not limited to, epinephrine, antihistamines, corticosteroids, 
IV fluids, vasopressors, oxygen, bronchodilators, diphenhydramine, acetaminophen, and 
tocilizumab (see Section 11.3.3 or Appendix C for suggested management of infusion reactions, 
CRS, and neurologic toxicities). 
Subjects who experience IRAE after pembrolizumab exposure should receive specific therapy in 
accordance with the guidelines in Table 18 and/or the NCCN guidelines for management of IRAEs 
(Appendix E) 
In addition to required prophylactic medications, subjects may also receive the following 
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• Antiemetics, 
antidiarrheals, 
anticholinergics, 
antispasmodics, 
antipyretics, 
antihistamines, analgesics, antibiotics, antihyperglycemics, and other medications 
intended to treat symptoms related to cancer, cancer therapy, or concurrent conditions. 
Other antitumor treatments may not be received.  
• Antiviral treatments for subjects with a positive HBcAb (and negative HBV DNA test) 
at screening 
• Transfusions of blood products such as red blood cells (RBCs) and platelets, if 
medically indicated 
• Histamine receptor type 2 antagonists, or proton-pump inhibitors for treatment of 
indigestion, nausea, and/or vomiting 
• Multivitamins, provided they be documented on the concomitant medications eCRF. 
No other vitamins or supplements will be permitted during this study without prior 
notification and approval of the Medical Monitor. 
9.2.2. 
Excluded Medications 
Subjects may not concurrently receive other therapeutics for treatment of their malignancy. It is 
suggested that subjects not receive live prophylactic vaccinations while enrolled in the study. 
9.3. 
Subject Compliance 
The Sponsor or its designee will monitor the study according to GCP guidelines. All 
investigational therapy will be prepared and administered at the study site, and complete records 
of administration doses, times, durations, and supportive therapies will be kept. 
Dosing will be performed by trained, qualified personnel designated by the PI. The date and time 
of dosing will be documented on each dosing day. Comments will be recorded if there are any 
deviations from the planned dosing procedures. 
9.4. 
Blinding and Randomization of Study Treatment 
No randomization or blinding is required for this open-label trial. 
9.5. 
Procedure for Breaking the Randomization Code 
Not applicable. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
XmAb18087 
As of 27 April 2020, XmAb18087 has been given to 42 human subjects; hence, the safety profile 
associated with this agent is not well known and caution should be exercised as infusion reactions, 
CRS, allergic reactions, or other unexpected reactions may occur. 
10.1.1. 
Pretreatment of XmAb18087 
Because administration of XmAb18087 has been associated with nausea and vomiting and has 
also been associated with symptoms of infusion reaction/CRS in subjects and a severe CRS 
reaction in 1 subject, prophylactic medications are to be administered to all subjects before at least 
the first 
.  
10.1.2. 
Prophylaxis of Nausea and Vomiting 
The following antiemetic and antinausea prophylactic medications are to be administered to all 
subjects before at least the first 
 
 
 
 
If a subject experiences nausea and/or vomiting despite prophylaxis, 
 
 
 are recommended for treatment of the symptoms. 
Sites may also choose to use other or additional antinausea/vomiting medications for prophylaxis 
or treatment of symptoms, according to their practice and assessment of the subject’s responses. 
10.1.3. 
Prophylaxis of Infusion Reactions/Cytokine Release Syndrome: 
It is also required that all subjects receive the following medications before at least the first 4 doses 
the of study drug: 
a. Acetaminophen (Tylenol®): 650 mg PO once before dosing with XmAb18087 
b. Diphenhydramine (Benadryl®): 50 mg PO once before dosing with XmAb18087 
c. 10 to 20 mg IV dexamethasone (Decadron®) before dosing with XmAb18087 
If a subject receives 4 consecutive doses of XmAb18087 without ≥ Grade 1 infusion reaction or 
CRS, the prophylaxis described above may be modified, including elimination and/or reduced 
doses of some required medications. 
For guidelines on the treatment of infusion reactions and CRS, see Section 11.2 or Appendix C of 
this protocol. 
If at all possible, infusions of XmAb18087 should start before 2 PM local time. This is especially 
important for the C1D1 and any first dose at an escalated level to ensure that adequate staffing and 
services are available to manage a severe episode of CRS. In addition, either a Principal 


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Investigator or subinvestigator (MD) must be readily available during, and for a minimum of 
24 hours after, administration of an XmAb18087 dose.  
10.1.4. 
Administration of XmAb18087 
XmAb18087 administration should begin as soon as possible after the dosing solution is made. If 
there is a delay in administration, it 
 
The full-calculated dose will be 
administered based on the subject’s actual baseline weight measurement in kilograms. Following 
the first dose, subsequent doses will only be modified if the subject’s weight changes by more than 
10% from the Day -1 weight at which point it will be recalculated using the current weight. 
XmAb18087 should not be administered as an IV push or bolus. 
Study drug will be administered as an open-label solution at a constant rate 
 
 period. Precautions for CRS or 
infusion reactions or anaphylaxis should be observed during XmAb18087 administration. Due to 
the possibility that CRS, allergic reactions, or infusion reactions may occur, emergency 
resuscitation equipment (a “crash cart”) and medications including steroids and tocilizumab should 
be present in the immediate area where subjects are receiving their infusions. Additional 
supportive measures should be available and may include, but are not limited to: acetaminophen, 
antihistamines, corticosteroids, IV fluids, bronchodilators, epinephrine, vasopressors, oxygen, and 
tocilizumab. Please refer to Section 11.3 or Appendix C for management of infusion reactions, 
CRS, and neurologic toxicities. 
Vital signs will be measured and recorded as follows: immediately (within 60 minutes) prior to 
the infusion; during the infusion at 15, 30, and 60 minutes (± 5 minutes for each time point) from 
start time of the infusion; immediately (within 5 minutes) before EOI; and at 15, 30, and 
60 minutes (± 5 minutes for each time point), then hourly (± 5 minutes) for a 3-hour period, after 
EOI. Oxygen saturation levels will be captured with each vital sign collection; however, pulse 
oximetry monitoring must be maintained continuously throughout the entire admission or 
observation period for each administration of XmAb18087. All supportive measures consistent 
with optimal subject care will be provided throughout the study according to institution standards. 
For subjects who a) tolerate 3 consecutive infusions without an infusion reaction during the 
observation period and b) have completed 4 infusions at the highest dose for that subject, the 
postinfusion observation period and vital signs assessment may be reduced from 4 hours to 
2 hours. 
10.2. 
Pembrolizumab (Keytruda®) 
Pembrolizumab is an FDA-approved humanized monoclonal antibody that blocks the interaction 
between PD1 and its ligands, PDL1 and PDL2.  
10.2.1. 
Administration of Pembrolizumab 
In dosing cohorts incorporating pembrolizumab (Part B only), pembrolizumab will be 
administered by IV infusion on Days 15 and 36 of each 42-day cycle. Pembrolizumab will be 
provided by sites as standard of care for advanced MCC. 


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Vital signs associated with the pembrolizumab infusion will be measured and recorded as follows: 
immediately prior (within 10 minutes before blood sampling) to the start of the infusion; during 
the infusion at 5 and 15 minutes (± 2 minutes) from the start time of the infusion; immediately 
(within 2 minutes) before the EOI; and at 15 minutes (± 2 minutes) after EOI. During Cycle 1, the 
subject will be observed for 4 hours after the infusion. On subsequent pembrolizumab 
administration days, the subject may be discharged 15 minutes postinfusion, if stable. 
Pembrolizumab will be administered at a dose of 400 mg using a 30-minute IV infusion. 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 +15 minutes is permitted (ie, infusion time is 30 minutes [−5 minutes/+15 minutes]). For 
additional information, refer to the pharmacy manual and the pembrolizumab prescribing 
information (Keytruda® Package Insert, 2020). 
Pembrolizumab 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 (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for 
Injection, USP. 
10.2.2. 
Treatment of Overdose 
For this study, an overdose of pembrolizumab will be defined as any dose of 2000 mg or ≥ 5 × the 
indicated dose.  
No specific information is available on the treatment of overdose of XmAb18087, or of 
pembrolizumab. In the event of overdose of either drug, the participant should be observed closely 
for signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
10.3. 
Safety Criteria for Dose Adjustment or Stopping Dose  
10.3.1. 
Criteria for Adjustment or Stopping Dose of XmAb18087 
Subjects experiencing a significant toxicity should be treated with standard medical interventions 
(eg, acetaminophen for fever) as appropriate.  
For guidelines on management of infusion reactions/CRS/neurologic toxicity, and rules regarding 
study drug adjustment/discontinuation after an infusion reaction/CRS/neurologic toxicity, see 
Section 11.3.3 or Appendix C. 
Subjects experiencing an AE that meets AESC criteria (as defined in Section 7.8 above) will have 
subsequent dosing held until recovery to baseline or ≤ Grade 2 following the AE. In the event that 
a > Grade 2 drug-related toxicity persists > 14 days and/or 2 consecutive doses are missed, the 
subject will be permanently discontinued from the study drug treatment. Subjects who experience 
the same AE that meets AESC criteria on 2 consecutive infusions will be subsequently treated at 
one dose level lower than the dose at which the AE occurred. Rechallenge with study drug is not 
permitted for any Grade 4 toxicity. 


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10.3.2. 
Criteria for Adjustment or Stopping Dose of Pembrolizumab 
Refer to Table 18 for dose modification and management guidelines for IRAEs related to 
pembrolizumab. Additional guidelines from the NCCN on the diagnosis and management of 
IRAEs can be found in Appendix E. Rechallenge with pembrolizumab is not permitted for the 
following: 
• Any IRAE that requires permanent discontinuation of study drug according to the 
guidelines in Table 18. 
• Any severe (Grade 3) or life-threatening (Grade 4) infusion-related reaction. 
If it is determined that pembrolizumab must be permanently discontinued based on the above 
criteria, dosing with XmAb18087 must also be discontinued. 
10.4. 
Study Treatment Packaging and Labelling 
10.4.1. 
Packaging and Labelling of XmAb18087 
XmAb18087 and the IV Solution Stabilizer will be supplied in single-use glass vials. 
XmAb18087 and the IV Solution Stabilizer will be supplied by Almac. IMPs will be packaged 
and labeled according to applicable local and regulatory requirements. 
10.4.2. 
Storage of XmAb18087 
Vials containing XmAb18087 and IV Solution Stabilizer must be stored under refrigeration at 
 
 in an appropriately secured area accessible only to the pharmacist, the PI, or a duly 
designated person. Since XmAb18087 does not contain preservatives, opened vials of 
XmAb18087 must be used within 24 hours. 
10.4.3. 
Preparation of XmAb18087 
Note that XmAb18087 has PD effects in vivo at very low concentrations and therefore each 
product vial must be highly diluted before administration. 
Prior to administration, XmAb18087 will be diluted to the required final concentration in 1 or 
more ethylene/polypropylene copolymer infusion bags 
 
. Prior to dilution, the vial 
containing parenteral drug product should be inspected visually. If particulate matter and/or 
discoloration are noted, drug should not be administered, and the Sponsor should be notified. After 
dilution, the bag containing XmAb18087 should be gently inverted 2 to 3 times to mix the solution. 
THE BAG MUST NOT BE SHAKEN; excess agitation may cause aggregate formation. See the 
XmAb18087 Pharmacy Manual for additional details. 
10.4.4. 
Packaging and Labeling of Pembrolizumab 
Pembrolizumab will be obtained from commercial sources and administered to subjects in the 
combination therapy cohorts on Day 15 of each 42-day cycle as directed by the package insert 
(Keytruda® Package Insert, 2020). 


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10.4.5. 
Storage of Pembrolizumab 
Store under refrigeration at 2 °C to 8 °C, do not freeze, do not shake, and protect from light, as per 
the pembrolizumab prescribing information (Keytruda® Package Insert, 2020). 
10.5. 
Study Treatment Accountability, Handling, and Disposal 
Detailed instructions and procedures for study-drug dispensing are included in the Pharmacy 
Manual. 
Accurate accounting of all study drug must be maintained. The PI agrees to keep an inventory of 
study drugs using local investigational pharmacy drug accountability logs. Drug disposition 
records must be kept in compliance with applicable guidelines and regulations. 
These records shall include dates, quantities, batch numbers, expiry dates, and the unique code 
numbers assigned to the study drug and to the study subjects. 
The Investigator shall be responsible for ensuring records adequately document that the subjects 
were provided the doses specified in the protocol and that all study drug received from the Sponsor 
is reconciled. 
Upon completion or termination of the study, any used or partially used vials, unused study 
medication, diluted drug dosing solutions, or IV Solution Stabilizer should be destroyed in 
compliance with local investigational pharmacy policies or returned to the Sponsor or its designee. 


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11. 
ASSESSMENT OF SAFETY 
Adverse event reporting will begin with the signing of the informed consent document (Screening) 
and will continue until the end of the subject’s participation in the study: ie, until a subject has 
discontinued or completed the study.  
Safety and tolerability assessments will include the following: 
• AEs 
• Vital signs 
• PE findings 
• Clinical laboratory safety assessments 
• ECG parameters 
Biomarkers of CRS (IL-2, IL-6, IL-8, IL-10, IFN-γ, IL-13, IL-1B, and TNF-α) will also be 
collected as additional safety information. 
Details for management of hypersensitivity reactions, CRS, and neurologic toxicities are provided 
in Section 11.3.2, 11.3.3.3, and 11.3.3.4, respectively, as well as in Section 11.3.3 and Appendix C 
of this protocol. 
11.1. 
Adverse Events 
11.1.1. 
Definitions 
11.1.1.1.1. Adverse Event 
An AE is any untoward medical occurrence in a study-subject administered IMP. The AE does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to the 
IMP. Adverse events may include the onset of new illness and the exacerbation of preexisting 
conditions. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, eg, 
those occurring during treatment-free periods (including Screening or post-treatment follow-up 
periods), in association with study-related procedures and assessments, or under placebo. For 
IMPs, lack of efficacy may be an expected potential outcome and should not be reported as an AE, 
unless the event is unusual in some way, eg, greater in severity. 
Concomitant illnesses, which existed prior to entry into the clinical study, will not be considered 
AEs unless they worsen during the treatment period. Preexisting conditions will be recorded as 
part of the subject’s medical history. 
11.1.1.1.2. Serious Adverse Event 
AEs are classified as “serious” and “non-serious” for regulatory reporting purposes. The 
classification determines the procedures used to document and report the AE.  


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An SAE is an AE occurring during any study phase (ie, baseline, treatment, washout, or follow-up), 
and at any dose of the investigational product or comparator, that fulfills one or more of the 
following: 
• Results in death 
• Is life-threatening; this means that the subject was at immediate risk of death at the time 
of the event. It does not mean that the event hypothetically might have caused death if 
it were more severe. 
• Requires inpatient hospitalization or prolongation in existing hospitalization 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly or birth defect 
• Is an important medical event. Important medical events are events that may not be 
immediately life threatening but are clearly of major clinical significance. They may 
jeopardize the patient and may require intervention to prevent one of the other serious 
outcomes listed above.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or in a physician’s office, blood dyscrasias or seizures that do not result in 
subject hospitalization, and the development of drug dependency or drug abuse. Hospitalizations 
for planned surgical/medical elective procedures will not be reported as SAEs. In addition, 
hospitalizations of ≤ 24 hours will not be reported as SAEs. A death due to disease progress will 
not be considered an expedited report.  
The following will not be reported as an SAE: 
• Hospitalization for planned surgical/medical elective procedures per protocol for study 
drug administration, any admission required for disease assessments, or any admissions 
planned prior to enrollment (eg, planned surgical/medical elective procedures) will not 
be recorded/reported as an SAE.  
• Hospitalization or death due to disease progression. Signs/symptoms and conditions 
related to disease progression of the primary condition under the investigation (eg, 
tumor-related pain, metastasis, new lesions, etc).  
A distinction should be drawn between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above. For example, a mild degree of gastrointestinal 
bleeding requiring hospitalization for monitoring purposes would be considered an SAE but is not 
necessarily severe. Similarly, an AE that is severe in intensity is not necessarily an SAE. For 
example, alopecia may be assessed as severe in intensity but would not be considered an SAE. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
expedited reporting is appropriate. 
11.1.1.1.3. Abnormal Laboratory Values 
Clinically significant abnormal laboratory results which are not caused by the underlying disease 
or are not consistent with the subject’s medications will be recorded as AEs and the relationship 


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to the study drug will be indicated as below. Laboratory values outside the normal range will be 
assigned one of the following categories by the Investigator or designee: 
1. Not clinically significant, minor out of range value or finding. AE - No 
2. Not clinically significant, out of range value or finding explainable by anticipated or known 
effect of study drug or concomitant drugs. AE - No 
3. Clinically significant but consistent with the subject’s underlying disease. AE - No 
4. Clinically significant out of range value or finding. AE – Yes 
In general, a clinically significant laboratory value or finding would require some diagnostic or 
therapeutic intervention other than repeating the test. 
11.1.2. 
Recording of Adverse Events 
AEs should be collected and recorded for each subject from the date the ICF was signed until the 
end of their participation in the study, ie, the subject has discontinued or completed the study. All 
AEs experienced by a subject, irrespective of the suspected causality, will be monitored until the 
event has resolved or stabilized, until any abnormal laboratory values have returned to baseline or 
stabilized at a level acceptable to the Investigator and Sponsor medical representative, until there 
is a satisfactory explanation for the changes observed, or until the subject is lost to follow-up. 
Any new SAEs that are suspected to be related to study drug occurring up to 28 days after the last 
administration of study drug should be reported to ICON according to Section 11.1.5. Adverse 
events may be volunteered spontaneously by the study subject, discovered by the study staff during 
physical examinations, or by asking an open, nonleading question such as “How have you been 
feeling since you were last asked?” All AEs and any required remedial action will be recorded. 
The nature of AE, date (and time, if known) of AE onset, date (and time, if known) of AE outcome 
to date, severity, and action taken with the study drug because of the AE will be documented 
together with the Investigator’s assessment of the seriousness on the AE and causal relationship to 
study drug and/or study procedure. 
All AEs should be recorded individually unless, in the opinion of the Investigator, the AEs 
constitute components of a recognized condition, disease, or syndrome. In the latter case, the 
condition, disease, or syndrome should be named rather than each individual symptom. The date 
(and time, if known) that the Investigator or study site is first made aware of the AE (or any 
subsequent follow-up information is received) will be documented. The AEs will be coded using 
the current version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Each AE will be assessed by the Investigator with regard to the categories discussed in the sections 
below. 
11.1.2.1. Intensity 
The Investigator will assess all AEs for severity utilizing the NCI-CTCAE grading scale 
(Version 5.0). AEs not contained within CTCAE Version 5.0 will be rated on a five-point scale 
(Table 8): 


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Table 8: 
Severity Grading Scale  
Mild (Grade 1) 
Mild events are those which are easily tolerated with no disruption of 
normal daily activity.  
Moderate (Grade 2) 
 
Moderate events are those which cause sufficient discomfort to interfere 
with daily activity.  
Severe (Grade 3) 
Severe events are those which incapacitate and prevent usual activity.  
Life-threatening (Grade 4) 
 
An adverse event that has life-threatening consequences, for which urgent 
intervention is indicated, that puts the subject at risk of death at the time of 
the event if immediate intervention is not undertaken, or that causes 
blindness or deafness.  
Fatal (Grade 5)  
The termination of life as a result of an adverse event.  
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted for that day. Any change in severity of signs and symptoms 
over a number of days will be captured by recording a new AE, with the amended severity grade 
and the date (and time, if known) of the change. 
11.1.2.2. Causality 
The Investigator will assess the causality/relationship between the IMP and the AE. One of the 
following categories should be selected based on good medical and scientific judgment, 
considering the definitions in Table 9 and all contributing factors. 
 
 


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Table 9:  
Causality Grading Scale  
Related 
 
A clinical event, including laboratory test abnormality that occurs in a plausible time 
relationship to treatment administration, and which concurrent disease or other drugs or 
chemicals cannot explain. The response to withdrawal of the treatment (dechallengea) 
should be clinically plausible. The event must be definitive pharmacologically or 
phenomenologically, using a satisfactory rechallengeb procedure if necessary.  
Probably Related 
 
A clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the treatment, unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition.  
Possibly Related 
 
A clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the treatment, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on treatment withdrawal may be lacking 
or unclear.  
Unlikely Related 
 
A clinical event, including laboratory test abnormality, with a temporal relationship to 
treatment administration that makes a causal relationship improbable, and in which other 
drugs, chemicals, or underlying disease provide plausible explanations.  
Not Related 
 
A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration. May have negative dechallenge and 
rechallenge information. Typically explained by extraneous factors (eg, concomitant 
disease, environmental factors, or other drugs or chemicals).  
AE = adverse event. 
a Dechallenge is when a drug suspected of causing an AE is discontinued. If the symptoms of the AE disappear 
partially or completely, within a reasonable time from drug discontinuation, this is termed a positive dechallenge. 
If the symptoms continue despite withdrawal of the drug, this is termed a negative dechallenge. Note that there are 
exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-relatedness clearly exists (for 
example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
b Rechallenge is when a drug suspected of causing an AE in a specific subject in the past is readministered to that 
subject. If the AE recurs upon exposure, this is termed a positive rechallenge. If the AE does not recur, this is termed 
a negative rechallenge. 
11.1.2.3. Action Taken with Study Treatment 
Action taken with XmAb18087 (and pembrolizumab, when applicable) will be reported as one of 
the following: 
• Dose not changed 
• Dose reduced 
• Drug interrupted 
• Drug withdrawn 
• Not applicable 
11.1.2.4. Outcome 
Outcome will be defined as follows: 
• Death related to adverse event 
• Not recovered or not resolved 


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• Recovered or resolved 
• Recovered or resolved with sequelae 
• Recovering or resolving 
• Unknown 
11.1.3. 
Preidentified Immune-Mediated Adverse Events 
See the pembrolizumab package insert (Keytruda® Package Insert, 2020) for a description of 
potential IRAEs. Guidelines for the management of IRAEs can be found in Table 18 and 
Appendix E.  
11.1.4. 
Adverse Events of Special Interest 
IRAEs (Part B only) and infusion reactions (hypersensitivity reactions and CRS) are designated 
events of special interest in this protocol. Refer to Section 11.3. 
11.1.4.1. Deaths 
Should a death occur within the study period or within 28 days after the last administration of 
study drug (or until the subject initiates other anticancer therapy, whichever comes first), an AE 
form and an SAE form should be completed, detailing the AE that resulted in the death (death is 
an outcome, not an event). The SAE must be reported to the Medical Monitor within 24 hours. 
The report should contain a comment regarding the coinvolvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death. 
11.1.4.2. Pregnancy 
The teratogenic potential of XmAb18087 is unknown. Based on its mechanism of action, 
pembrolizumab can cause fetal harm when administered to a pregnant woman; however, there are 
no available human data informing the risk of embryo-fetal toxicity (Keytruda® Package Insert, 
2020). The Investigator and Sponsor have a responsibility to monitor the outcome of all 
pregnancies, including pregnancies in female partners of male participants, reported during the 
clinical study. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the IMP may have 
interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see below). 
Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. All 
notifications of pregnancy should be documented and reported through 120 days following 
cessation of study treatment (or through 30 days following cessation of study treatment if the 
subject initiates new anticancer therapy), whether or not there is an associated AE or SAE. 
Each pregnancy notification must be reported by the Investigator to the Sponsor and ICON within 
24 hours after becoming aware of the pregnancy. The Investigator must follow-up and document 
the course and the outcome of all pregnancies even if the subject was withdrawn from the clinical 
study or if the clinical study has finished. The follow-up period will be deemed to have ended 
when the health status of the child has been determined on its birth. 


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All outcomes of pregnancy must be reported by the Investigator to the Sponsor and ICON on the 
pregnancy outcome report form within 24 hours after he/she has gained knowledge of the normal 
delivery or elective abortion, or other outcome. 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (eg, maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, birth defect) and reported within 24 hours of awareness in accordance with 
the procedure for reporting SAEs. 
11.1.5. 
Reporting Serious Adverse Events 
The Investigator will review each potential SAE and evaluate the intensity and the causal 
relationship of the event to IMP. All potential SAEs will be recorded from signing of informed 
consent until the end of the subject’s participation in the study: ie, the subject has discontinued or 
completed the study, except for the long-term follow-up period. During the long-term follow-up 
period, only SAEs that come to the attention of the Investigator and that the Investigator believes 
to have a reasonable causal relationship to the IMP will be reported.  
The Investigator is responsible for reporting SAEs related to pembrolizumab to regulatory 
authorities per reporting guidelines. 
The Investigator is responsible for providing notification to ICON of any potential SAE, whether 
deemed IMP-related or not, that a subject experiences during his/her participation in study within 
24 hours of becoming aware of the event. ICON will provide the information to the Sponsor. 
The initial SAE form should be completed and emailed to 
 with the 
following information: 
• Study number 
• Subject number 
• Gender 
• Year of birth 
• Name of PI and full clinical site address 
• Name of the reporter 
• SAE event term 
• Details of SAE 
• Criterion for classification as “serious” 
• Study drug name, dose, and treatment start date 
• Date of SAE onset 
• Date of SAE first awareness (by Investigator or study site staff) 
• Causality assessment 


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ICON will request clarification of omitted or discrepant information from the initial notification. 
The Investigator or an authorized delegate is responsible for providing the requested information 
to ICON within 24 hours of the request. 
Initial reports of SAEs must be followed up as soon as possible with detailed descriptions; this 
may include clear photocopies of other documents as necessary (eg, hospital reports, consultant 
reports, autopsy reports, etc.) with the study subject’s personal identifiers removed. All relevant 
information obtained by the Investigator through review of these documents will be recorded and 
forwarded to ICON within 24 hours of receipt of the information.  
If a new SAE report form for the same SAE is completed, then the Investigator must sign and date 
the SAE form and mark the form as “follow-up.” ICON and/or the Sponsor may also request 
additional information on the SAE in order to obtain the full clinical picture, to which the PI or an 
authorized delegate must respond to ICON within 24 hours of the request. 
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
 (Americas) 
 (Europe) 
Emergency contact number: 
 (within US) 
 (toll number and outside of US) 
1. E-mail your SAE form to the study specific e-mail address above. 
2. Provide ICON with the name of the PI, your name, the telephone number where you can be 
reached and the protocol number and title. 
3. Immediately forward the SAE form and any supporting documentation to ICON; this must be 
done within 24 hours of becoming aware of the event. 
11.1.6. 
Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored until 
the event has resolved or stabilized, until any abnormal laboratory values have returned to baseline 
or stabilized at a level acceptable to the Investigator and Sponsor medical representative, until 
there is a satisfactory explanation for the changes observed, or until the subject is lost to follow-up. 
11.1.7. 
Treatment/Reporting of Overdose 
In the event of an overdose, the physician should: 
• Contact the Medical Monitor immediately 
• Closely monitor the subject for any AE/SAE and laboratory abnormalities  
• Obtain a plasma PK sample if requested by the Medical Monitor (determined on a 
case-by-case basis) 
• Document the quantity and duration of the excess dose 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject. 


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All overdose cases should be reported as SAEs. 
11.2. 
Investigational New Drug Safety Reports 
During the course of the study, the Sponsor may determine that certain safety reports are required 
to comply with regulations. The PI may receive a letter called an “Investigational New Drug (IND) 
Safety Report.” These reports must be submitted to the IRB per local requirements as soon as 
possible, and documentation of this submission should be available to the Sponsor or ICON. 
11.3. 
Guidelines for Prophylaxis and Management of Hypersensitivity 
Reactions, Cytokine Release Syndrome, and Neurological Toxicity 
Attributed to XmAb18087  
Because administration of XmAb18087 has been associated with symptoms of infusion 
reaction/CRS in some subjects, it is required that all subjects receive the following medications 
before at least the first 4 doses of XmAb18087: 
a. Acetaminophen (Tylenol®): 650 mg PO once before dosing with XmAb18087 
b. Diphenhydramine (Benadryl®): 50 mg PO once before dosing with XmAb18087 
c. 10 to 20 mg IV dexamethasone (Decadron®) before dosing with XmAb18087 
If a subject receives 4 consecutive doses of XmAb18087 without ≥ Grade 1 infusion reaction/CRS, 
the prophylaxis described above may be modified, prophylactic medications are to be administered 
to all subjects before at least the first 4 doses of the study drug. 
11.3.1. 
Introduction and Grading 
Grading of toxicity, including allergic/hypersensitivity reactions, is by CTCAE version 5.0, except 
for CRS, which is graded using the American Society for Transplantation and Cellular Therapy 
(ASTCT) CRS Consensus Grading (Lee, 2019) See Table 10 for these definitions. 
All sites should review and implement the general guidelines for the use of tocilizumab and IV 
fluids discussed below in Sections 11.3.3.1 and 11.3.3.2. Otherwise, management of CRS and 
other infusion-related reactions should be per standard investigational site procedures. Or, if there 
are no local standards or if they are incomplete, the approaches discussed here may be used. 
The Xencor Medical Monitor (
) should be contacted immediately by email or 
phone if questions arise concerning the grade of an infusion reaction. 
 email is 
, and his telephone number is 
. 
 
 


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Table 10: 
American Society for Transplantation and Cellular Therapy Cytokine Release 
Syndrome Consensus Grading 
CRS Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fevera 
Temperature  
≥ 38 °C 
Temperature  
≥ 38 °C 
Temperature  
≥ 38 °C 
Temperature  
≥ 38 °C 
 
With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
 
And/orb 
Hypoxia 
None 
Requiring low-flow 
nasal cannulac or 
blow-by 
Requiring high-flow 
nasal cannula c, 
facemask, 
nonrebreather mask, 
or Venturi mask 
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release 
syndrome; CTCAE = Common Terminology Criteria for Adverse Events. 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0, but they do not influence CRS 
grading.  
a Fever is defined as temperature ≥ 38 °C not attributable to any other cause. In patients who have CRS then receive 
antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5 °C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow 
nasal cannula is classified as grade 3 CRS. 
c Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/minute. 
11.3.2. 
Cytokine Release Syndrome Versus Allergic or Hypersensitivity Reactions 
Cytokine release syndrome is mechanistically different from allergic/hypersensitive reactions 
(Lee, 2019), although some of the manifestations are common to both AEs and both have been 
reported to occur with therapeutic antibodies. An acute infusion reaction is often caused by a type 1 
hypersensitivity mechanism due to immunoglobulin-E (IgE)-mediated release of histamines and 
prostaglandins, although a direct interaction with mast cells and basophils can also occur. It is less 
clear how cytokine release is triggered, although it is likely to be associated with immune cell 
activation; in this case, there is evidence that immunologic cascade is initiated by triggering of 
CD3-expressing T lymphocytes, resulting in TNF-α mediated monocyte/macrophage activation 
and systemic toxic cytokine release (Li, 2019). 
Signs and symptoms usually develop during or shortly after drug infusion in hypersensitivity 
reactions, are more likely to occur after several doses of the drug and are largely related to 
histamine release. Typical signs and symptoms of hypersensitivity reaction include rash/urticaria, 
flushing, pruritus, fever, dyspnea, cough, and hypotension, although the following may also occur 
(Lenz, 2007): 
• Arthralgia  


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• Bronchospasm 
• Confusion, mental status changes, and/or delirium 
• Dizziness 
• Fatigue (asthenia, lethargy, malaise) 
• Hallucinations 
• Headache 
• Hypertension 
• Myalgia 
• Nausea and/or vomiting 
• Rigors/chills 
• Diaphoresis 
• Tachycardia 
Cytokine release syndrome, on the other hand, is more likely to occur after the first dose or first 
escalated dose of drug than after subsequent doses. It may begin somewhat later and is more likely 
to be associated with hepatic and neurologic complications, including the following: 
• Any of the hypersensitivity signs or symptoms listed above 
• Aphasia or word-finding difficulty  
• Elevated d-dimer and/or hypofibrinogenemia 
• Fatigue (asthenia, lethargy, malaise) 
• Gait disturbance/dysmetria 
• Hallucinations 
• Seizures 
• Transaminitis and/or hyperbilirubinemia 
• Tremor 
The Xencor Medical Monitor should be contacted immediately if questions arise concerning the 
grade and/or treatment of the infusion reaction.  
11.3.3. 
Treatment Guidelines for Cytokine Release Syndrome  
11.3.3.1. Use of Tocilizumab for Cytokine Release Syndrome 
Tocilizumab is a therapeutic antibody that interferes with binding of IL-6 to the IL-6 receptor. It 
has been used to decrease the severity and possibly mortality of severe CRS (Frey, 2017), and 
early administration may be useful in improving outcomes. Below are suggested guidelines for its 
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• Sufficient tocilizumab (dose of 8 mg/kg) should be readily available to the area where 
subjects are receiving their infusions and being observed post infusion. 
• Prompt tocilizumab therapy should be strongly considered if:  
− Oxygen saturation falls below 90% on room air, OR 
− Systolic blood pressure falls 20 mm Hg below predose measurements and below 
100 mm Hg, OR 
− Temperature of > 38 °C (100.4 °F) in the presence of new or worsening dyspnea 
and/or tachypnea and/or rigors and/or tachycardia (heart rate [HR] > 110 bpm), OR 
− Early discovery of hepatic transaminase elevation. (Note that peak transaminase 
elevation appears to occur within 24 hours, so that it is unlikely that tocilizumab 
treatment on the day after study drug administration would affect the course or 
outcome in the absence of concurrent symptoms or signs of CRS). 
• Repeat dosing of tocilizumab may be necessary if signs and symptoms persist or return 
after initial treatment. 
11.3.3.2. Fluid Management  
Cytokine release syndrome is sometimes associated with myocardial dysfunction, pulmonary 
edema, or capillary leak syndrome (Shimabukuro-Vornhagen, 2018). Although there are little or 
no data regarding use of anti-CD3 antibodies and the need for fluid management, it seems prudent 
to monitor subjects for weight gain and limit IV fluid administration in the acute setting.  
• If a subject is noted to have had a ≥ 10% increase in body weight over the previous 
2 weeks in association with new or significantly increased bilateral lower extremity 
edema, dosing should be delayed until this finding is evaluated and, if indicated, 
treated. 
• For acute hypotension, an IV fluid bolus should be limited to 500 mL of normal saline 
or the equivalent.  
• If there is not an adequate response to fluids, treatment with tocilizumab (and 
vasopressors, if necessary) should be considered rather than additional fluid boluses. 
11.3.3.3. Cytokine Release Syndrome Treatment Guidelines by Grade 
The following are treatment guidelines for XmAb18087 treatment-related infusion reactions (Lee, 
2019); since it can be difficult to differentiate between different infusion reaction etiologies, both 
are included here. 
Grade 1: 
• Administer acetaminophen and/or diphenhydramine or dexamethasone to treat signs 
and symptoms if clinically indicated. 
• Vital signs should be measured every 15 minutes or less as clinically indicated. 
• Obtain a blood sample for cytokine analysis during the event and approximately 
4 hours later, unless to scheduled cytokine monitoring is already in progress. 


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• Monitor the subject for worsening of condition; if severity of event increases to a higher 
grade, stop the infusion, administer appropriate treatment, and refer to guidelines below 
for more severe infusion reactions. 
• It may be useful to premedicate the subject with acetaminophen and antihistamines 
prior to the next infusion. 
Grade 2: 
• Hypotension responsive to fluids or a low dose of a single pressor, or mild respiratory 
symptoms treatable with low-flow oxygen are signs of Grade 2 toxicity. Older subjects 
or those with significant comorbidities may be at higher risk of decompensation in this 
situation. 
• Discontinue the infusion and administer acetaminophen and/or diphenhydramine or 
dexamethasone to treat signs and symptoms if clinically indicated. Once symptoms 
have resolved, slow the infusion rate by 50% of the baseline rate. If after 1 hour, the 
subject’s symptoms do not return and vital signs are stable, the infusion rate may be 
increased every 30 minutes, as tolerated, to the baseline rate. 
• Note that older subjects or those with significant comorbidities may be at higher risk 
of decompensation in this situation. When reactions occur in these vulnerable subjects, 
or in the case of rapidly escalating reactions, consider treatment with tocilizumab 4 to 
8 mg/kg IV over 1 hour, with or without dexamethasone 10 to 20 mg IV (or equivalent). 
• Vital signs should be measured every 15 minutes or less as clinically indicated. For 
subjects who are able to tolerate an increase in the infusion rate back to baseline and 
maintain normal blood pressure for 30 minutes after the rate increase then, at the 
discretion of the Investigator, the frequency of vital sign assessment may be reduced to 
every 30 minutes during the infusion. 
• Obtain a blood sample for cytokine analysis during the event and approximately 4 hours 
later, in addition to scheduled cytokine monitoring if already in progress. 
• Monitor the subject for worsening of condition; if severity of event increases to a higher 
grade, stop the infusion, administer appropriate treatment, and refer to guidelines below 
for Grades 3 and 4 infusion reactions. 
• Subjects with maximum Grade 2 infusion reaction may continue on study and should 
receive 
prophylactic 
premedication with 
acetaminophen 650 mg 
PO and 
diphenhydramine hydrochloride 25 to 50 mg IV or PO prior to all subsequent 
XmAb18087 infusions.  
Grade 3 and 4: 
• Stop the infusion and disconnect the infusion tubing from the subject. 
• Aggressive supportive care should be given immediately. Vasopressors, fluids, oxygen, 
epinephrine or bronchodilators, ventilatory support, antipyretics, and analgesics should 
be used as indicated. 


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• Treatment with tocilizumab 4 to 8 mg/kg IV over 1 hour with or without 
dexamethasone 10 mg IV (or equivalent) is strongly encouraged for CRS due to the 
high risk of progression and permanent organ dysfunction. 
• Hospital admission for observations is almost always indicated, usually to an intensive 
care unit, since an initial appearance of improvement may quickly yield to rapid 
decompensation. 
• Subjects with Grade 3 CRS or infusion reaction may be rechallenged once resolved. 
Subjects with recurrent Grade 3 or any Grade 4 infusion reaction should not receive 
further XmAb18087 treatment but will continue to be followed on the protocol (ie, for 
4 weeks after last dose). 
• Obtain a blood sample for cytokine analysis during the event and approximately 
4 hours later, in addition to scheduled cytokine monitoring if already in progress. 
• Obtain a sample for ADA testing as close to the onset of the event as possible, at the 
resolution of the event, and 28 days following the event. 
• Notify the Xencor Safety Monitor or Xencor Medical Monitor, 
 
(Telephone:
; Email: 
), immediately. 
11.3.3.4. Neurotoxicity 
 In addition to CRS, another toxicity observed after chimeric antigen receptor T cell (CAR-T) 
therapy and CD3 bispecific antibodies is neurotoxicity. Immune effector cell-associated 
neurotoxicity syndrome (ICANS) may manifest as delirium, encephalopathy, aphasia, lethargy, 
difficulty concentrating, agitation, tremor, seizures, and, rarely, cerebral edema (Lee, 2019). 
Neurotoxicity was previously considered in aggregate with CRS, but is now treated separately, 
due to its timing and response to treatment. 
Neurologic symptoms may occur during or after CRS symptoms, but rarely precede CRS 
symptoms. The earliest manifestations of ICANS are tremor, dysgraphia, mild difficulty with 
expressive speech (especially in naming objects), impaired attention, apraxia, and mild lethargy. 
Headache is a nonspecific symptom, frequently occurring during fever or after chemotherapy in 
patients without other neurologic dysfunction. Thus, headache alone is not a useful marker of 
ICANS. Expressive aphasia, on the other hand, appears to be a very specific symptom of ICANS 
(Lee, 2019).  
A consensus grading scheme, which is a slightly modified version of the CARTOX-10 screening 
tool, which incorporated key elements of the Mini-mental State Examination (MMSE), the 
Immune Effector Cell-Associated Encephalopathy (ICE) score, will be used for the grading of 
ICANS (Table 9). It is important to note that the 10-point ICE screening tool is helpful for 
assessing patients for encephalopathy; however, the grading of ICANS requires assessment of the 
10-point ICE score as well as evaluation of other neurologic domains, such as level of 
consciousness, motor symptoms, seizures, and signs of elevated ICP/cerebral edema, which may 
occur with or without encephalopathy. The ASTCT ICANS toxicity grading system is shown in 
Table 10. This grading scale will be used to assess neurotoxicity, rather than the CTCAE 5.0. 


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Table 11: 
Immune Effector Cell-associated Encephalopathy Scoring 
ICE 
Orientation: orientation to year, month, city, hospital: 4 points 
Naming: ability to name 3 objects (eg, point to clock, pen, button): 3 points 
Following commands: ability to follow simple commands (eg, “Show me 2 fingers” or “Close your eyes and 
stick out your tongue”): 1 point 
Writing: ability to write a standard sentence (eg, “Our national bird is the bald eagle”): 1 point 
Attention: ability to count backwards from 100 by 10: 1 point 
ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = Immune Effector Cell-Associated 
Encephalopathy (score). 
Scoring: 10, no impairment; 
7 - 9, Grade 1 ICANS; 
3 - 6, Grade 2 ICANS; 
0 - 2, Grade 3 ICANS; 
0 due to patient unarousable and unable to perform ICE assessment, Grade 4 ICANS (Lee, 2019). 
 
 


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Table 12: 
American Society for Transplantation and Cellular Therapy Immune Effector 
Cell-associated Neurotoxicity Syndrome Consensus Toxicity Grading for 
Adults 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scorea 
7 - 9 
3 - 6 
0 – 2 
0 (patient is 
unarousable and 
unable to perform 
ICE) 
Depressed level of 
consciousnessb 
Awakens 
spontaneously 
Awakens to voice 
Awakens only to 
tactile stimulus 
Patient is 
unarousable or 
requires vigorous or 
repetitive tactile 
stimuli to arouse. 
Stupor or coma 
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves rapidly 
or nonconvulsive 
seizures on EEG 
that resolve with 
intervention 
Life-threatening 
prolonged seizure 
(> 5 min); or 
Repetitive clinical 
or electrical seizures 
without return to 
baseline in between 
Motor findingsc 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
Elevated 
ICP/cerebral edema 
N/A 
N/A 
Focal/local edema 
on neuroimagingd 
Diffuse cerebral 
edema on 
neuroimaging; 
decerebrate or 
decorticate 
posturing; or cranial 
nerve VI palsy; or 
papilledema; or 
Cushing’s triad 
EEG = electroencephalogram; ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = Immune 
Effector Cell-Associated Encephalopathy (score); ICP = intracranial pressure; N/A = not applicable; VI = sixth. 
 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who has 
a generalized seizure is classified as grade 3 ICANS. 
a A patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient 
with an ICE score of 0 may be classified as Grade 4. 
b Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication). 
c Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, 
but they do not influence ICANS grading. 
d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. It may be graded according to CTCAE v5.0 (Lee, 2019). 
It has been speculated that high levels of IL-6 may directly mediate neurotoxicity in this situation 
(Lee, 2014).  


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Clinical management of neurotoxicity consists of the following:  
• Monitor subjects closely for signs and symptoms of these events (including 
administration of mental status and neurologic examinations when these seem 
clinically warranted). 
• If neurotoxicity becomes evident, a blood sample for cytokine analysis should be drawn 
at that time, and again 4 hours later, in addition to scheduled cytokine monitoring if 
already in progress.  
• If neurologic toxicity is Grade 4, discontinue XmAb18087, if still infusing. 
• For Grade 3 neurologic toxicity, withhold both drugs until the toxicity has recovered 
to ≤ Grade 1 (mild) and has remained at ≤ Grade 1 for at least 3 days before restarting 
therapy. Restart XmAb18087 at 75% of the previous dose. Restart pembrolizumab at 
the full dose. Escalate back to full dose at the time of the next dose if ≥ Grade 2 toxicity 
does not recur. If ≥ Grade 2 toxicity reoccurs at 75% dose, or if < Grade 2 toxicity takes 
more than 7 days to resolve, discontinue permanently. 
• For severe neurologic symptoms, administer additional dexamethasone 10 mg 
intravenously and repeat every 12 hours if symptoms do not abate rapidly, or treat 
according to the clinical site’s institutional protocol for such reactions. 
• For recurrent seizures, anticonvulsant therapy may be necessary. 
11.4. 
Guidelines for Prophylaxis and Management of Infusion Reactions 
Attributed to Pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion reactions, including severe 
hypersensitivity or anaphylaxis. Refer to the pembrolizumab prescribing information (Keytruda® 
Package Insert, 2020) for diagnosis, management, prophylaxis, and dose modification for 
infusion-related reactions related to pembrolizumab administration.  
11.5. 
Laboratory Assessments 
Safety clinical laboratory assessments will be performed by ICON Central Labs. Specified 
predosing safety laboratory assessments will also be performed by clinical site local laboratories 
so that site personnel are able to review the results before administering XmAb18087. In addition, 
investigators may also perform locally any laboratory assessments that they feel are necessary to 
protect subject safety.  
Blood samples should be taken using standard venipuncture techniques. Blood sampling will be 
performed according to site or laboratory standard operating procedures (SOPs). 
Unless otherwise prescribed within this clinical protocol, assessments during Cycle 1 Days 1, 8, 
and 15 should be completed ± 1 hour of the scheduled time; for other days during 
Cycle 1 ± 3 hours; and for subsequent cycles and within ± 2 days of the scheduled day. Disease 
assessments by RECIST and by radionuclide imaging should be performed within ± 2 days of the 
scheduled day. Imaging will be collected and stored for potential central assessment at a later date. 
Details for laboratory assessments, PK, PD, flow cytometry, and biobanking are provided in the 
Laboratory Manual. 


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The following laboratory variables will be determined as outlined below: 
Hematology: RBC, hemoglobin, erythrocyte mean corpuscular volume, RBC distribution width, 
white blood cell (WBC) with differential (percent and absolute; neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, and nucleated RBCs), and platelet count. 
Coagulation panel: prothrombin time/international normalized ratio and activated partial 
thromboplastin time. 
Clinical chemistry: Chemistry panel (sodium, chloride, potassium, bicarbonate, blood urea 
nitrogen, creatinine, glucose, uric acid, calcium, phosphorous, total bilirubin, ALT, AST, total 
protein, albumin, alkaline phosphatase, and lactate dehydrogenase), serum gamma-glutamyl 
transpeptidase, amylase, and lipase.  
Urinalysis: pH, specific gravity, ketones, leukocyte esterase, bilirubin, blood protein, RBCs, 
WBCs, hyaline casts, RBC casts, WBC casts, granular casts, waxy casts, broad casts, and fatty 
casts. 
Pregnancy test: Serum β-hCG pregnancy test for women of childbearing potential or FSH for 
postmenopausal women. 
11.6. 
Electrocardiogram Assessments 
The timing of ECGs is noted in Table 7. On all dosing days in Cycle 1 and selected dosing days in 
cycles after Cycle 1, supine ECGs will be performed predose. 
The 12-lead ECGs will be performed after the subject has been resting supine for ≥ 5 minutes. The 
ECG will include all 12 standard leads. The following ECG parameters will be collected: PR 
interval, QRS interval, RR interval, QT interval, and QTc interval. 
All ECGs must be evaluated by a qualified physician for the presence of abnormalities. 
11.7. 
Physical Examination 
Complete or abbreviated (symptom-directed) PEs will be performed as indicated in Table 7. 
The complete PE includes an assessment of general appearance and a review of systems 
(dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic, and psychiatric 
systems). 
An abbreviated PE is symptom-directed and need not include detailed examination of all systems. 
11.8. 
Vital Signs 
Vital signs will be assessed at as indicated in Table 7. All vital signs should be taken with the 
subject in the same position. On nondosing days, vital signs should be measured prior to blood 
sampling. The following vital signs will be measured: 
• Blood pressure (systolic and diastolic [mmHg]) 
• Heart rate (beats per minute [bpm]) 
• Respiratory rate (breaths per minute) 


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• Body temperature (°C) 
• Supine BP and heart rate recordings will be made after the study subject has been 
recumbent and at rest ≥ 5 minutes 
• Blood oxygen saturation by pulse oximetry. Oxygen saturation levels will be captured 
at each vital sign collection; however, pulse oximetry monitoring must be maintained 
continuously throughout the entire admission or observation period for each 
administration of XmAb18087. 


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12. 
ASSESSMENT OF EFFICACY 
Radiographic tumor evaluation will be performed at baseline and at all other disease assessment 
time points per RECIST 1.1 criteria (Appendix A). If additional clarification or detail is needed, 
please consult the literature referenced or the Sponsor’s Medical Monitor. 
The timing for these evaluations will be uniform. Initial evaluation will occur within 14 days 
(60 days for NETSPOT® gallium 68 dotatate PET/CT) before administration of the first dose of 
XmAb18087, and follow-up evaluation will be performed on Cycle 1 Day 40 ± 2 days. 
Reevaluation will be performed after every cycle, as long as the subject continues on study, and at 
EOT. NETSPOT® gallium 68 dotatate PET/CT scan will be performed and interpreted locally. 
Copies of images and reports will be collected and sent to Xencor, Inc., for interpretation and 
archiving. Scans used for RECIST assessments will be performed and interpreted locally. Copies 
of these images will be collected and stored for potential central assessment at a later date.  
13. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
13.1. 
Serum 
Sampling 
for 
Pharmacokinetic 
Analyses, 
Anti-drug 
Antibodies, Cytokines, and Inflammatory Factors 
The Sponsor or designee will provide cryotubes, labels, and requisition forms. Serum cryotubes 
will be labeled at the clinical site with the subject number, date, visit day and time point, and time 
of sampling. Samples will be stored on site at -70 °C until the Sponsor notifies the sites to ship the 
samples on dry ice to the designated laboratory for sample analysis. Detailed instructions for 
processing and shipping serum samples are provided in the Laboratory Manual. Venous blood 
samples for serum analyses of PK, ADA, and the cytokine and inflammation panel will be obtained 
according to the Schedule of Assessments (Table 7). 
13.2. 
Pharmacokinetics 
Samples for PK analysis will be collected at the times specified in the Schedule of Assessments 
(Table 7). The exact time and date of the blood draw must be accurately recorded using an 
unambiguous format such as DD MON YYYY and HH:MM on a 24-hour clock. Missed samples 
will be considered protocol deviations. 
13.3. 
Pharmacodynamics 
Baseline and serial assessment of B-cell, NK-cell, and T-cell numbers and T-cell activation will 
be assessed in peripheral venous blood. The Sponsor/designated vendor will provide blood 
sampling tubes, label, requisition forms, and shipping containers. Samples for flow cytometry 
should be shipped immediately at ambient temperature. Detailed instructions for processing and 
shipping flow cytometry samples are provided in the Laboratory Manual. For the sampling 
schedules, see the Schedule of Assessments (Table 7). 
Antibodies to MCPyV tumor antigens will be measured at baseline and end of treatment. Refer to 
the Laboratory Manual for instructions on sample procurement, processing, and shipping. 


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Formalin-fixed paraffinized archival tumor samples and optional fresh tumor biopsies will be 
assessed by immunohistochemistry for tumor cell SSTR2 expression and immune cell expression 
of proliferation, exhaustion, and other markers and for transcriptomics by Nanostring. 
13.4. 
Biobanking Samples 
Additional exploratory genetic, cellular, and/or serum markers of potential future interest may be 
explored if evidence of therapeutic activity is seen with XmAb18087. For biobanking, blood 
obtained for flow cytometry will be sent to Navigate BioPharma, where serum, PBMCs, and 
extracted nucleic acid will be aliquoted and stored at -70 °C. Biobanking is voluntary and requires 
specific subject consent. 


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14. 
STATISTICAL EVALUATION 
14.1. 
Sample Size and Power 
This study is being performed in 3 parts: MCC monotherapy (Part A), MCC combination therapy 
(Part B), and SCLC monotherapy (Part C). No formal power analyses were performed for efficacy 
endpoints for the initial dose escalation cohorts. After identification of each RD, Part A, Part B, 
and Part C will enroll expansion cohorts using a 2-stage design (Schultz, 1973).  
In Part A, up to 9 subjects will be enrolled at the RD. If at least 1 subject shows a response by 
RECIST 1.1 criteria, then enrollment will continue up to a total of 22 subjects. A true response 
rate of 40% has statistical power of 84% to rule out a lower inactivity rate of 16% with a one-sided 
Type I error rate of 5%.  
In Part B, up to 12 subjects will be enrolled at the RD. If at least 4 subjects show a response by 
RECIST 1.1 criteria, enrollment will continue up to a total of 30 subjects. A true response rate of 
67% has statistical power of 84% to rule out a lower inactivity rate of 43% with a one-sided Type I 
error rate of 5%.  
In Part C, up to 9 subjects will be enrolled at the RD. If at least 1 subject shows a response by 
RECIST 1.1 criteria, then enrollment will continue up to a total of 30 subjects.  
Subjects who are not evaluable may be replaced. Up to 142 subjects will be enrolled. The total 
number of subjects enrolled will depend upon the number of safety run-in cohorts required to 
identify the RD for each Part. A true response rate of 30% has statistical power of 82% to rule out 
a lower inactivity rate of 11% with a one-sided Type I error rate of 5%. 
14.2. 
Statistical Methods 
Before database lock, a statistical analysis plan (SAP) will be issued as a separate document, 
providing detailed methods for the analyses outlined below. Any deviations from the planned 
analyses will be described and justified in the final integrated clinical study report. 
Unless otherwise specified, continuous variables will be summarized with N (ie, sample size), 
mean, median, standard deviation, minimum and maximum, and discrete variables will be 
summarized with frequencies and percentages. Safety and efficacy summaries will be performed 
for Parts A, B, and C separately and, for safety, also for the combined arms. For each Part, 
summary tables will be provided for each dose cohort and for the dose cohorts combined. 
14.3. 
Study Endpoints 
14.3.1. 
Primary Endpoints 
The primary endpoints are as follows:  
• Safety of (1) XmAb18087 monotherapy in MCC and SCLC, and (2) XmAb18087 and 
pembrolizumab combination therapy in MCC, as assessed by the following: 
− Incidence of treatment-emergent AEs (TEAEs) 
− Incidence of clinically significant changes in safety laboratory tests, PE findings, 
vital signs, and ECGs 


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− Incidence and severity of CRS 
• Efficacy of (1) XmAb18087 monotherapy in MCC and SCLC, and (2) XmAb18087 
and pembrolizumab combination therapy in MCC using RECIST 1.1 assessment of 
CT/MRI imaging, as well as aggregate data, for the following: 
− ORR 
− CR rate 
− PR rate 
14.3.2. 
Secondary Endpoints 
The secondary endpoints are as follows: 
• Efficacy of (1) XmAb18087 monotherapy in MCC and SCLC, and (2) XmAb18087 
and pembrolizumab combination therapy in MCC using RECIST 1.1 assessment of 
CT/MRI imaging, as well as aggregate data, for the following: 
− Duration of response 
− PFS 
− OS 
• PK characterization of XmAb18087, when administered as monotherapy and in 
combination with pembrolizumab, based on the parameters of Cmax, time to reach 
maximum concentration (tmax), half-life (t1/2), area under the serum concentration-time 
curve from time zero to infinity (AUC0-∞), clearance (CL), volume of distribution (Vd), 
and volume of distribution at steady state (Vdss). Further details will be defined in a PK 
analysis plan. 
• Assessment of immunogenicity by incidence of anti-XmAb18087 antibodies and 
qualitative assessment of safety outcomes 
• PK characterization of pembrolizumab, when administered in combination with 
XmAb18087, based on parameters similar to those for XmAb18087, with further 
details to be provided in a PK analysis plan. 
14.3.3. 
Exploratory Endpoints 
The exploratory endpoints are as follows: 
• Assessment of peripheral blood for cell surface markers by flow cytometry and similar 
bioanalytical methods that evaluate the response of selected immune system cells 
following administration of XmAb18087 as a monotherapy and in combination with 
pembrolizumab, including changes in lymphocyte subsets and in T-cell activation and 
exhaustion markers 
• PD characterized by NETSPOT (gallium 68 dotatate) PET/CT results and by 
tumor-cell expression of SSTR2 and PDL1 and tumor-infiltrating immune-cell 
expression of PD1/PDL1 and other markers by immunohistochemistry, in response to 
administration of XmAb18087 monotherapy and in combination with pembrolizumab 


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• PD: IHC SSTR2 panel 
• PD: MCC and SCLC IHC panels 
• Correlation of clinical/radiographic response with MCPyV serology (MCC subjects 
only) 
• Additional exploratory genetic, cellular, and/or serum markers of potential future 
interest. If evidence of therapeutic activity is seen with XmAb18087, biobanked 
samples may be assessed for genetic and immunologic factors that might predict 
response or nonresponse (optional part of study and may be reported separately from 
the clinical study report). Samples will not be retained for more than 15 years. 
14.4. 
Analysis Populations 
The populations defined below will be used for analysis: 
• Safety population: All subjects who are enrolled and receive at least 1 infusion of 
XmAb18087.  
• Evaluable population: All subjects who are enrolled, receive at least 1 cycle (Parts A 
and C: 6 doses XmAb18087, Part B: 5 doses XmAb18087 and 1 dose pembrolizumab) 
of XmAb18087 and have at least 1 postbaseline RECIST 1.1 assessment of tumor 
imaging available. 
• PD population: All subjects who are enrolled, receive at least 1 dose of XmAb18087 
(and 1 infusion of pembrolizumab, when relevant for a particular PD assessment), and 
have at least 1 preinfusion and 1 postinfusion set of biomarker data available for 
analysis.  
• PK populations: All subjects who are enrolled and receive at least 1 dose of 
XmAb18087 (ie, the XmAb18087 PK population) or 1 infusion of pembrolizumab (ie, 
the pembrolizumab PK population), and have at least 1 set of postinfusion PK data 
available for analysis.  
Continuous data will be presented using descriptive statistics: number of subjects (N), mean, 
standard deviation, median, minimum, and maximum. Categorical data will be summarized by the 
number and percentage, where the percentage is presented in brackets to 1 decimal place. Safety 
and efficacy summaries will be provided for the monotherapy and combination therapy arms 
separately, as well as for the combined arms. 
14.5. 
Subject Characteristics and Disposition 
The SAP will define analysis parameters for the study and takes precedence over this protocol 
section. 
Demographic (age, gender, ethnic origin, race) and baseline characteristics (eg, height, weight, 
body mass index, ECOG performance status, etc.) will be summarized, as will disease-related 
characteristics (including any available genetic data), prior anticancer therapy, and relevant 
supportive care therapies. 
A summary of subject disposition will include the following: 


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• Number of subjects enrolled 
• Number of subjects who received treatment 
• Number of subjects who complete the study treatment (1 cycle) 
• Number of subjects who terminated treatment and reason for discontinuation of 
treatment 
• Number of subjects who complete 6-month and 12-month follow-up period 
• Number of subjects who terminated study and reasons for study terminations 
14.6. 
Safety Assessment 
Safety variables will include AEs, PE findings, vital signs, ECGs, and laboratory values. 
The extent of exposure to XmAb18087 monotherapy, as well as exposure in combination with 
pembrolizumab, will be summarized by dose cohort based on the number of infusions administered 
and the number of treatment cycles completed, as well as the total dose received. Additional 
summaries of drug exposure will be provided based on the PK parameters described in Section 13. 
Reasons for missed infusions or early permanent discontinuation of XmAb18087 will be reported. 
Summary tables and listings will be provided for all reported AESC. 
Adverse events will be coded using the latest version of MedDRA. The verbatim term recorded by 
the Investigator will be mapped to System Organ Class (SOC) and Preferred Term using MedDRA. 
Treatment-emergent AEs are defined as events with onset dates on or after the start of study 
treatment or events that are present before the first infusion of XmAb18087 and subsequently 
worsen in severity. 
Adverse-event-related endpoints include the following: 
• TEAEs 
• Treatment-emergent SAEs (TESAEs) 
• Treatment-related TEAEs (for XmAb18087 or for pembrolizumab, if they can be 
distinguished) 
• Treatment-related TESAEs (for XmAb18087 or for pembrolizumab, if they can be 
distinguished) 
• TEAEs by severity that are defined by NCI-CTCAE, Version 5.0 
• TEAEs resulting in the permanent discontinuation of XmAb18087 and/or 
pembrolizumab. 
All AE-related endpoints will be summarized by MedDRA SOC and preferred term. At each level 
of summation, subject will be counted once under the greatest severity and strongest study drug 
relationship. All AEs will be included in the listings. 
The hematology, chemistry, and other laboratory values and change from baseline values will be 
summarized descriptively for each scheduled assessment time point and grouped by dosing cohort. 
The baseline value for each laboratory value is defined as the last assessment performed on or prior 


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to the date of first dose of study treatment. The toxicity grades for laboratory tests will be based 
on NCI-CTCAE Version 5.0 criteria. The use of blood transfusions (platelets, RBCs) and/or 
growth factor support will be reported. Similar analyses will be done for chemistry tests (including 
liver and renal function tests). Subject listings of all laboratory data collected during the study will 
be presented. Laboratory values outside normal limits will be identified in the subject listings and 
will include flags for high and low values. 
Vital sign results (blood pressure, pulse, respirations, temperature, and blood oxygen saturation by 
pulse oximetry) and change from baseline values will be summarized descriptively for each 
scheduled time point. The baseline value for each vital sign measurement is defined as the last 
assessment performed on or prior to the date of first dose of study treatment. Additionally, the vital 
signs measured immediately (within 60 minutes) before each infusion of XmAb18087; at 15, 30, 
and 60 minutes from the start of the infusion (± 5 minutes for each time point); immediately (within 
5 minutes) before EOI; at 15, 30, and 60 minutes after the EOI (± 5 minutes for each time point); 
and then hourly (± 5 minutes) for 3 hours postinfusion will be summarized. The change of vital 
signs values from preinfusion will be summarized for each postinfusion point. Preinfusion 
assessments are defined as last vital assessment prior to the same infusion. Subject listings of all 
vital data collected during the study will be presented. 
Electrocardiogram values and change from baseline values will be summarized descriptively for 
each scheduled time point. Subject listings of all ECG data collected during the study will be 
presented. 
14.7. 
Efficacy Assessment 
The objective of these analyses is to explore the effects of XmAb18087 when administered 
repeatedly as a single agent across a range of dose levels, in combination with pembrolizumab, 
and at RD for each Part of the study. 
The assessment of antitumor effects of XmAb18087 will be based on response criteria defined in 
RECIST 1.1 (Appendix A). 
The number and percentage of subjects achieving a best overall response of complete response 
(CR; confirmed and unconfirmed), partial response (PR; confirmed and unconfirmed), stable 
disease, progressive disease, and not evaluable will be presented. 
Overall response rate is defined as subject’s best response of PR or better. The number and percent 
of subjects who achieved ORR will be summarized. Two-sided exact 95% confidence intervals for 
the ORR will be determined using the binomial distribution. The duration of objective response 
will be calculated from the time of initial response (PR or better) to the first documentation of 
relapse (recurrence after CR) or progression (after PR). 
The evaluable population defined in Section 14.4 will be used for summary of ORRs and duration 
of response. 
Depending on the completeness of the available follow-up data, an analysis of PFS, measured 
relative to Day 1, will be performed based on the Kaplan-Meier method. Median time and its 95% 
confidence interval, as well as the 25th and 75th quartiles with their 95% confidence intervals, will 
be summarized. Progression will be determined using the criteria described in 
RECIST 1.1 (Appendix A). The date of progression is defined as the date of progression or death. 


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The date of censoring for subjects who end the study without documented progression will 
correspond to the date the last tumor assessment was performed. Subjects who terminated from 
study without postbaseline tumor assessment will be censored at Day 1. 
Progression-free survival will be presented based on the safety population for the overall study. 
The potential antitumor effects of XmAb18087 may also be evaluated in other subgroups of 
subjects. The specifications for these and other similar analyses will be described in the SAP and 
supersedes any protocol specifications. 
14.8. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters including Cmax, tmax, t1/2, AUC0-∞, CL, Vd, and Vdss will be estimated 
using either noncompartmental or compartmental methods, whichever best describes the observed 
data. Pharmacokinetic parameters for XmAb18087 will be compared with and without 
pembrolizumab administration. 
Pharmacokinetic parameters at presumed steady-state will include area under the serum 
concentration-time curve during a dosing interval (t; AUCt; where t is 1 week), steady-state 
concentration (Css), minimum steady-state concentration (Cmin,ss), steady-state fluctuation in 
concentrations (%Fluct), time of minimum concentration (tmin) and predicted accumulation 
(accumulation index, AI). The observed accumulation will be computed as the ratio of Cmax and 
AUCt at presumed steady state versus Cmax and AUCt after the first dose. Trough concentrations 
(Ctrough) at predose will be used to evaluate the approach to steady state. 
All PK parameters will be computed using actual elapsed time to PK sampling event and to dose 
event start and stop, calculated relative to the first dose start of infusion and the dose start for each 
infusion. Dose used to compute PK parameters will be the actual dose delivered during the infusion 
duration. 
Dose proportionality across dose levels will be characterized by plotting Cmax and AUC0-∞ and 
AUCt versus dose. Similarly, the kinetic parameters t1/2, tmax, CL, Vd, and Vdss across dose levels 
will be characterized by plots of these parameters versus dose. 
Exploratory analyses may be performed to evaluate the relationship between 1 or more of the 
estimated PK parameters and selected safety, efficacy, and other serum protein assessment 
parameters described previously. The serum profile of XmAb18087 versus time will be evaluated 
with respect to any antibodies to XmAb18087 that may accelerate clearance. 
A similar analysis of Pembrolizumab PK will be performed and details of both analyses will be 
described in a PK Analysis Plan. 
14.9. 
Immunogenicity Assays 
The incidence and titer of anti-XmAb18087 ADA will be reported by dose cohort and sample 
collection time point. 


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15. 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The Investigator or institution shall provide direct access to source data and documents for 
study-related monitoring, audits, IRB/Independent Ethics Committee (IEC) review, and regulatory 
inspection. 
The Sponsor or its designee will monitor the study according to GCP guidelines. The PI and study 
center will permit the Sponsor, its representatives, FDA, and other regulatory agencies direct 
access to all original source data and documents for study monitoring audits and inspections. All 
requested information must be entered into the eCRF in the EDC database. The completed eCRF 
must be promptly reviewed and electronically signed and dated by the PI. 
The PI may be subjected to a field audit by the Sponsor, ICON, and/or FDA inspectors in order to 
validate the participation of subjects in the study and to verify the data reported in the clinical 
database. The Sponsor should be notified immediately of any audits scheduled by any regulatory 
authorities. Copies of audit reports from regulatory authorities should be promptly forwarded to 
the Sponsor. 
The Sponsor and PI uphold the principle of the subject’s right to protection against invasion of 
privacy. Throughout this study, all data collected and analyzed by the Sponsor will be identified 
only by an identification number. 
ICON will provide the study sites access to the EDC database that will be used to collect the 
required subject eCRF data for this trial. The eCRF must be supported by the corresponding 
information in the source document. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
16.1. 
Conduct of the Study 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor or its 
representatives may conduct a quality assurance audit. 
The study shall be performed in a manner that will implement and maintain quality control and 
quality assurance procedures with written SOPs to ensure that the study is conducted and data are 
generated, documented, and reported in compliance with the protocol, International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, and 
applicable regulatory requirements. 
The study will be conducted in compliance with the following: 
• The protocol 
• Ethical principles of the Declaration of Helsinki (Version 2013) and its amendments 
• The principles of the GCP provided in the ICH Harmonized Tripartite Guidelines for 
GCP 1996 
• FDA regulations (Code of Federal Regulations [CFR], Sections 312.50 and 312.56) 
• All applicable national laws and regulations including but not limited to 
country-specific GCP 
Any significant protocol deviations must be documented on the eCRF. 
16.2. 
Study Monitoring 
The Sponsor or its designee will monitor the study according to GCP guidelines. The PI and study 
center will permit the Sponsor, its representatives, FDA, and other regulatory agencies direct 
access to all original source data and documents for study monitoring audits and inspections. All 
requested information must be entered into the eCRF in the EDC database. The completed eCRF 
must be promptly reviewed and electronically signed and dated by the PI. 
During the study, a Xencor monitor or representative will have regular contacts with the 
investigational site for the following: 
• Provide information and support to the investigators. 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRFs, and that investigational product accountability checks 
are being performed. 
• Perform source data verification. This includes a comparison of the data in the CRFs 
with the subject’s medical records at the hospital or practice, and other records relevant 
to the study. This will require direct access to all original records for each subject (eg, 
clinic charts). 
• Record and report any protocol deviations not previously sent to ICON or Xencor. 


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• Confirm AEs and SAEs have been properly documented on CRFs, that any SAEs have 
been forwarded to ICON, and that those SAEs that met criteria for reporting have been 
forwarded to the IRB/IEC. 
The Monitor will be available between visits if the Investigator(s) or other staff need information 
or advice. 
The PI may be subjected to a field audit by the Sponsor, ICON, and/or FDA inspectors in order to 
validate the participation of subjects in the study and to verify the data reported in the clinical 
database. The Sponsor should be notified immediately of any audits scheduled by any regulatory 
authorities. Copies of audit reports from regulatory authorities should be promptly forwarded to 
the Sponsor. 
The Sponsor and PI uphold the principle of the subject’s right to protection against invasion of 
privacy. Throughout this study, all data collected and analyzed by the Sponsor will be identified 
only by an identification number. 
ICON will provide the study sites access to the EDC database that will be used to collect the 
required subject eCRF data for this trial. The eCRF must be supported by the corresponding 
information in the source document. 


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17. 
ETHICS 
17.1. 
Institutional Review Board/Independent Ethics Committee 
The PI will submit the protocol, protocol amendments, ICF, Investigator’s Brochure, and any 
subject recruitment materials to the IRB/IEC for approval, as required by 21 CFR, Part 56. 
It is required that a valid IRB/IEC approve, in writing, the conduct of this clinical study, together 
with the Investigator’s ICF, prior to study initiation. Until written approval by the IRB/IEC has 
been received by the Sponsor, no subject may undergo any procedures solely for the purpose of 
determining eligibility for this study. 
The PI must provide study progress reports to the IRB/IEC at least annually for all IND studies or 
more frequently if required by applicable guidelines, regulations, or institutional procedures. 
The PI must promptly notify the IRB/IEC of any SAEs occurring at the site, as well as any IND 
safety reports reported to the FDA, regardless of the reporting site location. 
The Sponsor reserves the right to amend the protocol during the course of the study. It is the PI’s 
responsibility to obtain IRB/IEC approval of any protocol amendments and to implement them in 
a timely manner. Protocol amendments in the form of an administrative letter signed by the PI 
should be submitted to the IRB/IEC for review. All protocol amendments must have IRB/IEC 
review and approval prior to implementation. 
If a protocol amendment substantially alters the study design or increases the potential risk to 
subjects, the ICF must be revised and submitted to the IRB/IEC for review and approval. The 
revised ICF must be used to obtain consent from subjects currently enrolled in the study if they 
are affected by the amendment and for all subsequent subjects prior to enrollment. 
Documentation of IRB/IEC approval of the protocol, ICF, and other applicable study documents 
must be provided to the Sponsor or its agent, ICON, before commencement of this study. Copies 
of all study-related correspondence between the PI and IRB/IEC must be maintained in the site 
regulatory binder. 
17.2. 
Good Clinical Practice 
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor and 
the Investigator abide by the principles of the ICH guidelines on GCP as outlined in 
CPMP/ICH/135/95 and the Declaration of Helsinki (Version 2013). The clinical study also will be 
carried out in keeping with national and local legal requirements (in accordance with US IND 
regulations [21 CFR Parts 50, 56, and 312]). 
The Investigator will be responsible for the care of the subjects throughout the study. If the 
Investigator is not present at the study site, he/she will leave instructions for the staff and a 
telephone number where he/she can be reached. 
17.3. 
Written Informed Consent 
The PI(s) at each center will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Subjects must also 


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be notified that they are free to discontinue from the study at any time. The subject should be given 
the opportunity to ask questions and allowed time to consider the information provided. 
The PI is responsible for ensuring that subjects sign an appropriately approved ICF prior to 
enrolling the subject in the study. Any required signatures must be obtained before conducting any 
study procedures. 
Each subject must sign a statement that he/she has given consent for the subject’s participation in 
the study that complies with the requirements of 21 CFR Part 50. A copy of the signed ICF must 
be provided to the subject, another copy kept with the study records, and the original kept with the 
subject’s medical records. In addition, the medical records will include documentation of the 
informed consent process. 
A sample of any ICF to be used in this study that has been approved by the IRB/IEC must be 
forwarded to the Sponsor or its agent, ICON. 
17.4. 
Protocol Approval and Amendment(s) 
Before the start of the clinical study, the clinical study protocol and other relevant documents will 
be approved by the IRB/IEC, in accordance with local legal requirements. The Sponsor must 
ensure that all ethical and legal requirements have been met before the first subject is enrolled in 
the clinical study. 
This protocol is to be followed exactly. Any deviations should be agreed on by both the Sponsor 
and the Investigator, with the appropriate written and approved protocol amendments made to 
reflect the changes agreed upon. Protocol amendments must be released by the responsible staff 
and receive IRB/IEC approval prior to implementation (as appropriate). Where the deviation 
occurs for the well-being of the subject, the Sponsor must be informed of the action agreed upon. 
Administrative changes may be made without the need for a formal amendment but will also be 
mentioned in the integrated clinical study report. All amendments will be distributed to all study 
protocol recipients with appropriate instructions. 
17.5. 
Subject Confidentiality 
Adequate records have to be maintained for the study, including but not limited to subject medical 
records, eCRFs, laboratory reports, worksheets, nursing notes, signed ICFs, product forms, SAE 
forms, and information regarding subject discontinuation and reasons for discontinuation. The 
confidentiality of each record with subject identification is to be guaranteed by the clinical 
Investigator. 
18. 
DATA HANDLING AND RECORD KEEPING 
18.1. 
Case Report Forms/Source Data Handling 
The Investigator shall be provided with standardized case report forms (CRFs) and shall ensure 
that all data from subject visits are promptly entered into the CRFs in accordance with the specific 
instructions given. The Investigator must sign each CRF to verify the integrity of the data recorded. 


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A list of the normal ranges for all laboratory tests to be undertaken forms part of the documentation 
to be collated prior to study start. If a central laboratory has been selected to conduct any or all 
tests, it is essential that all samples be analyzed at that laboratory. 
The Investigator must maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and PE reports. 
Data to be recorded directly on the CRFs (ie, no prior written or electronic record of data) and 
considered to be source data must be identified in the protocol. 
18.2. 
Retention of Essential Documents 
The Investigator or institution should maintain the study documents as specified in the ICH 
guidelines on GCP and as required by the applicable regulatory requirements. The Investigator or 
institution should take measures to prevent accidental or premature destruction of these documents. 
18.3. 
Principal Investigator’s Record Requirements 
The PI shall retain study drug disposition records, copies of CRFs (or electronic files), and all 
source documentation (such as original ECG tracings, laboratory reports, and 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 the Sponsor, whichever is longer. The PI must 
contact the Sponsor prior to destroying any records associated with the study. If the PI withdraws 
from the study (due to relocation, retirement, etc.), the records shall be transferred to a mutually 
agreed upon designee, such as another PI or the IRB/IEC. Notice of such transfer will be provided 
in writing to the Sponsor. 


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19. 
PUBLICATION POLICY 
By signing the clinical study protocol, the Investigator agrees with the use of results of the clinical 
study for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals. If necessary, the competent authorities will be notified 
of the Investigator’s name, address, qualifications, and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without receiving approval 
from the Sponsor in advance. Authorship criteria for all publications of Xencor-sponsored clinical 
trials are based on the International Committee of Medical Journal Editors guidelines, “Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals” (Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, 2010). Authorship credit can be granted only to 
those who make substantial contributions to the publication. 
At a minimum, study results will be published on www.clinicaltrials.gov on all primary and 
secondary outcomes, no later than 1 year after completion of the study (including completion of 
the study if it has been terminated early). 
This protocol and other study documents contain trade secrets and commercial information that is 
privileged and confidential. Such information is not to be disclosed unless required by laws or 
regulations. The PI agrees to use this information only in conducting this study and is not allowed 
to use it for other purposes without written consent from the Sponsor. Results obtained from this 
study are the property of the Sponsor. 


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APPENDIX A. RECIST GUIDELINES 
RECIST GUIDELINES 
Selected Definitions and Tables from Revised RECIST Guidelines (Version 1.1) 
1. Measurability of tumor at baseline 
At baseline, tumor lesions will be categorized as measurable or nonmeasurable as follows: 
1.1 Measurable tumor lesions 
Lesions must be accurately measured in at least 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as nonmeasurable) 
• 20 mm by chest X-ray 
2. Measurability of lymph nodes at baseline 
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. 
3. Nonmeasurable lesions 
Nonmeasurable lesions are all other lesions, including the following: 
• Small lesions (longest diameter < 10 mm or pathological lymph nodes with P10 to 
< 15 mm short axis) as well as truly nonmeasurable lesions  
• Lesions considered truly nonmeasurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 
4. Response criteria 
4.1 Target lesions 
• A maximum of 5 target lesions may be identified and assessed for response. 
• The following definitions are used to determine objective tumor response for target 
lesions. 
1. Complete Response (CR): Disappearance of all target lesions 
− Any pathological lymph nodes (whether target or nontarget) must have 
reduction in short axis to < 10 mm. 
2. Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters 


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3. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
4. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of diameters while 
on study. 
4.2 Nontarget lesions 
While some nontarget lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. The following 
tumor response definitions apply to the group of nontarget lesions: 
• Complete Response (CR): Disappearance of all nontarget lesions and normalization of 
tumor marker level. All lymph nodes must be nonpathological in size (< 10 mm short 
axis). 
• Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance 
of tumor marker level above the normal limit 
• Progressive Disease (PD): Unequivocal progression of existing nontarget lesions. 
(Note: the appearance of 1 or more new lesions is also considered progression.) 
4.3 New lesions 
The appearance of new malignant lesions denotes disease progression. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of preexisting lesions). This is particularly important 
when the subject’s baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the subject 
who has visceral disease at baseline and while on study has a CT or MRI of the brain which reveals 
metastases. The subject’s brain metastases are considered to be evidence of PD even if he/she did 
not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. 
5. Evaluation of overall response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment, taking into account any requirement for confirmation. On occasion a response 


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may not be documented until after the end of therapy, so protocols should be clear if post-treatment 
assessments are to be considered in determination of best overall response.  
The subject’s overall response assignment will depend on the findings of both target and nontarget 
disease and will also take into consideration the appearance of new lesions. 
This is captured in Table 13 (below). 
Table 13: 
Assessment of Overall Response in Subjects with Target (± Nontarget Disease) 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any  
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
 
Sources: 
Eisenhauer E, Therasse P, and Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1), Eur J Can. 2009; 45: 228-247. 
 
Chalian H, Tore H, Horowitz J, et al. Radiologic assessment of response to therapy: Comparison 
of RECIST versions 1.1 and 1.0, Rad Onc 2011; 31: 2093-2105. 
 


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APPENDIX B. ECOG PERFORMANCE SCALE 
Table 14:  
ECOG Performance Scale  
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all predisease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, light 
housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all selfcare, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any selfcare. Totally 
confined to bed or chair. 
5 
Dead 
ECOG=Eastern Cooperative Oncology Group. 


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APPENDIX C. PROPHYLAXIS AND MANAGEMENT OF NAUSEA AND 
VOMITING AND HYPERSENSITIVITY REACTIONS, 
CYTOKINE RELEASE SYNDROME, AND 
NEUROLOGICAL TOXICITY 
Prophylaxis and Management of Nausea and Vomiting 
The Xencor Medical Monitor (
) should be contacted immediately by email or 
phone if questions arise concerning the grade of an infusion reaction. 
 email is 
, and his telephone number is 
. 
Because administration of XmAb18087 has been associated with nausea and vomiting and with 
mild symptoms of infusion reaction/CRS in some subjects, the following prophylactic medications 
are to be administered for all subjects before at least the first 
:  
 
 
 
If a subject experiences nausea and/or vomiting despite prophylaxis,
 
 
 are recommended for treatment of the symptoms. 
Sites may also choose to use other/additional antinausea/vomiting medications for prophylaxis or 
treatment of symptoms, according to their practice and assessment of the subject’s responses. 
Guidelines for Prophylaxis and Management of Hypersensitivity Reactions, 
Cytokine Release Syndrome, and Neurological Toxicity Attributed to 
XmAb18087 
Because administration of XmAb18087 has been associated with symptoms of infusion 
reaction/CRS in some subjects, it is required that all subjects receive the following medications 
before at least the first 4 doses of XmAb18087: 
c. Acetaminophen (Tylenol®): 650 mg PO once before dosing with XmAb18087 
d. Diphenhydramine (Benadryl®): 50 mg PO once before dosing with XmAb18087 
e. 10 to 20 mg IV dexamethasone (Decadron®) before dosing with XmAb18087 
If a subject receives 4 consecutive doses of XmAb18087 without ≥ Grade 1 infusion reaction/CRS, 
the prophylaxis described above may be modified, prophylactic medications are to be administered 
to all subjects before at least the first 4 doses of the study drug. 
Introduction and Grading 
Grading of toxicity, including allergic/hypersensitivity reactions, is by CTCAE version 5.0, except 
for CRS, which is using the ASTCT CRS Consensus Grading (Lee, 2019). See Table 15 for these 
definitions. 
All sites should review and implement the general guidelines for the use of tocilizumab and IV 
fluids discussed below. Otherwise, management of CRS and other infusion-related reactions 


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should be per standard investigational site procedures. Or, if there are no local standards or if they 
are incomplete, the approaches discussed here may be used. 
Table 15.  
American Society for Transplantation and Cellular Therapy Cytokine 
Release Syndrome Consensus Grading 
CRS Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fevera 
Temperature  
≥ 38 °C 
Temperature  
≥ 38 °C 
Temperature  
≥ 38 °C 
Temperature  
≥ 38 °C 
 
With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
 
And/orb 
Hypoxia 
None 
Requiring low-flow 
nasal cannulac or 
blow-by 
Requiring high-flow 
nasal cannula c, 
facemask, 
nonrebreather mask, 
or Venturi mask 
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release 
syndrome; CTCAE = Common Terminology Criteria for Adverse Events. 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0, but they do not influence CRS 
grading.  
a Fever is defined as temperature ≥ 38 °C not attributable to any other cause. In patients who have CRS then receive 
antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5 °C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow 
nasal cannula is classified as grade 3 CRS. 
c Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/minute. 
 
Cytokine Release Syndrome Versus Allergic or Hypersensitivity Reactions 
Cytokine release syndrome is mechanistically different from allergic/hypersensitive reactions 
(Lee, 2014), although some of the manifestations are common to both AEs and both have been 
reported to occur with therapeutic antibodies. An acute infusion reaction is often caused by a type 
1 hypersensitivity mechanism due to IgE-mediated release of histamines and prostaglandins, 
although a direct interaction with mast cells and basophils can also occur. It is less clear how 
cytokine release is triggered, although it is likely to be associated with immune cell activation; in 
this case, there is evidence that immunologic cascade is initiated by triggering of CD3-expressing 
T lymphocytes, resulting in TNF-α mediated monocyte/macrophage activation and systemic toxic 
cytokine release (Li, 2019). 
Signs and symptoms usually develop during or shortly after drug infusion in hypersensitivity 
reactions, are more likely to occur after several doses of the drug and are largely related to 
histamine release. Typical signs and symptoms of hypersensitivity reaction include rash/urticaria, 


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flushing, pruritus, fever, dyspnea, cough, and hypotension, although the following may also occur 
(Lenz, 2007): 
• Arthralgia  
• Bronchospasm 
• Confusion, mental status changes, and/or delirium 
• Dizziness 
• Fatigue (asthenia, lethargy, malaise) 
• Hallucinations 
• Headache 
• Hypertension 
• Myalgia 
• Nausea and/or vomiting 
• Rigors/chills 
• Diaphoresis 
• Tachycardia 
Cytokine release syndrome, on the other hand, is more likely to occur after the first dose or first 
escalated dose of drug than after subsequent doses. It may begin somewhat later and is more likely 
to be associated with hepatic and neurologic complications, including the following: 
• Any of the hypersensitivity signs or symptoms listed above 
• Aphasia or word-finding difficulty  
• Elevated d-dimer and/or hypofibrinogenemia 
• Fatigue (asthenia, lethargy, malaise) 
• Gait disturbance/dysmetria 
• Hallucinations 
• Seizures 
• Transaminitis and/or hyperbilirubinemia 
• Tremor 
The Xencor Medical Monitor should be contacted immediately if questions arise concerning the 
grade and/or treatment of the infusion reaction.  
Treatment Guidelines for Cytokine Release Syndrome 
Use of Tocilizumab for Cytokine Release Syndrome 
Tocilizumab is a therapeutic antibody that interferes with binding of IL-6 to the IL-6 receptor. It 
has been used to decrease the severity and possibly mortality of severe CRS (Frey, 2017), and 


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early administration may be useful in improving outcomes. Below are suggested guidelines for its 
use: 
• Sufficient tocilizumab (dose of 8 mg/kg) should be readily available to the area where 
subjects are receiving their infusions and being observed post infusion. 
• Prompt tocilizumab therapy should be strongly considered if:  
− Oxygen saturation falls below 90% on room air, OR 
− Systolic blood pressure falls 20 mm Hg below predose measurements and below 
100 mm Hg, OR 
− Temperature of > 38 °C (100.4 °F) in the presence of new or worsening dyspnea 
and/or tachypnea and/or rigors and/or tachycardia (HR > 110 bpm), OR 
− Early discovery of hepatic transaminase elevation. (Note that peak transaminase 
elevation appears to occur within 24 hours, so that it is unlikely that tocilizumab 
treatment on the day after study drug administration would affect the course or 
outcome in the absence of concurrent symptoms or signs of CRS). 
• Repeat dosing of tocilizumab may be necessary if signs and symptoms persist or return 
after initial treatment. 
Fluid Management  
Cytokine release syndrome is sometimes associated with myocardial dysfunction, pulmonary 
edema, or capillary leak syndrome (Shimabukuro-Vornhagen, 2018). Although there are little or 
no data regarding use of anti-CD3 antibodies and the need for fluid management, it seems prudent 
to monitor subjects for weight gain and limit IV fluid administration in the acute setting.  
• If a subject is noted to have had a ≥ 10% increase in body weight over the previous 
2 weeks in association with new or significantly increased bilateral lower extremity 
edema, dosing should be delayed until this finding is evaluated and, if indicated, 
treated. 
• For acute hypotension, an IV fluid bolus should be limited to 500 mL of normal saline 
or the equivalent.  
• If there is not an adequate response to fluids, treatment with tocilizumab (and 
vasopressors, if necessary) should be considered rather than additional fluid boluses. 
Cytokine Release Syndrome Treatment Guidelines by Grade 
The following are treatment guidelines for XmAb18087 treatment-related infusion reactions (Lee, 
2014); since it can be difficult to differentiate between different infusion reaction etiologies, both 
are included here. 
Grade 1: 
• Administer acetaminophen and/or diphenhydramine or dexamethasone to treat signs 
and symptoms if clinically indicated. 
• Vital signs should be measured every 15 minutes or less as clinically indicated. 


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• Obtain a blood sample for cytokine analysis during the event and approximately 
4 hours later, unless scheduled cytokine monitoring is already in progress. 
• Monitor the subject for worsening of condition; if severity of event increases to a higher 
grade, stop the infusion, administer appropriate treatment, and refer to guidelines below 
for more severe infusion reactions. 
• It may be useful to premedicate the subject with acetaminophen and antihistamines 
prior to the next infusion. 
Grade 2: 
• Hypotension responsive to fluids or a low dose of a single pressor, or mild respiratory 
symptoms treatable with low-flow oxygen are signs of Grade 2 toxicity. Older subjects 
or those with significant comorbidities may be at higher risk of decompensation in this 
situation. 
• Discontinue the infusion and administer acetaminophen and/or diphenhydramine or 
dexamethasone to treat signs and symptoms if clinically indicated. Once symptoms 
have resolved, slow the infusion rate by 50% of the baseline rate. If after 1 hour, the 
subject’s symptoms do not return and vital signs are stable, the infusion rate may be 
increased every 30 minutes, as tolerated, to the baseline rate.  
• Note that older subjects or those with significant comorbidities may be at higher risk 
of decompensation in this situation. When reactions occur in these vulnerable subjects, 
or in the case of rapidly escalating reactions, consider treatment with tocilizumab 4 to 
8 mg/kg IV over 1 hour, with or without dexamethasone 10 to 20 mg IV (or equivalent). 
• Vital signs should be measured every 15 minutes or less as clinically indicated. For 
subjects who are able to tolerate an increase in the infusion rate back to baseline and 
maintain normal blood pressure for 30 minutes after the rate increase then, at the 
discretion of the Investigator, the frequency of vital sign assessment may be reduced to 
every 30 minutes during the infusion. 
• Obtain a blood sample for cytokine analysis during the event and approximately 4 hours 
later, in addition to scheduled cytokine monitoring if already in progress. 
• Monitor the subject for worsening of condition; if severity of event increases to a higher 
grade, stop the infusion, administer appropriate treatment, and refer to guidelines below 
for Grades 3 and 4 infusion reactions. 
• Subjects with maximum Grade 2 infusion reaction may continue on study and should 
receive 
prophylactic 
premedication with acetaminophen 650 mg 
PO and 
diphenhydramine hydrochloride 25 to 50 mg IV or PO prior to all subsequent 
XmAb18087 infusions.  
Grade 3 and 4: 
• Stop the infusion and disconnect the infusion tubing from the subject. 


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• Aggressive supportive care should be given immediately. Vasopressors, fluids, oxygen, 
epinephrine or bronchodilators, ventilatory support, antipyretics, and analgesics should 
be used as indicated. 
• Treatment with tocilizumab 4 to 8 mg/kg IV over 1 hour with or without 
dexamethasone 10 mg IV (or equivalent) is strongly encouraged for CRS due to the 
high risk of progression and permanent organ dysfunction. 
• Hospital admission for observations is almost always indicated, usually to an intensive 
care unit, since an initial appearance of improvement may quickly yield to rapid 
decompensation. 
• Subjects with Grade 3 CRS or infusion reaction may be rechallenged once resolved. 
Subjects with recurrent Grade 3 or any Grade 4 infusion reaction should not receive 
further XmAb18087 treatment but will continue to be followed on the protocol (ie, for 
4 weeks after last dose). 
• Obtain a blood sample for cytokine analysis during the event and approximately 
4 hours later, in addition to scheduled cytokine monitoring if already in progress. 
• Obtain a sample for ADA testing as close to the onset of the event as possible, at the 
resolution of the event, and 28 days following the event. 
• Notify the Xencor Safety Monitor or Xencor Medical Monitor, 
 
(Telephone:
; Email:
), immediately. 
Neurotoxicity 
In addition to CRS, another toxicity observed after CAR-T cell therapy and CD3 bispecific 
antibodies is neurotoxicity. ICANS may manifest as delirium, encephalopathy, aphasia, lethargy, 
difficulty concentrating, agitation, tremor, seizures, and, rarely, cerebral edema (Lee, 2019). 
Neurotoxicity was previously considered in aggregate with CRS, but is now treated separately, 
due to its timing and response to treatment. 
Neurologic symptoms may occur during or after CRS symptoms, but rarely precede CRS 
symptoms. The earliest manifestations of ICANS are tremor, dysgraphia, mild difficulty with 
expressive speech (especially in naming objects), impaired attention, apraxia, and mild lethargy. 
Headache is a nonspecific symptom, frequently occurring during fever or after chemotherapy in 
patients without other neurologic dysfunction. Thus, headache alone is not a useful marker of 
ICANS. Expressive aphasia, on the other hand, appears to be a very specific symptom of ICANS 
(Lee, 2019).  
A consensus grading scheme, which is a slightly modified version of the CARTOX-10 screening 
tool, which incorporated key elements of the MMSE, the ICE score, will be used for the grading 
of ICANS (Table 9). It is important to note that the 10-point ICE screening tool is helpful for 
assessing patients for encephalopathy; however, the grading of ICANS requires assessment of the 
10-point ICE score as well as evaluation of other neurologic domains, such as level of 
consciousness, motor symptoms, seizures, and signs of elevated ICP/cerebral edema, which may 
occur with or without encephalopathy. The ASTCT ICANS toxicity grading system is shown in 
Table 16. This grading scale will be used to assess neurotoxicity, rather than the CTCAE 5.0. 
 


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Table 16: 
Immune Effector Cell-associated Encephalopathy Scoring 
ICE 
Orientation: orientation to year, month, city, hospital: 4 points 
Naming: ability to name 3 objects (eg, point to clock, pen, button): 3 points 
Following commands: ability to follow simple commands (eg, “Show me 2 fingers” or “Close your eyes and 
stick out your tongue”): 1 point 
Writing: ability to write a standard sentence (eg, “Our national bird is the bald eagle”): 1 point 
Attention: ability to count backwards from 100 by 10: 1 point 
ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = Immune Effector Cell-Associated 
Encephalopathy (score). 
Scoring: 10, no impairment; 
7 - 9, Grade 1 ICANS; 
3 - 6, Grade 2 ICANS; 
0 - 2, Grade 3 ICANS; 
0 due to patient unarousable and unable to perform ICE assessment, Grade 4 ICANS (Lee, 2019). 
 
 


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Table 17: 
American Society for Transplantation and Cellular Therapy Immune Effector 
Cell-associated Neurotoxicity Syndrome Consensus Toxicity Grading for 
Adults 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scorea 
7 – 9 
3 - 6 
0 – 2 
0 (patient is 
unarousable and 
unable to perform 
ICE) 
Depressed level of 
consciousnessb 
Awakens 
spontaneously 
Awakens to voice 
Awakens only to 
tactile stimulus 
Patient is 
unarousable or 
requires vigorous or 
repetitive tactile 
stimuli to arouse. 
Stupor or coma 
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves rapidly 
or nonconvulsive 
seizures on EEG 
that resolve with 
intervention 
Life-threatening 
prolonged seizure 
(> 5 min); or 
Repetitive clinical 
or electrical seizures 
without return to 
baseline in between 
Motor findingsc 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
Elevated 
ICP/cerebral edema 
N/A 
N/A 
Focal/local edema 
on neuroimagingd 
Diffuse cerebral 
edema on 
neuroimaging; 
decerebrate or 
decorticate 
posturing; or cranial 
nerve VI palsy; or 
papilledema; or 
Cushing’s triad 
EEG = electroencephalogram; ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = Immune 
Effector Cell-Associated Encephalopathy (score); ICP = intracranial pressure; N/A = not applicable; VI = sixth. 
 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who has 
a generalized seizure is classified as grade 3 ICANS. 
a A patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient 
with an ICE score of 0 may be classified as Grade 4. 
b Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication). 
c Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, 
but they do not influence ICANS grading. 
d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. It may be graded according to CTCAE v5.0 (Lee, 2019). 
It has been speculated that high levels of IL-6 may directly mediate neurotoxicity in this situation 
(Lee, 2014).  


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Clinical management of neurotoxicity consists of the following:  
• Monitor subjects closely for signs and symptoms of these events (including 
administration of mental status and neurologic examinations when these seem 
clinically warranted). 
• If neurotoxicity becomes evident, a blood sample for cytokine analysis should be drawn 
at that time, and again 4 hours later, in addition to scheduled cytokine monitoring if 
already in progress.  
• If neurologic toxicity is Grade 4, discontinue XmAb18087, if still infusing. 
• For Grade 3 neurologic toxicity, withhold both drugs until the toxicity has recovered 
to ≤ Grade 1 (mild) and has remained at ≤ Grade 1 for at least 3 days before restarting 
therapy. Restart XmAb18087 at 75% of the previous dose. Restart pembrolizumab at 
the full dose. Escalate back to full dose at the time of the next dose if ≥ Grade 2 toxicity 
does not recur. If ≥ Grade 2 toxicity reoccurs at 75% dose, or if < Grade 2 toxicity takes 
more than 7 days to resolve, discontinue permanently. 
• For severe neurologic symptoms, administer additional dexamethasone 10 mg 
intravenously and repeat every 12 hours if symptoms do not abate rapidly, or treat 
according to the clinical site’s institutional protocol for such reactions. 
• For recurrent seizures, anticonvulsant therapy may be necessary. 


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Appendix D. 
DOSE MODIFICATION AND TOXICITY MANAGEMENT 
FOR IMMUNE-RELATED ADVERSE EVENTS  
IRAEs may occur shortly after the first dose of pembrolizumab or up to several months after the 
last dose. Based on existing clinical data for pembrolizumab and other checkpoint inhibitors, most 
IRAEs were reversible and could be managed with dose interruptions, 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, or skin biopsy may be included as part of the evaluation. IRAEs known to be associated 
with pembrolizumab, as well as guidelines for dose modification and management when they 
occur, are described in the Keytruda Prescribing Information (Keytruda® Package Insert, 2020); 
these guidelines are summarized in Table 18.  
For additional information on diagnosis and management of IRAEs, see the NCCN Guidelines – 
Management of Immunotherapy-Related Toxicities (Appendix E).  
 
 


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Table 18: 
Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events in Patients Receiving Pembrolizumab 
General Instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, it can be resumed after AE has been reduced to Grade 1 or 0 
and corticosteroid has been tapered.  
3. 
For severe and life-threatening IRAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if IRAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity Grade or 
Conditions (CTCAE 
v5.0) 
Action Taken with 
Pembrolizumab 
IRAE 
Management with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Monitor participants for signs and 
symptoms of pneumonitis 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
Add prophylactic antibiotics for 
opportunistic infections 
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 participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis.  
Participants 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. 
Grade 4 
Permanently 
discontinue 
Immune-mediated 
hepatitis 
AST or ALT greater 
than 3 but no more 
than 5 times the ULN 
or total bilirubin 
greater than 1.5 but 
no more than 3 times 
the ULN 
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 Taken with 
Pembrolizumab 
IRAE 
Management with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-up 
In patients without 
liver metastases, AST 
or ALT greater than 
5 times ULN or total 
bilirubin greater than 
3 times ULN  
In patients with liver 
metastasis and 
Grade 2 AST or ALT 
at baseline, with an 
increase in AST or 
ALT of 50% or more 
relative to baseline 
that persists for at 
least 1 week 
Permanently 
discontinue 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Immune-mediated 
endocrinopathies 
Grades 3 or 4 
Withhold until 
clinically stable 
Administer 
corticosteroids and 
hormone 
replacement as 
clinically indicated 
Monitor participants for signs and 
symptoms of endocrinopathies 
Nephritis and 
Renal dysfunction 
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 
All other 
immune-related 
AEs 
Intolerable/persistent 
Grade 2 
Withhold 
Based on type and 
severity of AE, 
administer 
corticosteroids  
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 
Withhold or 
discontinue based on 
the type of event. 
Events that require 
discontinuation 
include, but are not 
limited to: 
Guillain-Barré 
Syndrome, 
encephalitis 
Grade 4 or recurrent 
Grade 3  
Permanently 
discontinue 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common 
Terminology Criteria for Adverse Events; GI = gastrointestinal; IRAE = immune-related adverse event; IV = 
intravenous; ULN = upper limit of normal. 
 
 


Xencor, Inc 
CONFIDENTIAL 
18 August 2020 
Protocol XmAb18087-02 
 
 
 
Version 1.0 
 
Page 133 of 145  
 
APPENDIX E. NATIONAL COMPREHENSIVE CANCER NETWORK 
AND AMERICAN SOCIETY OF CLINICAL ONCOLOGY: 
MANAGEMENT 
OF 
IMMUNOTHERAPY-RELATED 
TOXICITIES 
(IMMUNE 
CHECKPOINT 
INHIBITOR-RELATED TOXICITIES) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCCN: Continuing Education
Target Audience: This activity is designed to meet the educa
tional needs of oncologists, nurses, pharmacists, and other healthcare
professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive
Cancer Network (NCCN) is jointly accredited by the Accreditation
Council for Continuing Medical Education (ACCME), the Accredi
tation Council for Pharmacy Education (ACPE), and the American
Nurses Credentialing Center (ANCC), to provide continuing edu
cation for the healthcare team.
Medicine (ACCME): NCCN designates this journal based CME ac
tivity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians
should claim only the credit commensurate with the extent of their
participation in the activity.
Nursing (ANCC): NCCN designates this educational activity for a
maximum of 1.0 contact hour.
Pharmacy (ACPE): NCCN designates this knowledge based
continuing education activity for 1.0 contact hour (0.1 CEUs) of
continuing education credit. UAN: JA4008196 0000 20 004
H01 P
All clinicians completing this activity will be issued a certiﬁcate of
participation. To participate in this journal CE activity: (1) review the
educational content; (2) take the posttest with a 66% minimum
passing score and complete the evaluation at https://education.
nccn.org/node/86963; and (3) view/print certiﬁcate.
Pharmacists: You must complete the posttest and evaluation within
30 days of the activity. Continuing pharmacy education credit is reported
to the CPE Monitor once you have completed the posttest and evalu
ation and claimed your credits. Before completing these requirements,
be sure your NCCN proﬁle has been updated with your NAPB e proﬁle
ID and date of birth. Your credit cannot be reported without this in
formation. If you have any questions, please e mail education@nccn.org.
Release date: March 10, 2020; Expiration date: March 10, 2021
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN
Guidelines for Management of Immunotherapy Related Toxicities
• Describe the rationale behind the decision making process for de
veloping the NCCN Guidelines for Management of Immunotherapy
Related Toxicities
Disclosure of Relevant Financial Relationships
The NCCN staff listed below discloses no relevant ﬁnancial relationships:
Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD;
Karen Kaneﬁeld; and Kathy Smith.
Individuals Who Provided Content Development and/or Authorship Assistance:
John A. Thompson, MD, Panel Chair, has disclosed that he receives honoraria from AstraZeneca Pharmaceuticals LP; is a scientiﬁc advisor for and has equity
interest/stock options in Alpine Immune Sciences; and receives consulting fees from Calithera Biosciences, Inc. and Synthorx, Inc.
Bryan J. Schneider, MD, Panel Vice Chair, has disclosed that he receives grant/research support from Bristol-Myers Squibb Company, Genentech, Inc., and Incyte
Corporation.
Julie Brahmer, MD, Panel Member, has disclosed that she receives consulting fees from Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb
Company, Genentech, Inc., Merck & Co., Inc., and Syndax Pharmaceuticals Inc.; and she receives grant/research support from Bristol-Myers Squibb Company.
Philippe Armand, MD, PhD, Panel Member, has disclosed that he receives consulting fees from ., Merck & Co., Inc., Bristol-Myers Squibb Company, Pﬁzer Inc.,
Afﬁmed, Adaptive Biotechnologies Corp., Inﬁnity Pharmaceuticals, ADC Therapeutics, Celgene Corporation, MorphoSys AG, Daiichi Sankyo, Inc., Miltenyi Biotec;
receives grant/research support from Merck & Co., Inc., Bristol-Myers Squibb Company, Afﬁmed, Adaptive Biotechnologies Corp., Roche, Tensha Therapeutics,
Otsuka Pharmaceutical Co., Ltd, Sigma-Tau Pharmaceuticals, Inc., Genentech, Inc., and IGM Biosciences, Inc.; and receives honoraria from Merck & Co., Inc. and
Bristol-Myers Squibb Company.
Marianne Davies, DNP, RN, AOCNP, Panel Member, has disclosed that she is on the product/speakers bureau for AstraZeneca Pharmaceuticals LP, Bristol-Myers
Squibb Company, Genentech, Inc., and Merck & Co., Inc.
Marc S. Ernstoff, MD, Panel Member, has disclosed that he receives consulting fees from Bristol-Myers Squibb Company, Alkermes plc, and ImmuNext Inc.; and
receives grant/research support from EMD Serono, Merck & Co., Inc., and Alkermes plc.
Jeffrey A. Sosman, MD, Panel Member, has disclosed that he is a scientiﬁc advisor for and receives honoraria from Bristol-Myers Squibb Company, and receives
consulting fees from Genentech, Inc.
Alyse Johnson-Chilla, MS, Guidelines Coordinator, NCCN, has disclosed that she has no relevant ﬁnancial relationships.
Griselda Zuccarino-Catania, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed that her spouse is employed by Janssen Pharmaceuticals, Inc.
Anita Engh, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed that she has no relevant ﬁnancial relationships.
To view all of the conﬂicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.
This activity is supported by educational grants from AstraZeneca; Celgene Corporation; Coherus BioSciences; Genentech, a member of the Roche Group; and
TESARO, a GSK Company. This activity is supported in part by an educational grant from Bayer Healthcare Pharmaceuticals. This activity is supported by an
independent medical education grant from Bristol-Myers Squibb. This activity is supported by a medical education grant from Exelixis, Inc. This activity is
supported by an independent educational grant from Merck & Co., Inc.
NCCN GUIDELINES® INSIGHTS
CE
Management of Immunotherapy-Related
Toxicities, Version 1.2020
230
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NCCN GUIDELINES® INSIGHTS
CE
Management of Immunotherapy-Related
Toxicities, Version 1.2020
Featured Updates to the NCCN Guidelines
John A. Thompson, MD1,*; Bryan J. Schneider, MD2,*; Julie Brahmer, MD3,*; Stephanie Andrews, MS, ANP BC4;
Philippe Armand, MD, PhD5,*; Shailender Bhatia, MD1; Lihua E. Budde, MD, PhD6; Luciano Costa, MD, PhD7;
Marianne Davies, DNP, RN, AOCNP8,*; David Dunnington, MA9; Marc S. Ernstoff, MD10,*; Matthew Frigault, MD11;
Benjamin H. Kaffenberger, MD12; Matthew Lunning, DO13; Suzanne McGettigan, MSN, CRNP14;
Jordan McPherson, PharmD, MS, BCOP15; Nisha A. Mohindra, MD16; Jarushka Naidoo, MD3;
Anthony J. Olszanski, MD, RPh17; Olalekan Oluwole, MD18; Sandip P. Patel, MD19; Nathan Pennell, MD, PhD20;
Sunil Reddy, MD21; Mabel Ryder, MD22; Bianca Santomasso, MD, PhD23; Scott Shofer, MD, PhD24;
Jeffrey A. Sosman, MD16,*; Yinghong Wang, MD, PhD25; Ryan M. Weight, DO, MS26; Alyse Johnson Chilla, MS27,*;
Griselda Zuccarino Catania, PhD27,*; and Anita Engh, PhD27,*
ABSTRACT
The NCCN Guidelines for Management of Immunotherapy Related
Toxicities provide interdisciplinary guidance on the management of
immune related adverse events (irAEs) resulting from cancer immu
notherapy. These NCCN Guidelines Insights describe symptoms that
may be caused by an irAE and should trigger further investigation,
and summarize the NCCN Management of Immunotherapy Related
Toxicities Panel discussions for the 2020 update to the guidelines
regarding immune checkpoint inhibitor related diarrhea/colitis and
cardiovascular irAEs.
J Natl Compr Canc Netw 2020;18(3):230–241
doi: 10.6004/jnccn.2020.0012
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high level evidence, there is uniform
NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower level evidence, there is uni
form NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower level evidence, there is NCCN
consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major
NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise
noted.
Clinical trials: NCCN believes that the best management of
any patient with cancer is in a clinical trial. Participation in
clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines®) are a statement of evidence and consensus
of the authors regarding their views of currently accepted
approaches to treatment. The NCCN Guidelines Insights
highlight important changes in the NCCN Guidelines
recommendations from previous versions. Colored
markings in the algorithm show changes and the
discussion aims to further the understanding of these
changes by summarizing salient portions of the panel’s
discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full
NCCN Guidelines; further, the National Comprehensive
Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use, or
application of the NCCN Guidelines and NCCN Guidelines
Insights and disclaims any responsibility for their application
or use in any way.
The complete and most recent version of these
NCCN Guidelines is available free of charge at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2020.
All rights reserved. The NCCN Guidelines and the illustrations
herein may not be reproduced in any form without the
express written permission of NCCN.
1Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
2University of Michigan Rogel Cancer Center; 3The Sidney Kimmel
Comprehensive Cancer Center at Johns Hopkins; 4Mofﬁtt Cancer Center;
5Dana-Farber/Brigham and Women’s Cancer Center; 6City of Hope National
Medical Center; 7O’Neal Comprehensive Cancer Center at UAB; 8Yale Cancer
Center/Smilow Cancer Hospital; 9Patient Advocate; 10Roswell Park
Comprehensive Cancer Center; 11Massachusetts General Hospital Cancer
Center; 12The Ohio State University Comprehensive Cancer Center - James
Cancer Hospital and Solove Research Institute; 13Fred & Pamela Buffett Cancer
Center; 14Abramson Cancer Center at the University of Pennsylvania;
15Huntsman Cancer Institute at the University of Utah; 16Robert H. Lurie
Comprehensive Cancer Center of Northwestern University; 17Fox Chase Cancer
Center; 18Vanderbilt-Ingram Cancer Center; 19UC San Diego Moores Cancer
Center; 20Case Comprehensive Cancer Center/University Hospitals Seidman
Cancer Center and Cleveland Clinic Taussig Cancer Institute; 21Stanford Cancer
Institute; 22Mayo Clinic Cancer Center; 23Memorial Sloan Kettering Cancer
Center; 24Duke Cancer Institute; 25The University of Texas MD Anderson Cancer
Center; 26University of Colorado Cancer Center; and 27National
Comprehensive Cancer Network.
*Provided content development and/or authorship assistance.
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Overview
Immune checkpoints are part of the natural balance
of the immune system to prevent autoimmunity and
are exploited by cancer cells to suppress the immune
response. Immune checkpoint inhibitors (ICIs) block
proteins—namely PD-1, PD-L1, and CTLA-4—that allow
tumor cells to evade detection and killing by T cells.1–6
Since the FDA-approval of the CTLA-4 inhibitor ipilimumab
in 2011, ICIs have become a treatment option for several
advanced cancers. ICIs signiﬁcantly improve overall survival
and delay progression of tumors in patients with a variety of
cancers.7 Indications for ICIs have expanded dramatically
and now include a wide array of cancer types.1–8
A major drawback of ICI therapy is the potential for
immune-related adverse events (irAEs), which can aﬀect
any organ or tissue. The pharmacodynamics and phar-
macokinetics of ICI immunotherapy diﬀer greatly from
those of cytotoxic chemotherapy or targeted anticancer
therapy.9 Traditional cytotoxic chemotherapy often re-
sults in acute-onset emetic and myelosuppressive ef-
fects, whereas irAEs tend to be relatively delayed in onset
and inﬂammatory or autoimmune in nature.10–13 Al-
though the pathophysiology of ICI-related irAEs is not yet
fully elucidated, knowledge regarding the role of immune
checkpoint pathways in autoimmune disease provides
some clues. Many autoimmune diseases are related to
failure of T-cell tolerance and subsequent uncontrolled
activation of immune eﬀector cells. Early- and later-
onset irAEs may result from distinct mechanisms that
have yet to be elucidated. Typical earlier-onset, com-
mon irAEs appear to involve generalized epithelial in-
ﬂammation and may be observed in the form of rash,
colitis, and pneumonitis. Later-onset irAEs, which are
typically less common, tend to be more-localized, organ-
speciﬁc reactions. Research is ongoing into the speciﬁc
mechanisms underlying irAEs associated with speciﬁc
ICIs. The reported incidence of any-grade irAEs associated
with single-agent ICI treatment ranges widely across agents
and trials, from approximately 15% to 90%,14,15 and patterns
of toxicity may diﬀer between speciﬁc ICI agents.16 Severe
irAEs leading to discontinuation of treatment have oc-
curred in up to 13% of patients receiving anti–PD-1
monotherapy in clinical trials.17–24 Although combina-
tion regimens oﬀer the potential for enhanced eﬃcacy,
in general, observed toxicity with ICI-based combina-
tion regimens is greater than that for ICI monotherapy.
Recognizing Immune-Related Symptoms
Onset of irAEs can be immediate or delayed by as much
as 2 years, and can aﬀect any organ system.25 Early
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recognition of symptoms and prompt intervention
are key goals for the successful management of
immunotherapy-related toxicity. When encountering
one or more of these symptoms, asking appropriate
questions can help discern whether the patient is
experiencing a symptom due to disease progression,
an infection, some other condition, or an irAE.
Symptoms that may cause clinical suspicion of an
irAE include (main symptoms are bold and under-
lined; associated symptoms are underlined; possible
irAE type/diagnoses are in italics):
•
Change in bowel pattern compared with baseline,
especially if it is watery diarrhea, stool contains
blood or mucus, or cramping or severe abdominal
pain develop, may indicate colitis. However, blood in
the stools and/or fever may be because of other
causes of gastrointestinal bleeding, such as infection
or peptic ulcer disease or bleeding due to tumor.
•
Cough may be due to an upper respiratory infection,
but especially if the cough is dry or is coupled with
shortness of breath, it could indicate pneumonitis.
•
Headaches can be indicative of brain metastases, but
when presenting with fatigue, visual symptoms, nausea,
and other symptoms, may be indicative of hypophysitis
(inﬂammation of the pituitary).26 28 Headaches may
also be indicative of meningitis when coupled with a
stiﬀneck, photophobia, nausea, or fever. Headaches
can also be indicative of encephalitis if coupled with
fever, tiredness, confusion, mood change, memory
problems, stiﬀneck, and other symptoms. Head-
aches, head pain, and scalp tenderness, may be in-
dicative of giant cell arteritis.
•
Nausea is a common symptom that can accompany
certain cancer therapies. Nausea with abdominal pain/
bloating could indicate pancreatitis. Nausea that occurs
during infusion of an ICI, accompanied by fever/chills,
hypertension, hypotension, sweating, myalgia, cough,
or shortness of breath, may indicate an infusion-related
reaction.
•
Rashes are very common and may be accompanied by
itching that can lead to scratching and severe skin toxic-
ities causing edema, oozing, papulation, excoriations,
licheniﬁcation, which may indicate bullous dermatitis,
or separation of the dermis, a sign of Stevens-Johnson
syndrome/toxic epidermal necrolysis (SJS/TEN).
•
Fatigue is a common symptom that alone or coupled
with weight change, nausea, or other nonspeciﬁc symp-
toms may indicate a thyroid disorder,26 hypophysitis, or,
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rarely, adrenal insuﬃciency.28 Fatigue with tachycardia,
palpitations, increased stool frequency, and other
symptoms may be thyrotoxicosis.27 Fatigue accom-
panied by nausea, chest pain, shortness of breath,
arrhythmias, and other potentially nonspeciﬁc symp-
toms may be indicative of myocarditis. However, fatigue
may also be attributed to depression, an infection, dis-
ease progression, a hematologic abnormality, or another
condition.
•
Muscle or joint pain may be indicative of musculo-
skeletal toxicities. Muscle pain alone or with fatigue,
chest pain, and shortness of breath may be due to a
cardiac toxicity, because myocarditis may occur con-
currently with myositis.29 32
•
Muscle weakness may be indicative of neurologic tox-
icities, such as Guillain-Barr´e syndrome, or, if coupled
with vision changes, myasthenia gravis. Myasthenia
gravis related to immunotherapy may be associated
with myositis and myocarditis.31,33,34
•
Weight loss and nausea may be due to disease pro-
gression, but may also indicate a hepatic toxicity or an
endocrine toxicity.
For
many
patients,
routine
laboratory
monitoring,
comparisons to baseline, and targeted questions by the
treating healthcare providers will help identify some
of the less common but serious irAEs. The primary
facets of irAE management include early recognition
and grading of toxicity, immunosuppression, and in-
dividualized modiﬁcation to ICI administration. See
the complete version of the NCCN Guidelines (avail-
able at NCCN.org) for management strategies for these
and other ICI-related irAEs updated for 2020.
2020 Updates to the NCCN Guidelines
The NCCN Guidelines for Management of Immunotherapy-
Related Toxicities provide guidance on the management
of irAEs resulting from cancer immunotherapy, spe-
ciﬁcally ICI and CAR T-cell therapies. During the
meeting to update the guidelines for 2020, the panel
discussed updates to the management of many irAEs.
These NCCN Guidelines Insights highlight recommen-
dations for the assessment and treatment of ICI-related
irAEs related to the gastrointestinal and cardiovascular
systems.
Gastrointestinal Adverse Events: Diarrhea/Colitis
The most common gastrointestinal irAE presents as di-
arrhea and/or symptoms of colitis, which include watery
234
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diarrhea, cramping, urgency, abdominal pain, blood or
mucus in the stool, fever, or nocturnal bowel move-
ments. Diarrhea and/or colitis are the second most
commonly reported AEs with ICIs, and symptoms typi-
cally develop within 6 to 8 weeks of starting treatment.35,36
These gastrointestinal irAEs have been reported more
frequently with anti–CTLA-4 monotherapy than with
PD-1/PD-L1 inhibitors. In studies of CTLA-4 blockade,
diarrhea has been reported in up to half of patients, with
incidence typically reported between 30% and 40%.14,37
The highest rates of ICI-mediated diarrhea/colitis have
been observed with the addition of a PD-1/PD-L1 in-
hibitor to CTLA-4 blockade.38–40
Detection, Initial Assessment, and Grading
of Diarrhea/Colitis
To facilitate early detection of diarrhea/colitis, patient
education is key. It is important to determine the
patient’s baseline bowel habits prior to initiation of
immunotherapy. Patients are encouraged to report
changes in their bowel habits to the treatment team in
order to facilitate early detection of colitis that may occur
before the next scheduled clinic visit (see IMMUNO-1,
page 232). Most cases present as diarrhea (increased
frequency of bowel movements), but as described earlier,
a variety of other colitis symptoms often occur. Severity
of the diarrhea (ie, increase in number bowel move-
ments per day compared with baseline) and the
presence and severity of other colitis symptoms de-
termine the grade of the gastrointestinal irAE (Table 1).
Hemodynamic instability and life-threatening com-
plications
(eg,
ischemic
bowel,
perforation,
toxic
mega-colon) may be associated with high-grade gas-
trointestinal irAEs. Table 1 shows grading for these ad-
verse events, based on elements from CTCAE version 5.0
(colitis, enterocolitis, diarrhea),41 Brahmer et al,42 and
additions from the NCCN Panel (see ICI GI-1 footnotes,
page 233).
Stool evaluation to rule out infectious etiology,
speciﬁcally Clostridium diﬃcile, ova, parasites, and
viral pathogens, is an important element of workup for
patients with suspected immunotherapy-related di-
arrhea and/or colitis. For patients presenting with
grade 1 diarrhea (increase of ,4 bowel movements per
day above baseline) and no symptoms of colitis, some
panel members defer stool testing until diarrhea has
persisted and not improved with conservative treatment
(loperamide or diphenoxylate for 2–3 days), or symptoms
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have progressed (frequency of bowel movements in-
creased and/or colitis symptoms developed). Blood or
mucus in the stools, fever, and/or other symptoms of
colitis (watery diarrhea, cramping, urgency, abdominal
pain, nocturnal bowel movements) should prompt a
thorough workup for infection, including stool evalua-
tion. Patients presenting with blood in the stool should
also be evaluated for other causes of gastrointestinal
bleeding, including peptic ulcer disease and malignant
bleeding, among others (eg, diverticulosis, angiodysplasia,
hemorrhoids, ischemia). Diarrhea/colitis associated with
immunotherapy can rapidly increase in severity, and
therefore therapy to manage these gastrointestinal irAEs
can be initiated while awaiting test results.
Measurement of fecal lactoferrin and calprotectin,
2 markers of inﬂammation, should also be considered
as part of initial workup, depending on institutional
availability. Calprotectin provides a quantitative measure
of inﬂammation; low levels indicate mild inﬂammation
or normal endoscopy and high levels correlate with
ulceration.43 Fecal lactoferrin is a noninvasive, qualitative
biomarker that can predict colitis risk.44,45
For patients who present with diarrhea/colitis grade
2 or higher (as deﬁned in Table 1), abdominal/pelvic CT
with contrast and gastrointestinal consultation for further
evaluation (ie, colonoscopy or ﬂexible sigmoidoscopy 6
esophagogastroduodenoscopy [EGD] with biopsy) should
be considered. Symptom-based grading (listed in
Table 1) may guide prompt initiation of therapy (eg,
steroids); however, imaging and biopsy results can
help establish the etiology of the problem and assess
the likelihood that more aggressive management ap-
proaches will be needed. Although retrospective case
reviews suggest that symptom grade may not correlate
with colitis severity as observed by endoscopy and
histology,46,47 results from a recent retrospective study
suggest that lactoferrin results may be used to inform
prioritization of endoscopy.43 This study found that
among
patients
with
immune-mediated
diarrhea/
colitis, lactoferrin levels were strongly correlated with
inﬂammation observed by endoscopy (70% sensitivity),
and even more strongly correlated with inﬂammation
detected by histologic evaluation of endoscopy biopsy
specimens (90% sensitivity).43 Histologic ﬁndings were
correlated with the need for intravenous steroids and/or
inﬂiximab/vedolizumab for irAE management.43 Early
endoscopy, deﬁned as #7 days after onset of immune-
mediated diarrhea/colitis compared with .7 days, was
associated with signiﬁcantly shorter duration of symp-
toms (47 vs 19 days; P
.026) and shorter steroid treat-
ment duration (49 vs 74 days; P
.053),43 presumably
because earlier endoscopy triggered earlier initiation of
management. Performing endoscopy #30 days from
onset of diarrhea/colitis (vs .30 days) was associated
with signiﬁcantly shorter duration of steroid treatment, a
trend toward shorter duration of symptoms, and a sig-
niﬁcant reduction in recurrence of symptoms (50% vs
21.8% of patients; P
.001). Better outcomes for patients
who undergo endoscopy within 30 days of onset may be
due to the earlier initiation of inﬂiximab/vedolizumab
(15 vs 31 days from onset; P
.030). Given the results of
this recent study,43 early endoscopy with biopsy within
the ﬁrst 2 weeks of the onset of symptoms is strongly
recommended for all patients with positive lactoferrin
results, even those who have only grade 1 symptoms (per
Table 1). Fever and tenderness upon abdominal exam-
ination may be an indication of bowel perforation
warranting immediate imaging and treatment.
Management of Mild (Grade 1) Events
For patients presenting with mild diarrhea (grade 1,
deﬁned as an increase of ,4 bowel movements per day)
with no other symptoms of colitis (Table 1), the NCCN
Guidelines recommend hydration, considering holding
immunotherapy, and monitoring the patient closely to
determine whether diarrhea is worsening or other
Table 1. Gradinga for Colitis/Diarrheab
Terms
Diarrhea: increase in frequency and/or loose or watery bowel
movements
Colitis: inﬂammation of the colon
Enterocolitis: inﬂammation of the small and large intestines
Grade 1
• Increase of ,4 bowel movements per day above baseline
• Mild increase in ostomy output compared with baseline
• No symptoms of colitis (watery diarrhea, cramping, urgency,
abdominal pain, blood and mucus in the stool, fever,
nocturnal bowel movements)
Grade 2
• Increase of 4–6 bowel movements per day above baseline
• Moderate increase in ostomy output compared with baseline
• Mild/moderate colitis symptoms: watery diarrhea, cramping,
urgency, abdominal pain, blood and mucus in the stool, fever,
nocturnal bowel movements
• Limiting instrumental ADLsd
Grade 3
• Increase of .6 bowel movements per day above baseline
• Severe increase in ostomy output compared with baseline
• Severe colitis symptoms: watery diarrhea, incontinence,
cramping, urgency, abdominal pain, blood and mucus in the
stool, fever, ileus, nocturnal bowel movements, peritoneal
signs
• Limiting self-care ADLse
• Hemodynamic instability
• Hospitalization indicated
Grade 4
• Same as grade 3, but with:
• Other serious/life-threatening complications (eg, ischemic
bowel, perforation, toxic mega-colon)
• Urgent intervention indicated
Abbreviation: ADLs, activities of daily living.
aFor all adverse events, grade 5 is deﬁned as death.
bDeﬁnitions incorporate elements from CTCAE version 5.0 (colitis,
enterocolitis, diarrhea),41 Brahmer et al, 2018,42 plus additions from the NCCN
Panel (ICI GI-1 footnotes, page 233).
dInstrumental ADLs refer to preparing meals, shopping for groceries or clothes,
managing money, etc.
eSelf-care ADLs include bathing, dressing and undressing, feeding self, using
the toilet, taking medications, and not bedridden.
236
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symptoms of colitis develop (see ICI GI-1, page 233).
Loperamide or diphenoxylate/atropine may be used,
although some panel members prefer to wait before
starting, out of concern about obscuring signs of
worsening diarrhea, which may delay initiation of
treatment (eg, steroids) that actually reverses underlying
immunotherapy-related inﬂammation, if present. If di-
arrhea persists or progresses, or no improvement is seen
after 2 to 3 days of loperamide or diphenoxylate/atropine,
tests for infections workup should be obtained and levels
of fecal lactoferrin should be checked if not already done.
Cases of grade 1 diarrhea (increase of ,4 bowel move-
ments per day) with no other symptoms of colitis, docu-
mented absence of infection, and a negative lactoferrin
result, may be managed conservatively (hydration and
loperamide or diphenoxylate/atropine), with the addition
of mesalamine or cholestyramine, if necessary. If lacto-
ferrin results are positive, however, endoscopy should be
strongly considered, if not already performed, even if the
only symptom is grade 1 diarrhea. Patients with a positive
lactoferrin
result
and
persistent/progressive
diarrhea
should be treated as those with moderate (grade 2)
diarrhea/colitis (see next section), because these cases are
likely to require more aggressive management, even if the
diarrhea has not yet reached the grade 2 threshold (in-
crease of $4 bowel movements per day above baseline)
and no other colitis symptoms have yet developed.
Tools for Management of Grade 2 or Higher Events
Corticosteroids are typically the ﬁrst line of treatment
of diarrhea/colitis of grade 2 or higher. In retrospective
reviews of patients with ICI-related diarrhea/colitis,
symptoms resolved with corticosteroid treatment in
approximately half of individuals.36,46,48 However, for
some cases, corticosteroids fail to control symptoms
and the diarrhea/colitis may persist or worsen and
become life-threatening in the absence of more ag-
gressive management.
Inﬂiximab is a monoclonal anti–tumor necrosis
factor alpha (TNF-a) antibody used for treating various
autoimmune diseases, including Crohn’s disease, ulcer-
ative colitis, rheumatoid and psoriatic arthritis, and
psoriasis.49–51 Inﬂiximab has become a commonly used
agent for treating steroid-refractory irAEs that develop
during ICI therapy.25,52 Case studies report on the success-
ful use of inﬂiximab for treating severe, steroid-refractory
colitis associated with ipilimumab.48,53,54 An FDA-approved
biosimilar is an appropriate substitute for inﬂiximab.
Vedolizumab is an integrin antagonist that binds to
a4b7 integrin, blocking its interaction with mucosal
addressin cell adhesion molecule-1 (MAdCAM-1),
inhibiting the migration of T cells across the endothe-
lium into inﬂamed gastrointestinal tissues. Vedolizu-
mab is currently indicated for treating gastrointestinal
inﬂammation due to ulcerative colitis and Crohn’s
disease.55,56 Case reports have described the use of
vedolizumab for the treatment of ICI-induced diarrhea/
colitis.56–58 Vedolizumab binds to gut homing lympho-
cytes and may provide more speciﬁc immune suppression
for the inﬂamed gastrointestinal mucosa, thereby the-
oretically avoiding suppression of antitumor immune
responses.
Introduction of either inﬂiximab or vedolizumab
within 10 days of onset of colitis can reduce the dura-
tion of symptoms and improve steroid taper success.59
Treatment with $3 doses of inﬂiximab or vedolizumab,
and achieving endoscopic or histologic remission are
associated with lower risk of colitis relapse. This is im-
portant because endoscopic remission is often a better
predictor of a cure than clinical remission, in which cases
repeat endoscopy may be helpful.
Case studies suggest that transplantation of fecal
microbiota from healthy donors may resolve cases of
diarrhea/colitis that are resistant to corticosteroids,
inﬂiximab, and vedolizumab.60
Management of Moderate (Grade 2) Diarrhea/Colitis
For moderate diarrhea/colitis (grade 2), deﬁned as an
increase of 4 to 6 bowel movements per day above
baseline and/or mild to moderate symptoms of colitis (as
detailed in Table 1), the NCCN Guidelines recommend
holding immunotherapy and administering prednisone/
methylprednisolone (1–2 mg/kg/d) (see ICI GI-1, page
233). If no improvement is noted within 2 to 3 days of
starting steroid treatment, the NCCN Guidelines re-
commend continuing steroids and considering adding
inﬂiximab (or FDA-approved biosimilar) or vedoli-
zumab, preferably within 2 weeks from onset of di-
arrhea. A tuberculosis test (blood test preferred) should
be obtained before administering the ﬁrst dose of inﬂix-
imab or vedolizumab, although treatment can be initi-
ated before results are received.
Management of Severe (Grade 3–4) Events
For severe diarrhea/colitis (grade 3–4), deﬁned as an
increase of .6 bowel movements per day above baseline
and/or severe symptoms of colitis (Table 1), inpatient
care should be considered if needed to provide adequate
supportive care (see ICI GI-2, page 234). Intravenous
methylprednisolone, 1 to 2 mg/kg/d, should be admin-
istered. After improvement in diarrhea/colitis is noted,
the steroid dose may be tapered, usually over 4 to 6 weeks
(see later discussion). For diarrhea/colitis related to ipili-
mumab, the NCCN panel recommends permanent dis-
continuation if serious or life-threatening diarrhea/colitis
occurs. For diarrhea/colitis associated with PD-1/PD-L1
inhibitors, therapy should be held for grade 3, with con-
sideration of rechallenge upon resolution of symptoms
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below grade 1. The immunotherapy agent(s) responsible
for immune-related grade 4 diarrhea/colitis should be
permanently discontinued.
If no improvement is noted within 2 to 3 days on
intravenous methylprednisolone (1–2 mg/kg/d), the
NCCN Guidelines recommend continuing steroids and
strongly considering adding inﬂiximab (or FDA-approved
biosimilar) or vedolizumab, preferably within 2 weeks of
onset, especially for patients with high-risk endoscopic
features.43 Fecal transplantation may be considered for
colitis refractory to immunosuppressant therapy, based
on institutional availability and expertise.60
Duration of Treatment of Immune-Related
Diarrhea/Colitis
For disease monitoring after receiving colitis treatment,
checking the levels of calprotectin provides a quantita-
tive measure of inﬂammation; low levels indicate mild
inﬂammation or normal endoscopy and high levels cor-
relate with ulceration.43 Repeat endoscopy to assess en-
doscopic healing may be helpful to guide colitis treatment
duration, but is optional. Endoscopy has revealed co-
lonic ulcerations more commonly in steroid-refractory
cases.36,46,48
Retrospective analysis of patients with refractory
diarrhea/colitis found higher infection rates among pa-
tients treated with long-duration steroids (.30 days).
Long-duration corticosteroid without inﬂiximab was
associated with increased infection risk compared
with short-duration steroid plus inﬂiximab, suggesting
that earlier nonsteroid immunosuppressive therapy
may confer better outcomes.47 If a systemic cortico-
steroid is given, treatment should be continued until
symptoms improve to grade 1 or better, then dose tapered
over 4 to 6 weeks. In cases in which inﬂiximab or vedo-
lizumab is used, a shorter taper may help minimize the
complication of infection, provided that the diarrhea/
colitis (or other concomitant irAEs) does not worsen
during the taper. Intravenous methylprednisolone should
be converted to oral prednisone when appropriate.
The duration of therapy with TNF-a blocker (inﬂix-
imab) or integrin blocker (vedolizumab) is not clearly
deﬁned. Evidence supports the use of up to 3 doses (at
weeks 0, 2, and 6) to reduce risk of recurrence and increase
likelihood of endoscopic/histologic remission.59
Cardiovascular Adverse Events
Eﬀorts to characterize cardiac irAEs associated with
ICI therapy have begun to provide a better under-
standing of ICI-associated myocarditis. Case series
reveal a variety of potential manifestations of car-
diovascular irAEs, including myocarditis, pericarditis,
arrhythmias, cardiomyopathy, cardiac ﬁbrosis, heart
failure, and cardiac arrest.61–65 Data collected over
4 years from 8 sites revealed 35 cases of ICI-mediated
myocarditis, which were compared with a sample of
patients on ICI therapy without myocarditis.62 Preva-
lence was 1.14% in this patient population, with a median
onset of 34 days from initiation of treatment. However,
recent evidence suggests that ICI-associated cardiovas-
cular toxicity, myocarditis in particular, is more common
than initially thought.33,34,62,66
Myocarditis symptoms are nonspeciﬁc, such as my-
algia, shortness of breath, and chest pain, which could also
be attributed to pneumonitis or other irAEs.29 It is rare, but
potentially severe, associated with myositis/myasthenia
gravis, and is more common with anti–CTLA-4/anti–
PD-(L)1 combination therapy. A recent report analyzed
a total of 40 case reports describing cardiac irAEs and
found that even with rapid assessment and initiation of
immunosuppression, mortality was still high at 23%.67 In
fatal cases, conduction abnormalities were the mode of
death and ejection fraction was preserved.
Cardiac irAEs have been associated with ipilimumab,
pembrolizumab, and nivolumab. Based on multicenter
registry data, myocarditis was observed more often in
patients receiving combination ICI therapy and in
those with diabetes.62 Recent analysis of the WHO
database revealed 101 individual case safety reports of
severe myocarditis following initiation of ICI therapy.34
Of these cases, 57% had received anti PD-1 mono-
therapy and 27% received combination PD-1/PD-L1
plus CTLA-4 inhibitor. For cases with available dosing
information (n
59), 64% (n
38) had received only 1 or
2 ICI doses at the time of toxicity onset. Concurrent
severe irAEs, most commonly myositis and myasthenia
gravis, were reported for 42% of cases. Data on cardio-
vascular comorbidities were not available, but only 25%
of patients with myocarditis were on medication to treat
cardiovascular disease or diabetes.34
Preexisting cardiovascular pathology was identiﬁed
in more than half of patients (5/8) in one case series.61
Co-occurrence with noncardiac irAEs was also observed
in .50% of patients. Corticosteroids and/or supportive
care measures were helpful to improve symptoms in
most cases, although permanent cardiotoxicity and
fatalities also occurred despite intervention.61 Myositis
and myocarditis were observed to co-occur in a recent
study of ICI-related fatalities. Notably, myasthenia gravis
also co-occurred in 10% of fatal myocarditis cases.33 Case
reports of ICI-related myocarditis have reported irAE ﬂare
during steroid taper or ICI rechallenge.68,69
Management
Baseline EKG and individualized assessment in consul-
tation with cardiology should be considered as indicated.
Periodic testing should be considered for patients with ab-
normal baseline or symptoms (see IMMUNO-1, page 232).
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Once a cardiac irAE is suspected, immediate cardiology
consultation and intensive care unit–level monitoring is
recommended (see ICI CARDIO-1, page 235). Assessment
should include telemetry monitoring and electrocardio-
gram. Recommended laboratory testing includes cardiac
biomarkers (creatine kinase and troponin levels) and in-
ﬂammatory biomarkers (erythrocyte sedimentation rate,
C-reactive protein level, and WBC count). To rule out
other potential causes, evaluation may include viral
titers, echocardiogram, or biopsy in the case of severe
symptoms. When feasible, cardiac MRI may provide
additional diagnostic information.70
Table 2 summarizes grading for cardiovascular ad-
verse events that may be associated with ICI therapy,
based on elements from CTCAE version 5.0 (myocarditis,
pericarditis, ventricular arrhythmia),41 Brahmer et al,42
and additions from the NCCN Panel (see ICI CARDIO-1
footnotes, page 235). In the setting of severe (grade 3)
cardiac irAE, arrhythmia may be accompanied by
signiﬁcant echocardiogram ﬁndings without hypoten-
sion, and cardiac biomarkers above the upper limit of
normal (ULN). Life-threatening (grade 4) cardiac irAEs
are denoted by arrhythmia, hemodynamic instability,
and cardiac biomarkers .3 times the ULN. Transient
pacemaker may be recommended in patients with
arrhythmia.67 Immunotherapy should be permanently
discontinued for any grade 3 or 4 cardiovascular irAEs.
The panel recommends methylprednisolone pulse
dosing (1 g/d for 3–5 days). In a multicenter registry
report, corticosteroids were administered in 89% of cases
with myocarditis, with high-dose steroids resulting in
better treatment response.62 Elevated troponin and higher
rates of major adverse cardiac events, which were deﬁned
as “the composite of cardiovascular death, cardiogenic
shock, cardiac arrest, and hemodynamically signiﬁcant
complete heart block,” were observed more commonly
among patients who were treated with lower-dose corti-
costeroid.62 The NCCN Panel recommends treating with
steroids until cardiac function returns to baseline, then
dose taper over 4 to 6 weeks.
Beyond treatment with high-dose steroids, there are
few data to suggest the optimal subsequent therapy should
steroids fail. Treatment options for both severe (grade 3) or
life-threatening cases (grade 4) are the same given the
rapid progression of cardiac irAE. If no improvement is
noted within 24 hours, the addition of other potent im-
munosuppressive agents should be considered, such as
antithymocyte globulin (ATG),62,67,71–73 inﬂiximab61,67,71,74
or an FDA-approved biosimilar, intravenous immuno-
globulin (IVIG),67,73,75 or mycophenolate.76
ATG is a polyclonal antibody derived from lym-
phoid cell immunized horses or rabbits, which reverses
immunotoxicity by inducing T-cell depletion. Data sup-
porting use of ATG to treat myocarditis and arrhythmia
are limited to a number of single case reports with fa-
vorable outcomes.62,67,71 Inﬂiximab has also been used
in cases studies to treat cardiotoxicities,61,67,71,74 but it is
important to note that it is contraindicated for patients
who have heart failure.29,77 IVIG is used to reduce the
levels of antibodies that may be causing damage. IVIG
was successfully used in a case report of smoldering
ICI-related myocarditis that initially responded to cor-
ticosteroids but ﬂared upon taper,68 and has been used for
years in the setting of cardiac rejection.73,75 Mycophenolate
mofetil is an antiproliferative agent that is used for cardiac
transplant patients.76
Two additional immunosuppressive agents may be
used based on case studies. A case report of a patient on
pembrolizumabwith conﬁrmed myositis–myasthenia gravis
overlap syndrome with worsening cardiac arrhythmia after
methylprednisolone, mycophenolate, plasmapheresis, and
rituximab described a successful outcome after treatment
with alemtuzumab,65 a monoclonal antibody that binds to
Table 2. Gradinga for Select Cardiovascular
Eventsb
Terms
Myocarditis: inﬂammation of the muscle tissue of the heart
Pericarditis: irritation to the layers of the pericardium (the
protective sac around the heart)
Other cardiovascular irAEs: arrhythmias, impaired ventricular
function, conduction abnormalities
Grade 1
• Asymptomatic
• Abnormal cardiac biomarkers (creatine kinase, troponin)
• Abnormal ECG or physical ﬁndings (eg, rub) consistent with
pericarditis
Grade 2
• Mild symptoms or symptoms with moderate activity or
exertion: may include chest pain, myalgia, dyspnea,
arrhythmia, palpitations, peripheral edema, pleural effusion,
fatigue
• Abnormal screening tests: cardiac biomarkers (creatine
kinase, troponin), ECG
• For arrhythmia: expedited cardiology evaluation indicated
Grade 3
• Symptoms at rest or with minimal activity or exertion, or new
onset of symptoms: may include chest pain, myalgia,
dyspnea, arrhythmia, palpitations, peripheral edema, pleural
effusion, fatigue
• Pericarditis with physiologic consequences (eg, pericardial
constriction)
• Cardiac biomarkers (creatine kinase and troponin) .ULN
• Signiﬁcant echocardiogram ﬁndings without hypotension
Grade 4
• Moderate to severe decompensation (worsening signs and
symptoms): may include congestive heart failure, chest pain,
myalgia, dyspnea on exertion, arrhythmia, palpitations,
peripheral edema, pleural effusion, fatigue
• Hemodynamic instability (hypotension/cardiomyopathy)
• Cardiac biomarkers (creatine kinase and troponin) .33 ULN
• Life-threatening
• Urgent intervention indicated (eg, continuous intravenous
therapy or mechanical hemodynamic support for
myocarditis)
Abbreviations: ECG, electrocardiogram; irAEs, immune-related adverse
events; ULN, upper limit of normal.
aFor all adverse events, grade 5 is deﬁned as death.
bCardiovascular events that can be associated with cancer immunotherapy.
Deﬁnitions incorporate elements from CTCAE version 5.0 (myocarditis,
pericarditis, ventricular arrhythmia),41 Brahmer et al,42 and additions from the
NCCN Panel (see ICI CARDIO-1 footnotes, page 235).
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CD52 on some immune cells and leads to destruction of
peripheral immune cells. Similarly, one case reported
success using abatacept78 (a CTLA-4 agonist that aﬀects
T cells and may lead to rapid inactivation of the normal
immune response) in a patient receiving nivolumab
who developed glucocorticoid-refractory myocarditis
with concurrent myositis, who had also been treated
with plasmapheresis.
Conclusions
Proper management of ICI-related toxicities requires
early identiﬁcation of potential irAEs in order to
administer adequate treatment. Recent case studies
and clinical experience have changed irAE manage-
ment strategies, which have been incorporated in the
2020 update of NCCN Guidelines for Management
of Immunotherapy-Related Toxicities. These NCCN
Guidelines Insights provide context for topics that
were discussed by the panel during the 2020 update
meeting.
To participate in this journal CE activity, go to
https://education.nccn.org/node/86963
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diarrhea and colitis in patients with advanced malignancies: retrospective
review at MD Anderson. J Immunother Cancer 2018;6:37.
48.
Jain A, Lipson EJ, Sharfman WH, et al. Colonic ulcerations may predict
steroid-refractory course in patients with ipilimumab-mediated entero-
colitis. World J Gastroenterol 2017;23:2023–2028.
49.
Sﬁkakis PP. The ﬁrst decade of biologic TNF antagonists in clinical
practice: lessons learned, unresolved issues and future directions. Curr Dir
Autoimmun 2010;11:180–210.
50.
Reimold AM. TNFalpha as therapeutic target: new drugs, more appli-
cations. Curr Drug Targets Inﬂamm Allergy 2002;1:377–392.
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Wolfe RM, Ang DC. Biologic therapies for autoimmune and connective
tissue diseases. Immunol Allergy Clin North Am 2017;37:283–299.
52.
Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-
related adverse effects of immune checkpoint inhibitors: a review. JAMA
Oncol 2016;2:1346–1353.
53.
Pag `es C, Gornet JM, Monsel G, et al. Ipilimumab-induced acute severe
colitis treated by inﬂiximab. Melanoma Res 2013;23:227–230.
54.
Merrill SP, Reynolds P, Kalra A, et al. Early administration of inﬂiximab for
severe ipilimumab-related diarrhea in a critically ill patient. Ann Phar-
macother 2014;48:806–810.
55.
Entyvio (vedolizumab) for injection, for intravenous use [prescribing in-
formation]. Deerﬁeld, IL: Takeda Pharmaceuticals America, Inc; 2019.
Available at: https://www.accessdata.fda.gov/drugsatfda docs/label/
2019/125476s024lbl.pdf. Accessed May 2019.
56.
Bergqvist V, Hertervig E, Gedeon P, et al. Vedolizumab treatment for
immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol
Immunother 2017;66:581–592.
57.
Diana P, Mankongpaisarnrung C, Atkins MB, et al. Emerging role of
vedolizumab in managing refractory immune checkpoint inhibitor-
induced enteritis. ACG Case Rep J 2018;5:e17.
58.
Hsieh AH, Ferman M, Brown MP, Andrews JM. Vedolizumab: a novel
treatment of ipilimumab-induced colitis. BMJ Case Rep 2016;2016:
bcr2016216641.
59.
Abu-Sbeih H, Ali FS, Wang X, et al. Early introduction of selective im-
munosuppressive therapy associated with favorable clinical outcomes in
patients with immune checkpoint inhibitor-induced colitis. J Immunother
Cancer 2019;7:93.
60.
Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota trans-
plantation for refractory immune checkpoint inhibitor-associated colitis
[errata appears in Nat Med 2019;25:188]. Nat Med 2018;24:1804–1808.
61.
Heinzerling L, Ott PA, Hodi FS, et al. Cardiotoxicity associated with CTLA4
and PD1 blocking immunotherapy. J Immunother Cancer 2016;4:50.
62.
Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated
with immune checkpoint inhibitors. J Am Coll Cardiol 2018;71:1755–1764.
63.
Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with
combination immune checkpoint blockade. N Engl J Med 2016;375:
1749–1755.
64.
Yun S, Vincelette ND, Mansour I, et al. Late onset ipilimumab-induced
pericarditis and pericardial effusion: a rare but life threatening compli-
cation. Case Rep Oncol Med 2015;2015:794842.
65.
Esfahani K, Buhlaiga N, Th´ebault P, et al. Alemtuzumab for immune-related
myocarditis due to PD-1 therapy. N Engl J Med 2019;380:2375–2376.
66.
Varricchi G, Marone G, Mercurio V, et al. Immune checkpoint inhibitors and
cardiac toxicity: an emerging issue. Curr Med Chem 2018;25:1327–1339.
67.
Agrawal N, Khunger A, Vachhani P, et al. Cardiac toxicity associated with
immune checkpoint inhibitors: case series and review of the literature.
Case Rep Oncol 2019;12:260–276.
68.
Norwood TG, Westbrook BC, Johnson DB, et al. Smoldering myocarditis
following immune checkpoint blockade. J Immunother Cancer 2017;5:91.
69.
Tajmir-Riahi A, Bergmann T, Schmid M, et al. Life-threatening autoim-
mune cardiomyopathy reproducibly induced in a patient by checkpoint
inhibitor therapy. J Immunother 2018;41:35–38.
70.
Aquaro GD, Perfetti M, Camastra G, et al. Cardiac MR with late gadoli-
nium enhancement in acute myocarditis with preserved systolic function:
ITAMY study. J Am Coll Cardiol 2017;70:1977–1987.
71.
Tay RY, Blackley E, McLean C, et al. Successful use of equine anti-
thymocyte globulin (ATGAM) for fulminant myocarditis secondary to
nivolumab therapy. Br J Cancer 2017;117:921–924.
72.
Jain V, Bahia J, Mohebtash M, et al. Cardiovascular complications as-
sociated with novel cancer immunotherapies. Curr Treat Options
Cardiovasc Med 2017;19:36.
73.
Kobashigawa J, Crespo-Leiro MG, Ensminger SM, et al. Report from a
consensus conference on antibody-mediated rejection in heart trans-
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Frigeri M, Meyer P, BanﬁC, et al. Immune checkpoint inhibitor-associated
myocarditis: a new challenge for cardiologists. Can J Cardiol 2018;34:
92.e1–92.e3.
75.
Rodriguez ER, Skojec DV, Tan CD, et al. Antibody-mediated rejection in
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ment activation products C4d and C3d as markers. Am J Transplant 2005;
5:2778–2785.
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Kobashigawa JA, Miller LW, Russell SD, et al. Tacrolimus with myco-
phenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac
transplant patients: 1-year report. Am J Transplant 2006;6:1377–1386.
77.
Kwon HJ, Cot ´e TR, Cuffe MS, et al. Case reports of heart failure after
therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003;
138:807–811.
78.
Salem JE, Allenbach Y, Vozy A, et al. Abatacept for severe immune
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2377–2379.
JNCCN.org | Volume 18
Issue 3 | March 2020
241
NCCN GUIDELINES® INSIGHTS
CE
Management of Immunotherapy-Related
Toxicities, Version 1.2020


Signature Page for VV-CLIN-001702 v1.0
Prot_XmAb18087-02_v1.0_18Aug2020_CLEAN
Approval
20-Aug-2020 23:36:07 GMT+0000


Signature Page for VV-CLIN-001702 v1.0
Prot_XmAb18087-02_v1.0_18Aug2020_CLEAN
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20-Aug-2020 23:36:07 GMT+0000

SAP_001.pdf: 
Xencor, Inc. 
XmAb18087-02 
Statistical Analysis Plan
CONFIDENTIAL 
1 
STATISTICAL ANALYSIS PLAN 
DATE 
29 AUGUST 2022 
VERSION 
1.0 
PROTOCOL TITLE: 
A Phase 1b/2 Multiple-Dose Study to Evaluate the Safety and Efficacy of XmAb®18087 ± 
Pembrolizumab in Subjects with Advanced Merkel Cell Carcinoma or Extensive-stage Small 
Cell Lung Cancer (DUET-1-02) 
NCT #: NCT04590781


Xencor, Inc. 
XmAb18087-02 
Statistical Analysis Plan 
CONFIDENTIAL 
2 
 
 
8/29/2022 | 
Signature 
Date 
8/29/2022 | 
Signature 
Date 
 
SIGNATURE PAGE 
 
This document has been authored by: 
 
 
 
 
 
 
 
 
 
 
Xencor, Inc. 
12:10:50  PM 
 
 
 
 
This document has been reviewed and approved by: 
 
 
 
 
 
 
 
 
6:44:23 PM P 
 
 
 
Xencor, Inc. 
 
 
 
 
 
 
 
 
12:36:46 PM P 
 
 
 
Xencor, Inc. 
8/29/2022 | 
Signature 
Date 


 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS .......................................................................................5 
2. 
INTRODUCTION ........................................................................................................6 
3. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ..........................................................7 
3.1. 
Primary Objectives .......................................................................................................7 
3.2. 
Secondary Objectives ...................................................................................................7 
3.3. 
Study Endpoints ............................................................................................................7 
4. 
STUDY DESIGN AND SCHEDULE OF ASSESSMENTS .......................................9 
4.1. 
Study Design .................................................................................................................9 
4.2. 
Schedule of Assessments ............................................................................................11 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................12 
5.1. 
Changes in Planned Analyses from the Protocol ........................................................12 
5.2. 
Derived and Transformed Data...................................................................................12 
5.2.1. 
Study Day ...................................................................................................................12 
5.2.2. 
Missing Data ...............................................................................................................12 
5.2.2.1. 
Partial/Missing Dates ..................................................................................................12 
6. 
STATISTICAL CONSIDERATIONS .......................................................................13 
6.1. 
Determination of Sample Size ....................................................................................13 
6.2. 
Interim Analyses .........................................................................................................13 
6.3. 
Final Analyses ............................................................................................................13 
7. 
ANALYSIS POPULATIONS ....................................................................................14 
8. 
DISPOSITION, DEMOGRAPHICS, BASELINE CHARACTERISTICS 
AND MEDICAL HISTORY ......................................................................................15 
8.1. 
Disposition of Subjects ...............................................................................................15 
8.2. 
Protocol Deviations ....................................................................................................15 
8.3. 
Demographics and Baseline Characteristics ...............................................................15 
8.4. 
Medical History ..........................................................................................................15 
9. 
TREATMENTS AND MEDICATIONS ....................................................................16 


 
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9.1. 
Prior and Concomitant Medications ...........................................................................16 
9.2. 
Extent of Exposure to Investigational Drug ...............................................................16 
9.3. 
Investigational Drug Compliance and Dose Intensity ................................................16 
10. 
EFFICACY ANALYSES ...........................................................................................17 
11. 
SAFETY ANALYSES ...............................................................................................19 
11.1. 
Adverse Events ...........................................................................................................19 
11.2. 
Deaths .........................................................................................................................19 
11.3. 
Clinical Laboratory Evaluations .................................................................................19 
11.4. 
Physical Examination and Eastern Cooperative Oncology Group  
Performance Status .....................................................................................................19 
11.5. 
Vital Signs ..................................................................................................................19 
11.6. 
Electrocardiograms .....................................................................................................19 
12. 
REFERENCES ...........................................................................................................20 
 
 
 
 
 
 


 
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1. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
BMI 
body mass index 
Cmax  
maximum observed serum concentration 
Cmin[trough]  
trough concentration 
CR 
complete response 
CRS 
cytokine release syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ICH 
International Conference on Harmonisation 
IV 
intravenous 
MCC 
Merkel cell carcinoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
US National Cancer Institute 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD1 
programmed cell death 1 
PDL1 
programmed cell death ligand 1 
PFS 
progression-free survival 
PK/PD 
Pharmacokinetics/Pharmacodynamics 
PR 
partial response 
RD 
recommended dose 
RECIST 
Response Evaluation Criteria In Solid Tumors  
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
SRC 
Safety Review Committee 
TEAE 
treatment-emergent AE 


 
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2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the methods to be used for analysis and reporting of 
clinical data collected throughout the study. It is intended to supplement the study protocol 
(Version 1.0, 18 August 2020), which contains details regarding the design and conduct of the 
study. This plan should be read in conjunction with the study protocol and the electronic case 
report forms (eCRFs).  
The study has been terminated early by the sponsor. Only 4 subjects have been enrolled in the 
study. No efficacy or pharmacokinetic-pharmacodynamic (PK-PD) analyses will be performed. 
Due to the small sample size, only demographics, baseline characteristics, safety, and efficacy 
listings will be generated. 
 


 
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3. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
3.1. 
Primary Objectives 
1. To determine the safety and efficacy (by overall response rate [ORR], complete response 
[CR], and partial response [PR] per Response Evaluation Criteria in Solid Tumors 
[RECIST] 1.1 criteria) of XmAb18087 monotherapy in subjects with advanced Merkel 
cell carcinoma (MCC) that has progressed after treatment with standard therapies 
2. To determine the safety and efficacy (by ORR, CR, and PR per RECIST 1.1 criteria) of 
XmAb18087 in combination with pembrolizumab in subjects with advanced MCC who 
have not received prior anti-programmed cell death 1 (PD1) or anti-programmed cell 
death ligand 1 (PDL1) therapies, and for whom pembrolizumab as a single agent is 
indicated 
3. To determine the safety and efficacy (by ORR, CR, and PR per RECIST 1.1 criteria) of 
XmAb18087 monotherapy in subjects with extensive-stage small cell lung cancer 
(SCLC) that has progressed after treatment with standard therapies 
3.2. 
Secondary Objectives 
1. To assess antitumor activity of XmAb18087 by progression-free survival (PFS) per 
RECIST 1.1 criteria, as well as overall survival (OS) and duration of response, when 
administered with and without pembrolizumab in subjects with advanced MCC, and as 
monotherapy in subjects with extensive-stage SCLC 
2. To characterize the PK and immunogenicity of XmAb18087 administered with and without 
pembrolizumab in subjects with advanced MCC, and as monotherapy in subjects with 
extensive-stage SCLC 
3. To assess the PK profile (Cmax and Cmin[trough]) of pembrolizumab when co-administered 
with XmAb18087 
3.3. 
Study Endpoints  
Safety: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of clinically significant changes in safety laboratory tests, physical 
examination findings, vital signs, and electrocardiograms (ECGs) 
• Incidence and severity of cytokine release syndrome (CRS) 


 
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Efficacy: 
• ORR 
• CR and PR rate 
• Duration of response 
• PFS 
• OS 


 
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4. 
STUDY DESIGN AND SCHEDULE OF ASSESSMENTS 
4.1. 
Study Design 
This is a Phase 1b/2, multiple-dose study of XmAb18087, both as a monotherapy and in 
combination with pembrolizumab in MCC subjects, and as monotherapy only in SCLC subjects. 
The study is designed in 3 parts, Part A, Part B, and Part C, shown in the figure below. 
Figure 1: 
Study Design 
 
MCC = Merkel cell carcinoma; PD1 = programmed cell death protein 1; PDL1 = programmed cell death ligand 1; 
SCLC = small cell lung cancer. 
 
Part A is designed to describe safety and efficacy, and to assess PK and immunogenicity of 
XmAb18087 monotherapy in subjects with advanced MCC. All eligible subjects will have 
relapsed or refractory disease that has previously been treated with all standard therapies for which 
they are eligible. 
Part A will enroll safety run-in cohorts to confirm the safety and tolerability of XmAb18087 
monotherapy administered intravenously (IV) with weekly step-up dosing for 42-day cycles. 
Additional subjects will then be enrolled into an expansion cohort and will receive XmAb18087 
monotherapy using the recommended dose (RD) identified following the safety run-in cohorts.  
Part B is designed to describe safety and efficacy, and to assess PK and immunogenicity of 
XmAb18087 in combination with pembrolizumab in subjects with advanced MCC. All eligible 
subjects may be treatment naïve or have relapsed or refractory disease after prior treatment; 


 
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however, subjects who have received prior treatment with anti-PD1 or anti-PDL1 therapeutics will 
not be eligible to participate in Part B. 
Part B will enroll additional safety run-in cohorts to confirm the safety and tolerability of 
XmAb18087 in combination with pembrolizumab. Subjects will receive step-up IV dosing of 
XmAb18087 (except for Cohort 1B, in which subjects will receive the same dose level on each 
dosing day) on Days 1, 8, 22, 29, and 36, and IV dosing of pembrolizumab on Day 15 of each 
42-day cycle. Additional subjects will be enrolled into an expansion cohort and will receive 
XmAb18087 plus pembrolizumab combination therapy using the RD identified following the 
safety run-in. 
Enrollment into Part B safety run-in cohorts (starting with Cohort 1B) may begin after the first 
safety run-in cohort in Part A (Cohort 1A, one dose level higher than Cohort 1B) has completed 
the first cycle and the regimen has been demonstrated to be tolerable.  
Part C is designed to describe safety and efficacy, and to assess PK and immunogenicity of 
XmAb18087 monotherapy in subjects with extensive-stage SCLC. All eligible subjects will have 
relapsed or refractory disease that has previously been treated with all standard therapies for which 
they are eligible. 
Part C of the study will enroll additional safety run-in cohorts to confirm the safety and tolerability 
of XmAb18087 monotherapy in this indication. The safety run-in will follow the same cohort 
schema as described for Part A to identify a RD for expansion in SCLC. Additional subjects will 
be enrolled into an expansion cohort and will receive XmAb18087 monotherapy using the RD 
identified following the safety run-in. 
Enrollment into Part C may begin concurrently with Part A. 
Part A, Part B, and Part C: The decision to advance to higher dose levels after each safety run-in 
cohort will be made by a Safety Review Committee (SRC) based on review of the aggregate safety 
data for all subjects in that cohort as well as cumulative safety data for the study overall. The SRC 
will be allowed to make adaptations to the dosing schema, if needed, in accordance with evolving 
trial safety and tolerability findings, as long as adaptations do not significantly increase subject 
risk. Any such adaptations would require a protocol amendment and Institutional Review Board 
(IRB) approval.  
In each safety run-in cohort, no more than 1 subject will receive the first infusion of XmAb18087 
on any given day. 
Subjects may be admitted and monitored on Day -1 (hospitalization is optional), and will be 
admitted on study days 1, 2, and 3 for their first dose of XmAb18087 and for at least 48 hours 
following the second dose. In addition, any subject who has shown symptoms of cytokine release 
syndrome (CRS) during inpatient admission will continue to be monitored as an inpatient for at 
least 24 hours after the symptoms have subsided. 


 
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4.2. 
Schedule of Assessments 
See study protocol Section 7.9 Study Assessments.  


 
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5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
All data analysis output will be generated using SAS version 9.4 or later.  
5.1. 
Changes in Planned Analyses from the Protocol  
The study has been terminated early by the sponsor. Only 4 subjects (2 in Part A and 2 in Part C) 
have been enrolled in the study. No efficacy or PK-PD analyses will be performed. Due to the 
small sample size, only listings for demographics, baseline characteristics, safety, and efficacy 
assessments will be generated. 
5.2. 
Derived and Transformed Data 
5.2.1. 
Study Day 
If the date of assessment occurs on or after the first dose date, then study day will be calculated 
as (date of assessment – date of first dose) + 1. If the date of assessment occurs prior to the first 
dose date, then study day will be calculated as (date of assessment – date of first dose). There is 
no study day 0. 
5.2.2. 
Missing Data 
Unless otherwise specified, missing data will be treated as missing, ie, no special handling/ 
missing data imputation will be performed.  
5.2.2.1. 
Partial/Missing Dates 
For partial dates, the algorithms for imputation will vary depending upon the parameter; missing 
or incomplete medications start and stop dates will be imputed to determine whether the 
medications are taken concomitantly. Eg, missing adverse event (AE) start dates will be imputed 
to determine whether the adverse events are treatment emergent. In listings, all dates will be 
listed as recorded. The details of imputation rules can be found in Appendix 11. 


 
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6. 
STATISTICAL CONSIDERATIONS 
6.1. 
Determination of Sample Size 
This study was planned in 3 parts: MCC monotherapy (Part A), MCC combination therapy (Part 
B), and SCLC monotherapy (Part C). No formal power analyses were performed for efficacy 
endpoints for the initial dose escalation cohorts. After identification of each RD, Part A, Part B, 
and Part C will enroll expansion cohorts using a 2-stage design.  
In Part A, up to 9 subjects will be enrolled at the RD. If at least 1 subject shows a response by 
RECIST 1.1 criteria, then enrollment will continue up to a total of 22 subjects. A true response 
rate of 40% has statistical power of 84% to rule out a lower inactivity rate of 16% with a 
one-sided Type I error rate of 5%.  
In Part B, up to 12 subjects will be enrolled at the RD. If at least 4 subjects show a response by 
RECIST 1.1 criteria, enrollment will continue up to a total of 30 subjects. A true response rate of 
67% has statistical power of 84% to rule out a lower inactivity rate of 43% with a one-sided 
Type I error rate of 5%.  
In Part C, up to 9 subjects will be enrolled at the RD. If at least 1 subject shows a response by 
RECIST 1.1 criteria, then enrollment will continue up to a total of 30 subjects.  
Subjects who are not evaluable may be replaced. Up to 142 subjects will be enrolled. The total 
number of subjects enrolled will depend upon the number of safety run-in cohorts required to 
identify the RD for each Part. A true response rate of 30% has statistical power of 82% to rule 
out a lower inactivity rate of 11% with a one-sided Type I error rate of 5%. 
Due to the early termination of this study, only 4 subjects have been enrolled. 
6.2. 
Interim Analyses 
No formal interim analysis is planned.  
6.3. 
Final Analyses 
Final analysis will occur after all subjects have had their 28 days post-end of treatment visit. 
 


 
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7. 
ANALYSIS POPULATIONS 
The populations defined below will be used for analysis: 
• 
Safety population: All subjects who are enrolled and receive at least 1 infusion of 
XmAb18087.  
• 
Evaluable population: All subjects who are enrolled, receive at least 1 cycle (Parts A 
and C: 6 doses XmAb18087, Part B: 5 doses XmAb18087 and 1 dose 
pembrolizumab) of XmAb18087 and have at least 1 postbaseline RECIST 1.1 
assessment of tumor imaging available. 
• 
PD population: All subjects who are enrolled, receive at least 1 dose of XmAb18087 
(and 1 infusion of pembrolizumab, when relevant for a particular PD assessment), and 
have at least 1 preinfusion and 1 postinfusion set of biomarker data available for 
analysis.  
• 
PK populations: All subjects who are enrolled and receive at least 1 dose of 
XmAb18087 (ie, the XmAb18087 PK population) or 1 infusion of pembrolizumab 
(ie, the pembrolizumab PK population), and have at least 1 set of postinfusion PK 
data available for analysis. 


 
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8. 
DISPOSITION, DEMOGRAPHICS, BASELINE 
CHARACTERISTICS AND MEDICAL HISTORY 
8.1. 
Disposition of Subjects 
A listing will be provided including the analysis population, first and last dose date, and the dates 
of and the primary reasons for the end of study treatment and end of study.  
8.2. 
Protocol Deviations 
Protocol deviations will be documented by the clinical research associates and project manager 
on an ongoing basis throughout the study. Protocol deviations will be collected separately from 
(ie, external to) the eCRF database, and will be listed and discussed in the clinical study report. 
8.3. 
Demographics and Baseline Characteristics 
The baseline and demographic characteristics will be listed for each subject. It will include age, 
sex, race, ethnicity, reproductive history, height, weight, and BMI.  
8.4. 
Medical History 
General medical history will be listed including system organ class, preferred term, and start and 
end dates. Medical history will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version 24.0 or higher.  
Initial diagnosis and prior disease-specific therapies will be listed separately.  


 
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9. 
TREATMENTS AND MEDICATIONS 
9.1. 
Prior and Concomitant Medications 
Prior medications are defined as medications that stopped before the date and time of the first 
dose; concomitant medications are defined as medications that are ongoing at the first dose or 
start after the first dose.  
9.2. 
Extent of Exposure to Investigational Drug 
Extent of exposure is defined as the total number of days a subject is exposed to investigational 
drug. Specifically, the duration will be calculated as (Date of Last Dose – Date of First Dose + 
1).  
9.3. 
Investigational Drug Compliance and Dose Intensity 
Investigational drug compliance will be calculated for each subject by taking into account 
whether a subject takes all doses of investigational drug as prescribed. The overall 
investigational drug compliance rate will be calculated as (the total number of doses 
administered / the total number of doses planned) ×100. The total number of doses planned is the 
total number of scheduled doses until the subject’s last dose. 
Relative dose intensity will be calculated as (the cumulative amount of study drug administered / 
the cumulative planned amount of study drug).  
 


 
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10. 
EFFICACY ANALYSES 
Efficacy analyses will be based on the RECIST 1.1 tumor assessment. Due to the small sample 
size, only listings will be generated. 
Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment. 
Duration of Response 
The duration of response will be calculated from the time of initial response (PR or better) to the 
first documentation of relapse (recurrence after CR) or progression (after PR) or death. Patients 
who terminated the study without documented disease progression will be censored at the last 
radiological assessment date.  
Time to Initial Response 
Time to initial response is defined as time from first dose to initial response (PR or better).  
Time to Best Overall Response 
Time to best overall response is defined as time from first dose to best overall response. If there 
are multiple best overall responses, the earliest one will be taken.  
Progression-Free Survival (PFS) 
PFS is defined as the time from the date of first dose of study treatment until the date of 
progressive disease or death, whichever is earlier. Subjects who end the study without 
documented progression will be censored.  
 
 


 
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Table 1: 
PFS Censoring Rules 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments 
First Dosing visit (Cycle 1 Day 1) 
Censored 
Documented progression  
Earliest of: 
Date of radiological assessment showing 
new lesion(s) (if progression is based on 
new lesions);  
or 
Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of target lesions); 
or 
Date of last radiological assessment of 
nontarget lesions (if unequivocal 
progression occurs based on nontarget 
lesions) 
Progressed 
No progression 
Date of last radiological assessment  
Censored 
Treatment discontinuation for 
undocumented progression 
Date of last radiological assessment 
Censored 
Treatment discontinuation for toxicity 
or other reason 
Date of last radiological assessment  
Censored 
New anticancer treatment started 
Date of last radiological assessment  
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessment 
visits 
Date of death 
Progressed 
Death or progression after missing 
more than one tumor assessment visit 
Date of death or progression 
Progressed 
PD = progressive disease; PFS = progression-free survival. 
 
 
Overall Survival (OS) 
OS is defined as time from first dose till death from any reason. Subjects who terminate the study 
without documented death will be censored on the date of the last visit/contact.  


 
Xencor, Inc. 
XmAb18087-02 
Statistical Analysis Plan  
CONFIDENTIAL 
 
 
19 
 
 
  
 
11. 
SAFETY ANALYSES 
11.1. 
Adverse Events 
AEs and serious AEs will be graded according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE v5.0) (except CRS, which is graded 
using the American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus 
Grading) and be described using the MedDRA by system organ class, preferred term, severity, 
and relationship to XmAb18087. 
Treatment-emergent AEs (TEAEs) will be marked. TEAEs are defined as events with onset dates 
on or after the start of study treatment or events that are present before the first infusion of 
XmAb18087 and subsequently worsen in severity.  
11.2. 
Deaths 
Listings will be provided to document all deaths on study, including those reported on End of 
Study and Long-Term Follow-Up/Survival Status eCRFs.  
11.3. 
Clinical Laboratory Evaluations 
Hematology, chemistry, coagulation, viral serology, and urinalysis laboratory values at each 
scheduled time point will be listed. Laboratory results outside predefined normal ranges and 
reported as clinically significant by investigators will be flagged in the data listings. 
11.4. 
Physical Examination and Eastern Cooperative Oncology Group  
Performance Status 
Physical examination results and Eastern Cooperative Oncology Group (ECOG) performance 
status results will be presented in separate data listings. 
11.5. 
Vital Signs 
Observed vital signs measurements at each scheduled time point will be listed for heart rate 
(beats/minute), respiratory rate (breaths/minute), systolic/diastolic blood pressure (mmHg), 
temperature (°C), and weight (kg).  
11.6. 
Electrocardiograms 
The ECG measurements at each study day will be listed for heart rate (bpm), PR interval (ms), 
QRS interval (ms), RR interval (ms), QT interval (ms), QTcF interval (ms), etc.  
ECG interpretations will be reported as normal, abnormal not clinically significant, or abnormal 
clinically significant.  


 
Xencor, Inc. 
XmAb18087-02 
Statistical Analysis Plan  
CONFIDENTIAL 
 
 
20 
 
 
  
 
12. 
REFERENCES 
1. 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):228-247. 
2. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline. Statistical 
principles for clinical trials (E9); 1998 Feb 5. 
3. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline. Structure and 
content of clinical study reports (E3); 1995 Nov 30. 
4. National Cancer Institute. Common terminology criteria for adverse events v5.0. NCI, 
NIH, DHHS; 2017 November 27. 
5. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982; 5(6):649-55. 
 


 
Xencor, Inc. 
XmAb18087-01 
Statistical Analysis Plan  
CONFIDENTIAL 
 
 
21 
 
 
  
 
APPENDIX 1. IMPUTATION OF PARTIAL AND MISSING DATES 
Adverse Event  
All AE start dates must be entered on the eCRF as complete dates. In the rare case that all or part 
of an AE start date is missing, but an AE end date is present and after the first dose date, then the 
AE start date will be imputed as follows for the purpose of determining treatment emergent flag 
only: 
Year of onset 
Month of 
onset 
Day of onset 
Onset date to be imputed as 
Missing 
Missing 
Missing 
Set date to first dose date 
year = year of first dose 
Missing 
Missing/Non-
missing 
Set month and day to those of 
first dose 
year ≠ year of first dose 
Missing 
Missing/Non-
missing 
Set month and day to January 1 
year = year of first dose 
Non-missing Missing 
Set day to the day of first dose  
year ≠ year of first dose 
Non-missing Missing 
Set day to first day of onset 
month 
If AE resolution date is present and prior to first dose date, then there is no need to impute 
incomplete AE start date, as the AE is not treatment emergent, and the event should be in the 
medical history.  
 
Concomitant Medications 
• If year and month are present and day is missing, then set day to first day of the 
month for start date and set day to last day of the month for end date. 
• If year and day are present and month is missing, then set month to January for start 
date and set month to December for end date. 
• If year is present and month and day are missing, then set month and day to January 
1st for start date and set month and day to December 31st for end date. 
• Completely missing dates will not be imputed. 


 
Xencor, Inc. 
XmAb18087-01 
Statistical Analysis Plan  
CONFIDENTIAL 
 
 
22 
 
 
  
 
• If start date is completely missing and end date is on or after the first dose, then the 
medication will be classified as concomitant; if the end date is missing, then the 
medication will be classified as ongoing. Medications for which the start and end 
dates are completely missing will be classified as concomitant. 
 


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