Phase II Trial of XmAb20717 in Patients With Advanced Biliary Tract Cancers
Phase: PHASE2
Conditions: Biliary Tract Cancer
Sponsor: Abramson Cancer Center at Penn Medicine

Protocol Title:  Phase II trial of XmAb20717 in patients with advanced biliary tract cancers
ClinicalTrials.gov Identifier:  NCT05297903
Document Date:  October 24, 2024

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CLINICAL RESEARCH PROTOCOL 
 
 
INVESTIGATIONAL 
PRODUCT(S): 
XmAb20717 
STUDY 
NUMBERS: 
IRB 
Number 
850515 
Other 
Protocol 
Identifiers 
UPCC 17221 
PROTOCOL(S) TITLE: 
Phase II trial of XmAb20717 in patients with advanced biliary 
tract cancers 
IND NUMBER: 
159672 
REGULATORY
SPONSOR: 
Mark O’Hara, MD 
University of Pennsylvania Perelman School of Medicine 
Perelman Center for Advanced Medicine 
3400 Civic Center Boulevard, South Tower, Floor 10 
Philadelphia, PA 19104 
FUNDING SPONSOR(S): 
Xencor, Inc. 
MEDICAL DIRECTOR 
Mark O’Hara, MD 
ORIGINAL PROTOCOL 
DATE: 
09 September 2021 
VERSION NUMBER: 
v 8.0 
VERSION DATE: 
24 October 2024 

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Abbreviations .................................................................................................................... 6 
1 
Study Summary .......................................................................................................... 8 
1.1 
Synopsis .................................................................................................................. 8 
1.2 
Key Roles and Study Governance ..................................................................... 10 
1.3 Schema ....................................................................................................................... 11 
2 
Introduction and RationalE .................................................................................... 11 
2.1 
Study Rationale ................................................................................................... 11 
2.2 
Background .......................................................................................................... 12 
2.2.1 
Therapeutic Bispecific Antibodies ............................................................... 12 
2.2.2 
XmAb20717 Investigational Product Description...................................... 12 
2.2.3 
Human Experience with XmAb20717 and Similar Molecules .................. 13 
2.2.4 
Assessment for Potential Study Products Drug-Drug Interactions .......... 17 
2.2.5 
Clinical Adverse Event Profile ..................................................................... 17 
2.2.6 
Dosing Rationale............................................................................................ 17 
2.3 
Risk/Benefit Assessment ..................................................................................... 18 
2.3.1 
Known Potential Risks .................................................................................. 18 
2.3.2 
Known Potential Benefits ............................................................................. 18 
2.3.3 
Assessment of Potential Risks and Benefits ................................................ 18 
3 
Study Objectives and Endpoints ............................................................................. 20 
4 
Study Plan ................................................................................................................. 22 
4.1 
Study Design ........................................................................................................ 22 
4.2 
Scientific Rationale for Study Design ................................................................ 22 
4.3 
Justification for Dose .......................................................................................... 22 
4.4 
Toxicity Management for Immune-Related Adverse Events .......................... 22 
4.5 
End of Study Definition ...................................................................................... 23 
5 
Study Population ...................................................................................................... 24 
5.1 
Inclusion Criteria ................................................................................................ 24 
5.2 
Exclusion Criteria ............................................................................................... 25 
5.3 
Lifestyle Considerations ..................................................................................... 26 
5.4 
Screen Failures .................................................................................................... 26 
5.5 
Strategies for Recruitment and Retention ........................................................ 26 
6 
Study Intervention ................................................................................................... 27 
6.1 
Study Intervention(s) Administration ............................................................... 27 
6.1.1 
Study Intervention Description .................................................................... 27 
6.1.2 
Dosing and Administration .......................................................................... 27 
6.2 
Preparation/Handling/Storage/Accountability................................................. 28 
6.2.1 
Acquisition and accountability .................................................................... 28 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................ 28 
6.2.3 
Product Storage and Stability ...................................................................... 28 
6.2.4 
Preparation .................................................................................................... 29 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................. 29 
6.4 
Study Intervention Compliance ......................................................................... 29 

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6.5 
Concomitant Therapy ......................................................................................... 29 
6.5.1 
Rescue Medicine ............................................................................................ 30 
7 
Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal ................................................................................... 30 
7.1 
Discontinuation of Study Intervention .............................................................. 30 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................... 31 
7.3 
Lost To Follow-Up ............................................................................................... 31 
8 
Study Assessment and Procedures ......................................................................... 33 
8.1 
Schedule of Study Procedures ............................................................................ 33 
8.2 
Study Evaluations and Measurements .............................................................. 34 
8.2.1 
Inclusion and exclusion criteria ................................................................... 34 
8.2.2 
Informed consent ........................................................................................... 35 
8.2.3 
Medical history and demographic data ....................................................... 35 
8.2.4 
Prior and concomitant medications ............................................................. 35 
8.2.5 
Cancer history and disease status ................................................................ 36 
8.2.6 
Vital Signs ...................................................................................................... 36 
8.2.7 
Full physical exam ......................................................................................... 36 
8.2.8 
Targeted physical exam ................................................................................ 36 
8.2.9 
ECOG performance status ........................................................................... 37 
8.2.10 
Laboratory Evaluations ................................................................................ 37 
8.2.11 
Pregnancy Testing ......................................................................................... 37 
8.3 
Efficacy Assessments ........................................................................................... 38 
8.3.1 
Antitumor effect ............................................................................................ 38 
8.3.2 
Definition of evaluable .................................................................................. 38 
8.3.3 
Disease parameters ........................................................................................ 39 
8.3.4 
Methods for evaluation of measurable disease ........................................... 40 
8.3.5 
Response criteria ........................................................................................... 40 
8.3.6 
Correlative studies ........................................................................................ 45 
8.4 
Safety and Other Assessments ........................................................................... 46 
8.4.1 
Toxicity evaluation ........................................................................................ 46 
8.5 
Adverse Events and Serious Adverse Events .................................................... 46 
8.5.1 
Definition of Adverse Events (AE) ............................................................... 46 
8.5.2 
Definition of Serious Adverse Events (SAE) ............................................... 46 
8.5.3 
Classification of an Adverse Event .............................................................. 47 
8.5.4 
Time Period and Frequency for Event Assessment and Follow-Up ......... 48 
8.5.5 
Adverse Event Reporting ............................................................................. 49 
8.5.6 
Serious Adverse Event Reporting ................................................................ 50 
8.5.7 
Reporting Events to Participants ................................................................. 50 
8.5.8 
Events of Special Interest ............................................................................. 50 
8.5.9 
Reporting of Pregnancy ................................................................................ 50 
8.6 
Unanticipated Problems ..................................................................................... 51 
8.6.1 
Definition of Unanticipated Problems (UP) ................................................ 51 

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8.6.2 
Unanticipated Problem Reporting ............................................................... 51 
9 
Statistical Considerations ........................................................................................ 52 
9.1 
Statistical Hypotheses ......................................................................................... 52 
9.2 
Sample Size Determination ................................................................................ 53 
9.3 
Populations for Analyses .................................................................................... 53 
9.3.1 
Efficacy Analysis ........................................................................................... 53 
9.3.2 
Safety Analysis ............................................................................................... 53 
9.4 
Statistical Analyses .............................................................................................. 53 
9.4.1 
General Approach ......................................................................................... 53 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................ 54 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................... 54 
9.4.4 
Safety Analyses .............................................................................................. 54 
9.4.5 
Baseline Descriptive Statistics ...................................................................... 54 
9.4.6 
Planned Interim Analyses............................................................................. 54 
9.4.7 
Sub-Group Analyses ..................................................................................... 54 
9.4.8 
Tabulation of Individual Participant Data ................................................. 55 
9.4.9 
Exploratory Analyses .................................................................................... 55 
10 Supporting Documentation and Operational Considerations ............................. 55 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................. 55 
10.1.1 
Informed Consent Process ............................................................................ 55 
10.1.2 
Study Discontinuation and Closure ............................................................. 56 
10.1.3 
Confidentiality and Privacy ......................................................................... 57 
10.1.4 
Future Use of Stored Specimens and Data ................................................. 58 
10.1.5 
Safety Oversight ............................................................................................ 58 
10.1.6 
Clinical Monitoring ....................................................................................... 58 
10.1.7 
Quality Assurance and Quality Control ..................................................... 59 
10.1.8 
Data Handling and Record Keeping ........................................................... 59 
10.1.9 
Protocol Deviations ....................................................................................... 60 
10.1.10 
Publication and Data Sharing Policy........................................................... 61 
10.1.11 
Conflict of Interest Policy ............................................................................. 61 
10.2 
Additional Considerations .................................................................................. 61 
10.3 
Protocol Amendment History ............................................................................ 61 
11 References ................................................................................................................. 62 
12 APPENDIX ............................................................................................................... 66 
12.1 
Schedule of Activities (SoA) ............................................................................... 66 
12.2 
National Comprehensive Cancer Network Management of 
Immunotherapy-related toxicities ..................................................................... 68 
12.3 
ECOG Performance Status ................................................................................ 78 

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PRINCIPAL INVESTIGATOR SIGNATURE 
STUDY 
SPONSOR: 
Mark O’Hara, MD 
STUDY TITLE: 
Phase II trial of XmAb20717 in patients with advanced biliary tract 
cancers 
STUDY ID 
PROTOCOL 
VERSION 
UPCC 17221 (PennIRB#850515) 
 
8.0 
I have read the referenced protocol. I agree to conduct the study in accordance to this 
protocol, in compliance with the Declaration of Helsinki, Good Clinical Practices (GCP), 
and all applicable regulatory requirements and guidelines. 
Principal 
Investigator Name   
 
Signature 
  
Affiliation: 
  
 
Date 
  

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Abbreviations 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BTCs 
Biliary tract cancers 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximal concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
Complete response 
CrCl 
Creatinine clearance 
CRF 
Case Report Form 
CTLA4 
Cytotoxic T-lymphocyte associated protein 
DOR 
Duration of response 
eCRF 
Electronic Case Report Forms 
Fab 
Fragment, antigen binding 
Fc 
Fragment, crystallizable 
FcRn 
Neonatal Fc receptor 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFP 
Fresh frozen plasma 
GAP 
Gemcitabine, nab-paclitaxel(abraxane), and cisplatin 
GCP 
Good Clinical Practice 
GemCis 
Gemcitabine and cisplatin 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
iCPD 
iRECIST confirmed progressive disease 
iCR 
Complete response by iRECIST 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
iPR 
Partial response by iRECIST 
irAEs 
Immune related adverse events 
IRB 
Institutional Review Board 
iSD 
Stable disease by iRECIST 
iUPD 
iRECIST unconfirmed progressive disease 
LLN 
Lower limit of normal 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD1 
Programmed cell death receptor 1 
PI 
Principal Investigator 

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PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
scFγ 
Single-chain variable fragment (immunoglobulin fusion protein) 
SoA 
Schedule of Activities 
ULN 
Upper limit of normal 
UP 
Unanticipated Problem 

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1 
STUDY SUMMARY 
1.1 
Synopsis 
 
Title: 
Phase II trial of XmAb20717 in patients with advanced biliary tract 
cancers 
Short Title: 
XmAb20717 in advanced BTCs 
Study 
Description: 
This is a single-arm, phase II clinical trial to evaluate the efficacy of 
XmAb20717 in patients with advanced biliary tract cancers who 
have progressed on, or were intolerant of, a gemcitabine-based 
chemotherapy regimen. 
Objectives: 
Primary Objective: To assess efficacy, in terms of ORR, of 
XmAb20717 when used to treat patients with advanced biliary tract 
cancers who have progressed on, or were intolerant of, a 
gemcitabine-based chemotherapy regimen. 
Secondary Objectives: To assess efficacy and safety in terms of 
PFS, ORR by iRECIST, DOR, OS, and incidence of AE’s in 
patients treated with XmAb20717 with advanced biliary tract 
cancers who have progressed on, or were intolerant of, a 
gemcitabine-based chemotherapy regimen. 
 
To assess the ORR within subgroups of patients defined by 
patients who have or have not received immune checkpoint 
inhibitor therapy prior to study enrollment. 
Exploratory Objectives: To assess for the presence of biomarkers 
predictive of treatment response using pre- and optional post- 
treatment biopsies for tumor next generation sequencing, gene- 
expression profiling, and tumor IHC for immune cell markers; and 
using serial peripheral blood analysis for circulating immune cells 
using multi-parameter flow-cytometry. 
Primary 
Endpoint: 
ORR is the primary endpoint and is defined per RECIST 1.1, 
representing the proportion of patients with best response being 
complete response (CR) or partial response (PR). 
Secondary 
Endpoints: 
PFS is a secondary endpoint and is defined as time from study 
enrollment until disease progression or death with censoring for 
loss to follow up. ORR by iRECIST is assessed using the 
guidelines outline in section 8.3.5.3. OS is an additional secondary 
endpoint and is defined as time from study enrollment until death 

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with censoring for loss to follow up. DOR is a secondary endpoint 
and is defined as time from measurement criteria being met for CR 
or PR (whichever is first recorded) to the first date that recurrent or 
progressive disease is objectively documented (taking as a 
reference for progressive disease the smallest measurements 
since the treatment started). Proportion of patients experiencing 
AEs on experimental therapy will be a secondary endpoint and will 
be categorized per CTCAE version 5.0. 
 
The secondary endpoint of ORR within subgroups of patients 
defined by receipt of prior immunotherapy will be defined in the 
same way as for the primary endpoint.   
Exploratory endpoints will include correlative endpoints. Tumor cell 
infiltrate will be assessed by IHC for immune cell markers and 
scored as number of cells expressing each marker per 40X field. 
Gene expression profiling will be performed on tumor tissue by 
RNAseq and each gene will be normalized to a standard, stably 
expressed gene. Multiparameter flow cytometry will be performed 
on peripheral blood and the number of cells expressing immune 
cell markers of interest will be expressed as cells per unit volume 
and as a percent of circulating mononuclear cells examined. 
 
 
Study 
Population: 
The study population will consist of 27 evaluable adult patients 
with advanced biliary tract cancer treated at the Abramson Cancer 
Center who have progressed, or were intolerant of, a gemcitabine- 
based chemotherapy regimen. 
Phase: 
Phase II 
Description of 
Sites/Facilities 
The study will take place at the Abramson Cancer Center at the 
University of Pennsylvania. 
Enrolling 
Participants: 
This is a single-site study at the Abramson Cancer Center at the 
University of Pennsylvania. 
Description of 
Study 
Intervention: 
Study participants will receive the recommended phase II dose 
(10mg/kg) of XmAb20717 by intravenous infusion on days 1 and 
15 of a 28-day cycle. 

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Study 
Duration: 
30 months 
Participant 
Duration: 
From enrollment until disease progression, unacceptable toxicity, or 
withdrawal of consent. Otherwise, investigational treatment will be 
discontinued after two years if patient has not otherwise met criteria 
for treatment discontinuation. Patients who have completed two 
years of treatment without disease progression or unacceptable 
toxicity and experience disease progression after treatment 
discontinuation may undergo re-treatment with the investigational 
treatment.  
 
1.2 
Key Roles and Study Governance 
Sponsor 
Medical Director 
Mark O’Hara, MD, Assistant Professor of 
Medicine 
Mark O’Hara, Assistant Professor of Medicine 
Abramson Cancer Center at the University of 
Pennsylvania 
Abramson Cancer Center at the University of 
Pennsylvania 
Perelman Center for Advanced Medicine 
3400 Civic Center Blvd, South Tower, Floor 10 
Philadelphia, PA 19104 
Perelman Center for Advanced Medicine 
3400 Civic Center Blvd, South Tower, Floor 10 
Philadelphia, PA 19104 
215-614-1858 
215-614-1858 
mark.ohara@pennmedicine.upenn.edu 
mark.ohara@pennmedicine.upenn.edu 

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1.3 Schema 
Study Schema: 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
INTRODUCTION AND RATIONALE 
2.1 
Study Rationale 
 
Biliary tract cancers (BTCs) are responsible for more than 7,000 deaths per year in the 
United States, and they are among the fastest growing causes of cancer death in the 
country.1 Estimated mortality due to BTCs has more than doubled in the past decade.2 
More than two-thirds of patients present with advanced disease that is not amenable to 
curative-intent surgery, and the mainstay of treatment for such patients is chemotherapy.3 
Initial treatment with gemcitabine and cisplatin (GemCis) provides a median progression- 
free survival (PFS) of 8.0 months and median overall survival (OS) of 11.7 months, while 
a triplet regimen adding nab-paclitaxel to GemCis (GAP) demonstrated a promising PFS 
of 11.8 months and OS of 19.2 months in a phase II trial.4,5 Except for the minority of 
patients with targetable alterations such as mismatch repair deficiency (2%) or FGFR2 
fusions (10-15% of intrahepatic cholangiocarcinoma), systemic treatment beyond 1st line 
chemotherapy has very limited efficacy, with standard therapy using 5-fluorouracil plus 
oxaliplatin (FOLFOX) increasing median overall survival less than one month (6.2 vs. 5.3 
months) compared to active symptom control in the ABC-06 study.67 
 
The activity of PD-1 and PD-L1 inhibitors for microsatellite stable BTCs has been largely 
disappointing, with response rates of 3-7% in the largest phase II trials.8–10 Combination 
therapy with PD-1/L1 inhibitors and CTLA-4 inhibitors, however, has proven more 
promising, with response rates of 10.8% with durvalumab plus tremelimumab and 23% 
with nivolumab plus ipilimumab.10,11 The activity of dual checkpoint blockade has also 
been demonstrated with chemoimmunotherapy combinations. 

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Xencor has developed a novel bispecific antibody targeting PD-1 and CTLA-4, 
XmAb20717, which has demonstrated activity in treatment-refractory solid tumors.14 We 
propose a single-arm phase II trial of XmAb20717 in patients with advanced BTC 
previously treated with gemcitabine-based chemotherapy to evaluate efficacy. 
 
2.2 
Background 
2.2.1 
Therapeutic Bispecific Antibodies 
 
The concept of recombinant antibodies that could bind two targets was developed in the 
late 1990s, but technical obstacles slowed development until recently. Now, advances in 
protein biology and recombinant expression techniques have led to several different 
formats for bispecific antibodies, each with different properties.15 Bispecific antibodies 
allow for simultaneous engagement with two targets, potentially increasing binding 
specificity, providing dual activation or blockade of two disease mediators simultaneously, 
or, in the case of cancer therapy, providing the blockade of two immune checkpoint 
inhibitors simultaneously. 
 
One limitation of several bispecific antibodies in development for oncology is that they are 
small and lack a full-fragment, crystallizable (Fc) region; they are therefore excreted 
rapidly from the body. Thus, they must be administered by continuous infusion if 
efficacious concentrations are to be maintained in the body.16 For ease of use, a larger 
construct with pharmacokinetics (PK) similar to that of humanized antibodies would, 
therefore, be preferable because it should allow intermittent administration on a weekly 
or biweekly basis. 
 
2.2.2 
XmAb20717 Investigational Product Description 
 
XmAb20717 is a humanized bispecific antibody that binds the immune checkpoint 
molecules PD-1 and CTLA4 in order to block signaling that prevents activated T cells from 
attacking and clearing tumor cells from the body. 
 
XmAb20717 has been designed to maintain full-length humanized monospecific antibody 
properties in a bispecific, enabling the design of stable molecules with favorable in vivo 
half-life and allowing for the use of standard antibody production methods. To generate 
XmAb20717, Xencor humanized and affinity optimized anti-PD-1 and anti-CTLA4 
antibodies and combined them in a single bispecific molecule. XmAb20717 is produced 
as a 3-chain scFv-Fab-Fc antibody (Figure 1) in which the single chain variable fragment 
(scFv) domain targets PD-1 and the fragment, antigen-binding (Fab) domain targets 
CTLA4. The neonatal Fc receptor (FcRn) affinity has been increased via amino acid 
engineering to improve serum half-life relative to antibodies containing native 
immunoglobulin G (IgG) Fc domains. 

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Figure 1: Schematic of XmAb20717 PD1 x CTLA4 Bispecific Monoclonal Antibody 
 
 
Anti-CTLA4 
Anti-PD1 
 
 
 
scFv 
 
 
 
 
 
 
 
 
CTLA4 = cytotoxic T-lymphocyte-associated protein; Fab = fragment, antigen binding; Fc 
= fragment, crystallizable; FcRn = neonatal Fc receptor; PD1 = programmed cell death 
protein 1; scFv = single-chain variable fragment (immunoglobulin fusion protein). 
 
2.2.3 
Human Experience with XmAb20717 and Similar Molecules 
 
XmAb20717 is a bispecific antibody that binds both PD-1 and CTLA4. Although no 
bispecific antibody that simultaneously targets both these checkpoint pathways has been 
approved for marketing, the validity of the targets for the treatment of cancer has been 
confirmed in numerous clinical trials and by FDA approval of six monoclonal antibodies 
targeting the PD-1/PD-L1 pathway and one monoclonal antibody targeting the CTLA4 
pathway in numerous oncologic indications.17–23 In addition, combination anti-PD1/anti- 
CTLA4 therapy has received FDA approval for treatment of multiple advanced tumor 
types.21,23 
 
Throughout the clinical trials of approved and newer checkpoint inhibitors targeting either 
the PD-1/PD-L1 or CTLA4 pathways, a characteristic and reasonably consistent safety 
profile has emerged that counts immune-related adverse events (irAEs) among the most 
frequent and consequential AEs. While almost any bodily system may be affected by 
drug-related autoimmune reactions, the most common irAEs have been skin toxicities, 
arthritis, and fatigue, and the most serious have been autoimmune pneumonitis, colitis, 
hypothyroidism/thyroiditis, pancreatitis, hepatitis, hypophysitis, adrenal insufficiency, 
nephritis/renal dysfunction, myocarditis, and diabetes.24 In clinical trials of combination 
therapies that target the PD-1/PD-L1 and CTLA4 pathways simultaneously, the 
Fab 

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incidences of some types of irAEs may differ from those observed with single therapy, but 
the types of irAEs have been very similar to those seen with single checkpoint therapy. 
 
2.2.3.1 
XmAb20717 Initial Clinical Experience in a Phase I Dose Escalation Study 
 
To date, XmAb20717 has been evaluated in a single, ongoing, Phase 1, first-in-human, 
two-part dose-escalation and expansion trial in adults with selected advanced solid 
tumors (Study XmAb20717-01). Part A was a standard 3 + 3 dose escalation designed to 
define a maximum tolerated dose, recommended dose, and regimen; to assess safety 
and tolerability; to assess PK and immunogenicity; and preliminarily to assess potential 
antitumor activity of XmAb20717 in subjects with selected advanced solid tumors. In Part 
A, subjects were enrolled sequentially in up to 8 dose-level cohorts (ranging from 0.15 to 
20.0 mg/kg Q2W) of up to 6 subjects each. Part B included treatment of up to 20 subjects 
each at the maximum tolerated dose or a recommended dose in the following cohorts: 
advanced melanoma, renal cell carcinoma (clear cell predominant type), non-small cell 
lung cancer, castrate-resistant adenocarcinoma of the prostate, checkpoint-inhibitor 
relapsed or refractory cutaneous melanoma, and a cohort of tumors for which there is 
published evidence of anti-tumor activity with anti-PD-1/L1 and/or anti-CTLA4-directed 
therapy but no FDA-approved anti-PD1/PD-L1 or anti-CTLA4-directed agents. 
 
2.2.3.2 
Pharmacokinetics 
 
In PK data from Study XmAb20717-01 dose escalation and expansion cohorts, 
XmAb20717 demonstrated a dose proportional PK profile (Figure 2). Preliminary 
population pharmacokinetic analysis of XmAb20717 was performed on the PK data from 
128 subjects. It was a two-compartmental linear model with a zero-order input (constant- 
rate infusion). Covariates in the model included baseline body weight and albumin level, 
and their effects on clearance and central volumes of distribution were modelled. 
Interindividual variability was estimated on the structural parameters using a full-block 
design and a proportional error model was used to describe the residual variability. 
Among subjects treated with 10 mg/kg Q2W, the mean values (standard deviation) of 
maximal concentration (Cmax) (μg/mL) and AUC (area under the curve) (h*μg/mL) were 
225.5 (54.4) and 41823.0 (11549.2), respectively. The terminal half-life was estimated to 
be 12.3 days. 
 
Figure 2: PK Profile for Dose Escalation and Expansion Cohorts in Study 
XmAb20717-01. 

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2.2.3.3 
Pharmacodynamics 
 
To evaluate peripheral blood pharmacodynamic activity of XmAb20717 in the dose 
escalation and expansion cohorts of Study XmAb20717-01, the proliferation marker ki67 
was measured in T-cell subsets by flow cytometry. Increased T-cell proliferation, in both 
CD4 and CD8 T cells, was observed with increasing dose, consistent with dual checkpoint 
blockade. Figure 3 shows the average maximum absolute change in ki67+ T cells in the 
periphery through Cycle 2; peripheral pharmacodynamic responses generally peaked at 
Cycle 2 Day 1 and diminished thereafter. The highest absolute change was observed at 
the 10.0 and 15.0 mg/kg doses. 
 
 
 

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Figure 3: Peripheral Pharmacodynamic Activity: Maximum Absolute Change from 
Baseline in T-Cell ki67 (Percent of Total CD4 or CD8+ T cells) 
 
 
 
2.2.3.4 
Safety Data 
 
A total of 145 subjects have been treated with XmAb20717 (safety population) in Study 
XmAb20717-01 as of May 10, 2021. Doses of 0.15 to 15.0 mg/kg IV have been 
administered Q2W in Part A without exceeding the maximum tolerated dose. A dose of 
10 mg/kg Q2W was selected for expansion cohorts in Part B. Of all treated subjects, the 
majority (110) have been treated at the 10mg/kg dose level. 
 
The most frequently reported treatment emergent adverse events (reported for >20% of 
subjects) in this clinical trial were fatigue (42.1%), pruritus (30.3%), anemia (28.3%), rash 
maculo-papular (27.6%), pyrexia (23.4%), and nausea (22.1%). The majority of treatment 
emergent adverse events considered related to the study drug in XmAb20717-01 are 
consistent with irAEs, which were reported in 75.5% of 110 subjects in the 10mg/kg dose 
group. The most frequently reported irAEs overall (reported for > 10% of subjects) were 
pruritus (26.9%), maculo-papular rash (25.5%), diarrhea (11.7%), rash (11.7%), and 
aspartate aminotransferase elevation (11.0%). The most frequent grade 3 or higher irAEs 
were maculo-papular rash (12.6%), acute kidney injury (3.9%), alanine aminotransferase 

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elevation (3.9%), aspartate aminotransferase elevation (3.9%), hyperglycemia (3.9%), 
and lipase elevation (3.9%). Grade 5 irAEs were reported for 2 subjects and included 
immune-mediated pancreatitis and myocarditis. 
 
Immune-related adverse events that have been observed in XmAb20717-01 are 
consistent with the types of irAEs reported in clinical trials and post-approval treatment 
data for other PD-1/PD-L1 and CTLA4-directed checkpoint inhibitors. The events 
observed in XmAb20717-01 have included both more commonly identified irAEs, such as 
rash and pneumonitis, as well as rare, but previously reported, irAEs that have been 
associated with checkpoint inhibitor therapy, such as immune-mediated myocarditis and 
immune thrombocytopenia. Although the frequencies of some types of irAEs thus far 
observed with XmAb20717 are different from those reported for similar events in subjects 
treated with other anti-PD-1/PD-L1 and -CTLA4 checkpoint inhibitors, data for 
XmAb20717 are currently insufficient to determine the frequencies of specific irAEs with 
any degree of certainty. It is therefore not possible to determine at this time whether or 
not the safety profile of XmAb20717 is significantly different from the safety profile of 
similar agents. 
 
2.2.3.5 
Clinical Activity 
 
At doses below 10mg/kg, best overall response was stable disease (SD). At 10mg/kg, 
best overall response was complete response (CR) in 1 subject and partial response (PR) 
in 9 subjects. The CR, observed in a subject with melanoma, was confirmed. PRs were 
observed in 2 subjects with melanoma, 2 subjects with renal cell carcinoma, 2 subjects 
with non-small cell lung cancer, 2 subjects with prostate cancer, and 1 subject with 
ovarian cancer. 
 
2.2.4 
Assessment for Potential Study Products Drug-Drug Interactions 
 
There are currently no known or hypothesized drug-drug interactions with XmAb20717. 
 
2.2.5 
Clinical Adverse Event Profile 
 
Immune-related adverse events that have been observed in XmAb20717-01 are 
consistent with the types of irAEs reported in clinical trials and post-approval treatment 
data for other PD-1/PD-L1- and CTLA4-directed checkpoint inhibitors as detailed in 
section 2.2.3.4. 
 
2.2.6 
Dosing Rationale 
 
Dose escalation to 15mg/kg of XmAb20717 was performed in the XmAb20717-01 phase 
I study and no maximum tolerated dose was identified. As highlighted in Figure 3, 

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pharmacodynamic measures of CD4+ and CD8+ T cell expansion in response to 
treatment noted maximum increases with doses of 10mg/kg and 15mg/kg. Based on this 
data, 10mg/kg was determined to the recommended dose for the expansion cohorts in 
part B of the study. When clinical activity was assessed, no objective responses were 
observed at doses of less than 10mg/kg, while 1 CR and 9 PRs (ORR 21.3%) were 
observed at the 10mg/kg dose with acceptable toxicity profile. On this basis, 10mg/kg IV 
on days 1 and 15 of a 28 day cycle will be the doses evaluated in the present study. 
 
2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
 
Current understanding of the risks associated with XmAb20717 in humans is based on 
preliminary data from 145 subjects with selected advanced solid tumors treated in an 
ongoing Phase 1 study (XmAb20717-01). Adverse events observed following treatment 
with XmAb20717 in this study were predominantly irAEs that are consistent with the types 
of irAEs reported in clinical trials and post-approval treatment data for other PD-1/PD-L1- 
and CTLA4-directed checkpoint inhibitors. Additional detail is included in section 2.2.3.4. 
 
2.3.2 
Known Potential Benefits 
 
As the current standard of care treatment (FOLFOX) after progression on, or intolerance 
of, gemcitabine based chemotherapy demonstrated only a 5% ORR and a marginal 1 
month increase in OS compared to best supportive care,7 the current research protocol 
offers the potential benefit of improved disease control. In the phase I XmAb20717-01 
study at the 10mg/kg dose, best overall response was complete response (CR) in 1 
subject with melanoma and partial response (PR) in 9 subjects (ORR of 21.3% among 
evaluable subjects), including subjects with melanoma, renal cell carcinoma, non-small 
cell lung cancer, prostate cancer, and ovarian cancer. Responses to immunotherapy are 
often durable and can substantially prolong survival in those with an objective response. 
Only one patient with cholangiocarcinoma was included in this study and was treated at 
the 10mg/kg dose, and did not experience a CR or PR to treatment. 
 
2.3.3 
Assessment of Potential Risks and Benefits 
 
As the risk associated with XmAb20717 appear proportional to the risks of FDA approved 
combination therapies with PD-1/PD-L1 and CTLA-4 check point inhibitors and the study 
treatment has the potential to improve disease response and disease control compared 
to an inadequate standard of care, the risk-benefit ratio favors participation in the study. 
Risks were minimized in the design of the study as patients with a higher likelihood of 
toxicity with immunotherapy, including active auto-immune conditions, are excluded from 
participation in the study. Additionally, the design of the study ensures that patients have 

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progressed on, or were intolerant of, effective first-line therapy for advanced biliary tract 
cancers which consists of gemcitabine-based chemotherapy. 
 
3 
STUDY OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
To assess efficacy, in terms of 
best overall treatment response 
(ORR), of XmAb20717 when 
used to treat patients with 
advanced BTCs who have 
progressed on, or were 
intolerant of, a gemcitabine- 
based chemotherapy regimen. 
ORR is the primary endpoint and is 
defined per RECIST 1.1, representing 
the proportion of patients with best 
response being complete response 
(CR) or partial response (PR). The 
primary endpoint for ORR will be met 
if 4 or more responses are observed 
in 27 evaluable patients indicating a 
significantly higher ORR than a null 
ORR of 5%. 
This degree in 
improvement in ORR 
would be clinically 
meaningful and would 
support further 
investigation of 
XmAb20717 in this patient 
population. 
Secondary 
To assess efficacy and safety, in 
terms of ORR by iRECIST, PFS, 
DOR, OS, and incidence of AEs 
in patients treated with 
XmAb20717 with advanced 
BTCs who have progressed on, 
or were intolerant of, a 
gemcitabine-based 
chemotherapy regimen. 
 
To assess the ORR within 
subgroups of patients defined by 
patients who have or have not 
received immune checkpoint 
inhibitor therapy prior to study 
enrollment. 
ORR by iRECIST is defined in section 
8.3.5.3. PFS is defined as time from 
study enrollment until radiographic 
disease progression per RECIST 1.1 
or death, with censoring for loss to 
follow up. OS is defined as time from 
study enrollment until death, with 
censoring for loss to follow up. DOR is 
defined as time from first treatment 
response to progression or death and 
will only be evaluable in patients with 
CR or PR to therapy. Proportion of 
patients experiencing AEs on 
experimental therapy will be a 
secondary endpoint and will be 
categorized per CTCAE version 5.0. 
 
The exploratory endpoint of ORR 
within subgroups of patients defined 
by receipt of prior immunotherapy will 
be defined in the same way as for the 
primary endpoint.   
Secondary endpoints will 
be descriptive and will 
allow for characterization 
of clinical efficacy and 
safety in terms of patient 
important outcomes. 
 
The assessment of ORR 
within subgroups of 
patients defined by 
receipt of prior immune 
checkpoint inhibitor 
therapy will help to 
characterize efficacy of 
the XmAb20717 in the 
growing population of 
patients who will receive 
immune checkpoint 
inhibitor therapy in the 
first-line setting. 
Tertiary 

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To assess, in an exploratory 
fashion, for the presence of 
biomarkers predictive of 
treatment response using pre- 
treatment biopsies for tumor 
next generation sequencing and 
tumor IHC for immune cell 
markers; and using pre- and 
post-treatment peripheral blood 
Tumor cell infiltrate will be assessed 
by IHC for immune cell markers and 
will be scored as the number of cells 
expressing each marker per 40X field. 
Gene expression profiling will be 
performed on tumor tissue by RNAseq 
and each gene will be normalized to a 
standard, stably expressed gene. 
Multiparameter flow cytometry will be 
Exploratory, correlative 
endpoints may result in 
definition of predictive 
biomarkers for treatment 
with XmAb20717 in this 
patient population and 
may provide additional 
information regarding 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
analysis for circulating immune 
cells using multi-parameter flow- 
cytometry. 
 
 
performed on peripheral blood and the 
number of cells expressing immune 
cell markers of interest will be 
expressed as cells per unit volume 
and as a percent of circulating 
mononuclear cells examined. Intra- 
patient comparisons will be made pre- 
and post- treatment with XmAb20717 
and inter-patient comparisons will be 
made between patients with treatment 
response and those without treatment 
response. 
 
 
mechanisms of treatment 
response or resistance. 
 
 
 
4 
STUDY PLAN 
4.1 
Study Design 
 
We hypothesize that XmAb20717 will be efficacious with a manageable toxicity profile 
when used for treatment of patients with advanced BTCs who have progressed on, or 
were intolerant of, gemcitabine-based systemic therapy. This is a phase II, single-arm trial 
using a Simon two-stage mini-max design with planned interim analysis for futility, as 
described in section 9.4.2, investigating XmAb20717 in patients with advanced BTCs who 
have progressed on, or were intolerant of, gemcitabine-based systemic therapy. The 
study intervention will consist of XmAb20717 administered intravenously at a dose of 
10mg/kg on days 1 and 15 of a 28-day cycle. Therapy with XmAb20717 will continue until 
disease progression, unacceptable toxicity, or withdrawal of consent. Patient enrollment 
will occur at a single site; the Abramson Cancer Center at the University of Pennsylvania. 
 
4.2 
Scientific Rationale for Study Design 
 
A single-arm phase II trial evaluating the response to treatment with XmAb20717 
compared to a historical null ORR of 5% is appropriate given the underwhelming second- 
line options available for patients with advanced BTCs that have progressed on, or were 
intolerant of, gemcitabine-based chemotherapy. The current standard of care option in 
this setting is FOLFOX from the ABC-06 trial, which increased median OS by 1 month 
compared to active symptom control and had an ORR of 5%.6 
 
4.3 
Justification for Dose 
 
Based on the phase I XmAb20717-01 trial, the dose for XmAb20717 or 10mg/kg 
administered intravenously on days 1 and 15 of a 28 day cycle was selected as the 
recommended dose for further study as detailed in section 2.2.6. 

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4.4 
Toxicity Management for Immune-Related Adverse Events 
 
IrAEs may involve every organ or tissue.25 Most irAEs occur within the first 12 weeks of 
exposure to an immune-checkpoint inhibitor, but some of them may appear with a delayed 
onset. Diagnosis of irAEs should be based on exposure to XmAb20717 and a reasonable 
immune-based mechanism of the observed AE. Whenever possible, histologic 
examination or other immune-based diagnostic evaluations should be used to support the 
diagnosis. Other etiologic causes, including AEs due to tumor progression, should be 
ruled out. 
 
The spectrum of irAEs is wide and can be general or organ-specific. Examples of general 
irAEs in patients treated with immune-checkpoint inhibitors are fatigue, fever, and chills. 
 
Organ-specific irAEs consist of pneumonitis, colitis, hepatitis, nephritis and renal 
dysfunction, skin adverse reactions, encephalitis, myocarditis, and endocrinopathies. 
 
Early recognition and management of irAEs associated with immune-oncology agents 
may mitigate severe toxicity. Medical management of irAEs should focus on suppressing 
the immune response with nonsteroidal and steroidal anti-inflammatory medication. 
Management algorithms, which provide guidelines on holding, rechallenging, and 
discontinuation of treatment, have been developed by the National Comprehensive 
Cancer Network (NCCN) (Appendix 12.2). The accurate diagnosis and subsequent 
treatment of irAEs are complex and not captured in any single guidance document, so 
the management of suspected irAEs is ultimately at the discretion of the treating 
investigator in consultation with the principal investigator. No dose modifications of 
XmAb20717 are permitted. 
 
If treatment with XmAb20717 is withheld for management of immune checkpoint inhibitor- 
related toxicities, it should be held until the toxicity has returned to baseline or Grade ≤ 1. 
Exceptions to this guideline may be permissible if deemed appropriate by the principal 
investigator. 
 
Patients with drug-related endocrinopathies controlled with hormone replacement such 
as insulin or adrenal replacement-dose steroids may resume treatment when toxicity has 
improved to Grade < 1. Dose interruption is not required for hyper- or hypothyroidism but 
supportive care (e.g. thyroid replacement) should be started per institutional standards. 
 
Corticosteroids are frequently indicated for Grade 3 or greater toxicities, and are 
necessary at times for lower grade toxicities. Guidance for their use and dosing is 
available in the NCCN guidelines for management of immune checkpoint inhibitor-related 
toxicities in Appendix 12.2.24 For any toxicity of XmAb20717 (regardless of grade) that, 
despite optimal supportive care, is felt by the treating Investigator to present a risk to 
safety of the patient, additional treatment delay or treatment discontinuation is permitted 

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at the discretion of the treating Investigator. 
 
4.5 
End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed all 
phases of the study through the end of treatment visit shown in the Schedule of Activities 
(SoA), Appendix Section 12.1. 
 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
 
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria: 
 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration 
of the study 
3. Male or female, aged > 18 years of age 
4. Patient must have advanced BTC including intrahepatic, perihepatic, or extrahepatic 
cholangiocarcinoma or gallbladder carcinoma with histologic or cytologic confirmation 
who have experienced progression, or intolerance of, systemic therapy with a 
gemcitabine-based regimen. 
5. Patients with tumors harboring an FGFR2 fusion, NTRK fusion, or IDH1 mutation must 
have received molecularly targeted therapy unless contraindicated or refused. 
Patients without sequencing results for FGFR2 fusions, NTRK fusions, or IDH1 
mutations at the time of screening are permitted to enroll in the study. If sequencing 
results demonstrating FGFR2 fusions, NTRK fusions, or IDH1 mutations become 
available after patients have enrolled on the study, patients will be informed of the 
results and available treatment options but may continue study treatment if they are 
deriving clinical benefit.   
6. ECOG performance status of 0 or 1. 
7. Measurable or evaluable disease as defined by RECIST v. 1.1. 
8. Available archival tissue or willingness to undergo biopsy during the screening period; 
this requirement can be waived if biopsy deemed infeasible or unsafe by the principal 
investigator 
9. For females of reproductive potential: Must have a negative serum pregnancy test 
performed within 7 days of first study treatment and must agree to use such a method 
during study participation and for an additional 3 months after the last study dose of 
XmAb20717. Reproductive potential is defined in section 8.2.11. 
10. For males of reproductive potential with female partners of reproductive potential 
(per section 8.2.11): Must use of condoms or other methods to ensure effective 
contraception with partner during the study and for an additional 4 weeks after the 
end of XmAb20717 administration as outlined in section 8.2.11. Male subjects must 
agree not to donate sperm from screening through 4 weeks after completion of study 
11. Must have adequate organ and hematopoietic function within 14 days of the start of 
study treatment as defined in Table 1. Labs from cycle 1 day 1 may be used for 

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eligibility. 
 
 
 

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Table 1: Baseline Laboratory Parameters 
Laboratory Test 
Required Value 
Absolute neutrophil count (ANC) 
≥ 1.0 x 109/L 
Platelet count 
≥ 60,000 x 109/L 
Hemoglobin 
≥ 8.0 x 109/L 
Alanine aminotransferase (ALT) 
≤ 3xULN (or 5xULN with liver involvement) 
Aspartate aminotransferase (AST) 
≤ 3xULN (or 5xULN with liver involvement) 
Serum creatinine or creatinine clearance 
(CrCl) 
≤ 1.5 x ULN or CrCl ≥ 50 mL/min by 
Cockcroft-Gault Formula 
Total Bilirubin 
≤ 2.0 x ULN 
 
5.2 
Exclusion Criteria 
 
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
1. Any concurrent condition requiring the continued or anticipated use of systemic 
steroids beyond physiologic replacement dosing (excluding non-systemic inhaled, 
topical skin, nasal, and/or ophthalmic corticosteroids). All other systemic 
corticosteroids above physiologic replacement dosing must be discontinued at least 
four weeks prior to first study treatment. 
2. Treatment with another investigational drug or other intervention within four weeks 
prior to the first study treatment date. 
3. Treatment with trans-arterial liver embolization, hepatic arterial infusion, or radiation 
doses of > 30 Gy within 4 weeks prior to the first study treatment date 
4. Treatment with chemotherapy within 3 weeks prior to the first study treatment date 
5. History of permanent discontinuation of a PD-1 or PD-L1 inhibitor therapy due to an immune 
related adverse event. 
6. Prior treatment with a CTLA-4 inhibitor 
7. Pregnant or breastfeeding 
8. Known allergic reactions to study drug components. 
9. Active brain metastases. Patients with brain metastases must have stable 
neurological status following local therapy (surgery or radiation) for at least four weeks 
prior to first study treatment and must be off steroids related to the brain metastases 
for at least two weeks prior to study treatment. 
10. Active drug or alcohol use or dependence as documented in the chart that, in the 
opinion of the investigator, would interfere with adherence to study requirements. 
11. Active bacterial, viral, parasitic, or fungal infection requiring IV therapy within 2 weeks 
of the start of protocol treatment. 
12. A secondary primary malignancy that, in the judgement of the investigator, may affect 
the interpretation of results. 
13. Prior organ allograft or allogeneic bone marrow transplantation. 
14. A history of, or active, pneumonitis or interstitial lung disease. 
15. Active autoimmune disease. Patients with vitiligo, type 1 diabetes mellitus, 
endocrinopathies manageable by hormone replacement, and psoriasis not requiring 
systemic treatment are permitted to enroll. Other autoimmune conditions may be 

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allowable at the discretion of the principal investigator. 
16. Receipt of a live-virus vaccine within 30 days prior to first dose of study drug (seasonal 
flu and COVID-19 vaccines are permitted, as long as they do not contain live virus and 
are not administered within 24 hours of planned administration of XmAb20717) 
17. Known human immunodeficiency virus (HIV) infection with CD4+ T-cell (CD4+) counts 
< 350 cells/μL, or an HIV viral load greater than 400 copies/mL, or a history of an 
acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 
the past 12 months, or who has not been on established antiretroviral therapy (ART) 
for at least 4 weeks prior to initiation of study drug dosing. (Effective ART is defined 
as a drug, dosage, and schedule associated with reduction and control of the viral 
load. HIV positive subjects who do not meet any of these exclusion criteria are eligible.) 
18. Any serious or uncontrolled medical or psychiatric disorder that, in the opinion of the 
investigator, would prevent the patient from providing informed consent, may increase 
the risk associated with study participation or study drug administration, impair the 
ability of the patient to receive study protocol therapy, or interfere with the 
interpretation of the study results. 
 
5.3 
Lifestyle Considerations 
 
Not applicable. 
 
5.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but have not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) 
because they temporarily meet an exclusion criterion, may be rescreened. Rescreened 
participants should be assigned the same participant number as for the initial screening. 
 
5.5 
Strategies for Recruitment and Retention 
 
Patients will be identified through the clinical practices of the Abramson Cancer Center 
and the Hospital of the University of Pennsylvania and its affiliated hospitals and through 
referrals from outside hospitals and physicians. The trial will be publicized on the websites 
of the Abramson Cancer Center and the Hospital of the University of Pennsylvania. This 
protocol will also be listed in the ClinicalTrials.gov database. Patients will be required to 
give written consent to participate before any screening tests or evaluations are 
conducted. 
 
Vulnerable populations such as pregnant women, prisoners, children, cognitively 
impaired participants lacking consent capacity, and employee volunteers will not be 

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eligible for participation in this research study and will not be recruited. 

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6 
STUDY INTERVENTION 
6.1 
Study Intervention(s) Administration 
6.1.1 
Study Intervention Description 
 
XmAb20717 is a humanized bispecific antibody that binds both PD-1 and CTLA4 as 
described in section 2.2.2. 
 
6.1.2 
Dosing and Administration 
 
A dose of 10mg/kg will be administered intravenously on days 1 and 15 of each 28 day 
cycle. Intravenous administration will occur over 1 hour (± 10 minutes). 
 
Clinical experience with XmAb20717 is limited. Caution should be exercised as infusion 
reactions, allergic reactions, or other unexpected reactions may occur. 
 
XmAb20717 administration should begin as soon as possible after the dosing solution is 
made. If there is a delay in administration, the dosing solution may be stored at 2°C to 
8°C for no more than 24 hours or at room temperature for no more than 4 hours prior to 
infusion. The full calculated dose will be administered based on the participant’s actual 
baseline weight measurement in kilograms. Following the first dose, subsequent doses 
will be modified only if the participant’s weight changes by more than 10% from the 
baseline (Day -1 or Day 1, assessment closest to the first dose) weight, at which point the 
dose will be recalculated using the current weight. 
 
XmAb20717 SHOULD NOT BE ADMINISTERED AS AN IV PUSH OR BOLUS. 
 
XmAb20717 will be administered as an open-label solution at a constant rate over a 1- 
hour period (± 10 minutes). Precautions for infusion reactions/anaphylaxis should be 
observed during XmAb20717 administration. Due to the possibility that allergic/infusion 
reactions may occur, emergency resuscitation equipment (a “crash cart”) should be 
present in the immediate area where participants 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, diphenhydramine, and oxygen. 
 
All supportive measures consistent with optimal patient care will be provided throughout 
the study according to institution standards. 

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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and accountability 
 
XmAb20717 will be supplied by The Almac Group. XmAb20717 will be stored by the 
Investigational Drug Service per the guidelines noted in section 6.2.3 below. 
 
Detailed instructions and procedures for study treatment (XmAb20717) dispensing are 
included in the Pharmacy Manual. 
 
Accurate accounting of all study treatment must be maintained. The Principal Investigator 
agrees to keep an inventory of study treatments 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, expiration dates, and the 
unique code numbers assigned to the study treatment and to the study participants. 
 
The Investigator shall be responsible for ensuring records that adequately document that 
the participants who were provided the doses specified in the protocol and that all study 
treatment received from the Sponsor are reconciled. 
 
Upon completion or termination of the study, any used or partially used vials and unused 
study medication or diluted drug dosing solutions should be destroyed in compliance with 
local investigational pharmacy policies or returned to the Sponsor or its designee. 
 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
 
XmAb20717 will be supplied in single-use glass vials. Each 10 mL vial is filled with 10.0 
mL of drug product containing 10.0 ± 1.0 mg/mL of XmAb20717 in 20 mM histidine, 250 
mM sorbitol, and 0.01% (w/v) polysorbate-80 at pH 6.2. Each product vial is intended to 
deliver 10.0 mL of drug solution. XmAb20717 will be packaged and labeled according to 
applicable local and regulatory requirements. 
 
XmAb20717 containing vials should appear as a transparent liquid free of particulate 
matter and/or discoloration. 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. 
 
6.2.3 
Product Storage and Stability 
 
Vials containing XmAb20717 must be stored under refrigeration at 2°C to 8°C in an 
appropriately secured area accessible only to the pharmacist, the Principal Investigator, 

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or a duly designated person. Since XmAb20717 does not contain preservatives, opened 
vials of XmAb20717 must be used within 24 hours. 
 
6.2.4 
Preparation 
 
Note that each XmAb20717 product vial must be diluted before administration. 
 
Prior to administration, XmAb20717 will be diluted to the required final concentration in 
an ethylene/polypropylene copolymer infusion bag containing 0.9% Sodium Chloride 
Injection, United States Pharmacopeia, and 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 XmAb20717 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 XmAb20717 Pharmacy Manual for additional details. 
 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
 
Not applicable 
 
6.4 
Study Intervention Compliance. 
 
Adherence to intravenous infusion with XmAb20717 will be directly observed and 
recorded in the electronic health record and the electronic case report form (eCRF) with 
each research infusion visit. 
 
6.5 
Concomitant Therapy 
 
For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorized/licensed clinician. Medications to be reported in 
the eCRF are concomitant prescription medications, over-the-counter medications and 
supplements. Medications will be reported in the eCRF per the SoA in Appendix 12.1. 
 
As stated in the exclusion criteria in section 5.2, participants will not be permitted to enroll 
in the study if, prior to study intervention, they require the use of systemic steroids beyond 
physiologic replacement dosing. 
 
No concomitant cancer therapeutics may be administered during treatment with 
XmAb20717, excluding adjuvant hormonal therapy for breast or prostate cancer. 

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6.5.1 
Rescue Medicine 
 
Due to the possibility that allergic/infusion reactions may occur, emergency resuscitation 
equipment (a “crash cart”) should be present in the immediate area where participants 
are receiving their infusions. Additional supportive measures will be available and may 
include, but are not limited to, acetaminophen, antihistamines, corticosteroids, IV fluids, 
bronchodilators, epinephrine, vasopressors, diphenhydramine, and oxygen. 
 
7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
 
Discontinuation from XmAb20717 treatment does not mean discontinuation from the 
study, and remaining study procedures should be completed as indicated by the study 
protocol. If a clinically significant finding is identified (including, but not limited to changes 
from baseline) after enrollment, the investigator or qualified designee will determine if any 
change in participant management is needed. Any new clinically relevant finding will be 
reported as an adverse event. 
 
Withholding or discontinuation of XmAb20717 due to irAEs should be guided by the 
NCCN guidelines for the management of immunotherapy related toxicities, outlined in 
Appendix 12.2, though the ultimate decision is at the discretion of the treating clinician 
and principal investigator. When XmAb20717 is held for toxicity (and not permanently 
discontinued), it may be reinitiated when AEs return to baseline or Grade < 1. Exceptions 
to this may be permissible if deemed appropriate by the principal investigator. If 
XmAb20717 is interrupted for more than 12 weeks, treatment should be discontinued 
unless continuation is approved by the principal investigator. 
 
For any toxicity of XmAb20717 (regardless of grade) that, despite optimal supportive care, 
is felt by the treating investigator to present a risk to safety of the study patient, additional 
treatment delay or treatment discontinuation is permitted at the discretion of the treating 
investigator. 
 
XmAb20717 will be discontinued after two years of treatment for patients remaining on 
treatment at that time. Patients who completed two years of XmAb20717 treatment but 
experience disease progression after treatment discontinuation will be permitted to re-
initiate treatment with XmAb20717.  
 
The data to be collected at the time of study intervention discontinuation will include the 
following: 
 
• Review of adverse events 
• Targeted physical examination 
• Vital signs and weight 

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• ECOG performance status 
• Lab testing including CBC with diff, CMP, and TSH with reflex free T4 
 
• Tumor imaging 
 
Further detail is presented in the Schedule of Activities in Appendix 12.1. 
 
After study treatment discontinuation, patients will have safety follow up for 90 days after 
treatment discontinuation for immune-related adverse events. Subsequently, patients will 
be followed within the medical record or  have telephone follow up every 6 months to 
complete two years as documented in the SoA in Appendix 12.1. 
 
7.2 
Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
• Pregnancy 
• Significant non-compliance with XmAb20717 treatment 
• If any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
not be in the best interest of the participant 
• Disease progression which requires discontinuation of XmAb20717 treatment 
• If the participant meets an exclusion criterion, not previously recognized, that 
precludes further study participation 
• Participant unable to receive XmAb20717 for 12 weeks. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded 
on the eCRF. Patients who sign the informed consent form but do not receive the study 
intervention may be replaced. Patients who sign the informed consent form and receive 
the study intervention, and subsequently withdraw, or are withdrawn or discontinued from 
the study at a point where they are not considered evaluable for efficacy endpoints per 
section 8.3.2 will be replaced. 
 
7.3 
Lost To Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled 
visits and is unable to be contacted by the study site staff. 
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 
• The site will attempt to contact the participant and reschedule the missed visit and 
counsel the participant on the importance of maintaining the assigned visit 

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schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record or study file. 
• Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENT AND PROCEDURES 
8.1 
Schedule of Study Procedures 
 
A schedule of study procedures is provided in Appendix 12.1 and procedures to occur at 
each visit is discussed below.  
 
Study procedures, including research collections and visits, that are missed due to SAEs 
will not be considered deviations and will be omitted. In other words, the study calendar 
will not be “paused” at the time of SAEs but will continue on and patients will resume 
scheduled study procedures when able without “making up” omitted study procedures.  
 
Visit 1 (Day -28 to 0) 
Screening 
• Obtain informed consent 
• Screen potential participants by inclusion and exclusion criteria 
• Obtain complete medical history and demographics, document 
• Prior and concomitant medication review 
• Tumor imaging of abdomen with CT or MRI, CT or MRI of pelvis, and CT chest 
within 28 days of the start of study therapy 
• Collection of labs including pregnancy test, CBC with diff, CMP, TSH with reflex 
free T4, CA-19-9, and CEA 
• Archival or fresh tumor biopsy 
• Physical exam, vital signs, height, weight and ECOG performance status 
Visit 2 (Day 1) 
Treatment initiation 
• Treatment with XmAb20717 
• Prior and concomitant medication review 
• Physical exam, vital signs, weight, and ECOG performance status 
• Baseline adverse events assessment 
• Labs including CBC with diff, CMP, TSH with reflex free T4, CA19-9, and CEA 
(CA-19-9 should only be measured on an ongoing basis if abnormal at baseline. 
CEA should only be measured on an ongoing basis if abnormal at baseline and 
CA 19-9 normal at baseline) 
• Peripheral blood testing for correlative studies drawn prior to treatment initiation 

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Visit 3 (Day 8) 
Visit for correlative evaluation (lab visit) 
• Peripheral blood assessment for correlative studies 
Visit 4 (Day 15) 
Treatment visit 
• Treatment with XmAb20717 
• Prior and concomitant medication review 
• Physical exam, vital signs, weight, and ECOG performance status 
• Review adverse events 
• Labs including CBC with diff, CMP, TSH with reflex free T4 
• Peripheral blood assessment for correlative studies 
Day 1 and Day 15 
Treatment visits cycle 2 and beyond 
• Treatment with XmAb20717 
• Prior and concomitant medication review 
• Physical exam, vital signs, weight, and ECOG performance status 
• Review adverse events 
• Labs including CBC with diff, CMP, TSH with reflex free T4 
• Tumor markers (CA 19-9 or CEA) should be checked on day 1 of each cycle if 
abnormal at baseline as above 
• Refer to Appendix Section 12.1, Schedule of Activities for additional interventions 
including peripheral blood assessment for correlative studies and tumor imaging 
End of treatment visit (can 
be conducted during a 
scheduled office visit, such 
as to review scans 
demonstrating progression, 
or separately) 
Treatment discontinuation assessments 
• Review adverse events 
• Targeted physical examination and ECOG performance status 
• Lab testing including CBC with diff, CMP, TSH with reflex free T4 
• Tumor markers (CA 19-9 or CEA) if abnormal baseline as above. 
• Tumor imaging if not performed in the prior 28 days 
30 and 90 days after last 
infusion with XmAb20717 
Safety follow-up 
• Phone call or office visit with nurse to review adverse events 
Every 6 months to 
complete 2 years from the 
end of treatment 
Follow-up 

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• 
Survival status assessment via medical records or by telephone 
• 
Post-study anti-cancer therapy status via medical records or by telephone 
 
 
 
 
8.2 
Study Evaluations and Measurements 
8.2.1 
Inclusion and exclusion criteria 
 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that participant qualifies for the trial. 
 
8.2.2 
Informed consent 
 
The investigator must obtain documented consent from each potential participant prior to 
enrollment in the clinical trial. Study specific procedures should not be conducted until a 
patient has provided consent, but testing obtained as standard of care prior to consent 
such as laboratory values and imaging may be used for study eligibility. 
 
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on the consent form along with the 
dated signature of the person conducting the consent discussion. 
 
A copy of the signed and dated consent form should be given to the participant prior to 
participation in the trial. 
 
The initial consent form, any subsequent revised written informed consent form, and any 
written information provided to the participant must receive the IRB’s approval/favorable 
opinion in advance of use. The participant and their legally acceptable representative 
should be informed in a timely manner if new information becomes available that may be 
relevant to the participant’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature. 
 
8.2.3 
Medical history and demographic data 
 
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions and any conditions diagnosed within the prior 10 years 
that are considered to be clinically significant by the investigator. This review will occur at 
study visits noted in the SoA in Appendix 12.1. Details regarding the disease for which the 
participant has been enrolled in this study will be recorded separately and not listed as 
medical history. Demographic data collected will include sex, date of birth, and 
race/ethnicity. 
 

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8.2.4 
Prior and concomitant medications 
 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the 
participant within 28 days prior to trial initiation. The following details will be collected: 
drug name, reason for treatment, dose/units, route of administration, frequency, start and 
end date of therapy.

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Treatment for the disease for which the participant has enrolled on the trial will be 
recorded separately and will not be listed under prior medication. 
 
Patients must be instructed not to take any medications, including over-the-counter 
products such as vitamins, minerals and other dietary supplements, without first 
consulting the Investigator. All concomitant medications must be recorded on the relevant 
eCRF. 
 
Supportive care and other medication, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the investigator and recorded in 
the relevant eCRF. 
 
The investigator or qualified designee will record medication taken by the participant 
during the trial. Review of prior and concomitant medications will occur during study visits 
indicated in the SoA in Appendix 12.1. 
 
8.2.5 
Cancer history and disease status 
 
The investigator or qualified designee will obtain details on the patient’s cancer diagnosis 
including site, date of diagnosis, stage, sites of metastatic disease, and prior anti-cancer 
treatment including surgery, systemic therapy, and radiation therapy. 
 
8.2.6 
Vital Signs 
 
The investigator or qualified designee will assess and record vital signs at time points 
indicated in the SoA in Appendix 12.1. Vital signs should include temperature, pulse, 
respiratory rate, oxygen saturation, weight and blood pressure. Height need only be 
measured once at the main screening visit per the SoA in Appendix 12.1. 
 
8.2.7 
Full physical exam 
 
The investigator or qualified designee will perform a complete physical exam during the 
main screening visit. Clinically significant abnormal findings should be recorded as 
medical history. 
 
8.2.8 
Targeted physical exam 
 
For cycles that do not require full physical exam per the SoA in Appendix 12.1, the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to treatment administration as determined by the investigator or directed 
by patient complaints. 

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8.2.9 
ECOG performance status 
 
ECOG performance status will be measured at specified visits in the SoA in Appendix 
12.1 according to Table 8 in Appendix 12.4. 
 
8.2.10 
Laboratory Evaluations 
 
Blood samples will be taken to be tested in the clinical laboratory at intervals specified in 
SoA in Appendix 12.1. 
 
Complete Blood Count: 
White blood cell (WBC) count with differential, hemoglobin, hematocrit, and platelet count 
 
Serum Chemistry: 
Sodium (Na), potassium (K), chloride (Cl), bicarbonate (HCO3), calcium (Ca), blood urea 
nitrogen (BUN), creatinine (Cr), total bilirubin(Tbili), alkaline phosphatase (ALP), AST, 
ALT, albumin (Alb) 
 
Tumor Markers: 
CA19-9 and CEA. CA19-9 will be repeated per SoA in Appendix 12.1 only if abnormal at 
screening. CEA will be repeated per SoA in Appendix 12.1 only if abnormal at screening 
AND CA19-9 is normal at screening. 
 
Thyroid Stimulating Hormone (TSH): 
Thyroid stimulating hormone (TSH); if abnormal, check free T4 
 
8.2.11 
Pregnancy Testing 
 
A serum pregnancy test will be performed at specified visits per SoA in Appendix 12.1 for 
female patients of reproductive potential. 
 
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 (using local reference ranges) OR have a 
history of hysterectomy and/or bilateral oophorectomy OR have a history of bilateral tubal 
ligation. 
 
Female subjects of childbearing potential must agree to use a highly effective method of 
birth control during and for at least 3 months after the last study dose of XmAb20717. Male 
subjects with female partners of reproductive potential must agree to use a highly effective 
method of birth control during and for 4 weeks after completion of the study (the last dose 
of XmAb20717 administered). Additionally, male subjects must agree to not donate sperm 
during and for 4 weeks after the completion of the study. 
 
Highly effective methods of birth control for women include hormonal birth control (oral, 

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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. For men on the study, highly effective methods 
of birth control include vasectomy (provided there has been a medical assessment of 
surgical success), or a condom in combination with double barrier methods, spermicide, 
hormonal birth control, or IUD used by the female partner. The list of methods above is 
not exhaustive and additional contraception methods may also be acceptable if approved 
by the study doctor. 
 
8.3 
Efficacy Assessments 
8.3.1 
Antitumor effect 
 
For the purpose of this study, patients will be evaluated for response every 8 weeks for 
24 weeks and then every 12 weeks thereafter by CT scan of the chest with or without 
contrast and CT scan and/or MRI of the abdomen with IV contrast (pelvis required only if 
disease documented in pelvis on baseline scan). The same imaging modality should be 
used throughout the study if possible. Baseline scans of the chest, abdomen, and pelvis 
must obtained within 28 days of the start of study therapy. 
 
8.3.2 
Definition of evaluable 
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with XmAb20717. 
 
Evaluable for efficacy endpoints, including overall response: Only those patients who 
have measurable disease present at baseline, have received at least two infusions (one 
cycle) of XmAb20717, and have had their disease re-evaluated by appropriate imaging 
after at least 4 and no more than 12 weeks from cycle 1 day 1 will be considered evaluable 
for efficacy endpoints including overall response. These patients will have their response 
classified according to the definitions stated below. Patients will be evaluable for the 
overall survival endpoint if they have received at least two infusions (one cycle) of 
XmAb20717, even if repeat imaging not performed. 
 
Patients who are not considered evaluable for ORR endpoint will be replaced. 

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8.3.3 
Disease parameters 
 
Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by 
chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
 
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. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to < 15mm short axis) 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions: All measurable and/or evaluable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. In patients who have received 
locoregional therapy to the liver, lesions that have not been treated locally should be 
preferentially chosen as target lesions. If a liver lesion that has been treated using 
locoregional therapy must be chosen as a target lesion, progression of the lesion is 
required after locoregional therapy, A sum of the diameters (longest for non-nodal lesions, 

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short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. 
 
Measurements of these lesions are not required, but the presence, absence, or in rare 
cases, unequivocal progression, of each should be noted throughout follow-up. 
 
8.3.4 
Methods for evaluation of measurable disease 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable. 
 
8.3.5 
Response criteria 
8.3.5.1 
Evaluation of target lesions (RECIST 1.1) 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 

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8.3.5.2 
Evaluation of non-target lesions 
 
Non-target lesions should be followed and labeled as ‘present’, ‘absent’, or ‘unequivocal 
progression’, defined as an overall level of substantial worsening in non-target disease, 
such that even in the presence of stable disease or partial response in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. 
‘Unequivocal progression’ of non-target disease will classify a patient has having 
progressive disease (PD). 
 
8.3.5.3 
Immune-related response in measurable lesions (iRECIST) 
 
iRECIST guidelines were established in 2017 to guide response assessments in clinical 
trials testing immune-therapeutics. Full details of the iRECIST criteria for this study can 
be found in Seymour L et al, Lancet Oncology 2017.26 
 
If initial RECIST 1.1-defined progression (ie, iUPD) is noted on imaging in the setting of 
clinical stability, patients may remain on study treatment and have confirmatory imaging 
in 4-8 weeks (study specified scans (every 8 or 12 weeks based on SoA in Appendix 12.2) 
should continue on initial schedule if patient remains on study). An assignment of clinical 
stability requires that no worsening of performance status has occurred, that no clinically 
relevant increases in disease-related symptoms such as pain or dyspnea occur that are 
thought to be associated with disease progression, and that no requirement for intensified 
management of disease-related symptoms exists, including increased analgesia, 
radiotherapy, or other palliative care. The imaging findings and the recommendation to 
continue with treatment despite iUPD should be discussed with the patient before a 
decision is made about whether or not to continue therapy. Patients who have iUPD and 
are not clinically stable should be designated as not clinically stable in the case report form. 
This designation will allow the best overall response to be calculated and the date of iUPD 
to be used in estimates of progression-free survival by iRECIST. 
 
If radiologic progression is confirmed (iCPD), they will be determined to have progressive 
disease by iRECIST and discontinued from study therapy, but if repeat imaging shows 
stable disease or response by RECIST 1.1 they may remain on study therapy with 
imaging continuing as previously scheduled every 8 weeks for 24 weeks then every 12 
weeks thereafter (cycle 3 day 1, cycle 5 day 1, etc.). 
 
Table 2: Comparison of RECIST 1.1 and iRECIST 
RECIST 1.1 
iRECIST 
Definitions of measurable 
and non-measurable 
disease; numbers and site 
of target disease 
Measurable lesions are 
≥10mm in diameter (≥ 
15mm for nodal lesions); 
maximum of five lesions 
No change from RECIST 
1.1; however, new lesions 
are assessed as per 
RECIST 1.1 but are 

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(two per organ); all other 
disease is considered non- 
target (must be ≥ 10 mm in 
short axis for nodal 
disease) 
recorded separately on the 
case report form (but not 
included in the sum of 
lesions for target lesions 
identified at baseline) 
Complete response, partial 
response, or stable 
disease 
Cannot have met criteria 
for progression before 
complete response, partial 
response, or stable 
disease 
Can have had iUPD (one 
or more instances), but not 
iCPD, before CR, PR, or 
SD 
New lesions 
Results in progression; 
recorded but not measured 
Results in iUPD but iCPD 
is only assigned on the 
basis of this category if at 
next assessment, 
additional new lesions 
appear or an increase in 
size of new lesions is seen 
(≥ 5 mm for sum of new 
lesion target or any 
increase in new lesion 
non-target); the 
appearance of new lesions 
when none have 
previously been recorded, 
can also confirm iCPD 
Confirmation of 
progression 
Not required (unless 
equivocal) 
Required 
Consideration of clinical 
status 
Not included in 
assessment 
Clinical stability is 
considered when deciding 
whether treatment is 
continued after iUPD 
“i” indicates immune responses assigned using iRECIST. RECIST = Response 
Evaluation Criteria in Solid Tumors. iUPD = unconfirmed progression. iCPD = confirmed 
progression. iCR = complete response. iPR = partial response. iSD = stable disease. 

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Table 3: Assignment of timepoint response using iRECIST 
Timepoint response with 
no previous iUPD in any 
category 
Timepoint response with 
previous iUPD in any 
category* 
Target lesions: iCR; non- 
target lesions: iCR; new 
lesions: no 
iCR 
iCR 
Target lesions: iCR; non- 
target lesions: non- 
iCR/non-iUPD; new 
lesions: no 
iPR 
iPR 
Target lesions: iPR; non- 
target lesions: non- 
iCR/non-iUPD; new 
lesions: no 
iPR 
iPR 
Target lesions: iSD; non- 
target lesions: non- 
iCR/non-iUPD; new 
lesions: no 
iSD 
iSD 
Target lesions: iUPD with 
no change, or with a 
decrease from last 
timepoint; non-target 
lesions: iUPD with no 
change or decrease from 
last timepoint; new lesions: 
yes 
Not Applicable 
New lesions confirm iCPD 
if new lesions were 
previously identified and 
they have increased in size 
(≥ 5 mm in sum of 
measures for new lesion 
target or any increase for 
new lesion non-target) or 
number; if no change is 
seen in new lesions (size 
or number) from last 
timepoint, assignment 
remains iUPD. 
Target lesions: iSD, iPR, 
iCR; non-target lesions: 
iUPD; new lesions: no 
iUPD 
Remains iUPD unless 
iCPD is confirmed on the 
basis of a further increase 
in the size of non-target 
disease (does not need to 
meet RECIST 1.1 criteria 
for unequivocal 
progression) 

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Target lesions: iUPD; non- 
target lesions: non- 
iCR/non-iUPD, or iCR; new 
lesions: no 
iUPD 
Remains iUPD unless 
iCPD is confirmed on the 
basis of a further increase 
in sum of measures ≥ 5 
mm; otherwise, 
assignment remains iUPD 
Target lesions: iUPD; non- 
target lesions: iUPD; new 
lesions: no 
iUPD 
Remains iUPD unless 
iCPD is confirmed based 
on a further increase in 
previously identified target 
lesion iUPD in sum of 
measures ≥ 5 mm or non- 
target lesion iUPD 
(previous assessment 
need not have shown 
unequivocal progression) 
Target lesions: iUPD; non- 
target lesions: iUPD; new 
lesions: yes 
iUPD 
Remains iUPD unless 
iCPD is confirmed on the 
basis of a further increase 
in previously identified 
target lesion iUPD sum of 
measures ≥ 5 mm, 
previously identified non- 
target lesion iUPD (does 
not need to be 
unequivocal), or an 
increase in the size or 
number of new lesions 
previously identified 
Target lesions: non-iUPD 
or progression; non-target 
lesions: non-iUPD or 
progression; new lesions: 
yes 
iUPD 
Remains iUPD unless 
iCPD is confirmed on the 
basis of an increase in size 
or number of new lesions 
previously identified. 
Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 
principles (Section 8.3.3); if no pseudoprogression occurs, RECIST 1.1 and iRECIST 
categories for complete response, partial response, and stable disease would be the 
same. 
*Previously identified in assessment immediately before this timepoint. “i” indicates 
immune responses assigned using iRECIST. iCR = complete response. iPR = partial 
response. iSD = stable disease. iUPD = unconfirmed progression. Non-iCR/non-iUPD = 
criteria for neither CR nor PD have been met. iCPD = confirmed progression. RECIST = 
Response Evaluation Criteria in Solid Tumors. 
 
 
 

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8.3.5.4 
Overall response rate 
 
Overall response rate (ORR) is defined as the proportion of patients who achieve a 
complete or partial response during the course of the study. The best response 
experienced by a patient (CR > PR > SD > PD) will be used. Responses will be 
determined by investigator review. The primary study endpoint will be use RECIST v. 1.1 
definitions (sections 8.3.5.1 and 8.3.5.2) to define overall response rate. Overall response 
rate by iRECIST criteria (section 8.3.5.3) will be a secondary endpoint. 
 
8.3.5.5 
Duration of response 
 
Duration of Overall Response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment 
started). 
 
8.3.5.6 
Progression-free survival 
 
PFS is defined as the duration of time from start of treatment to time of progression using 
RECIST v.1.1 criteria,26 death, or last patient contact when progression-free. For patients 
who are progression-free, PFS will be censored at the most recent date which documents 
progression-free status (i.e., scan date or clinical visit date). 
 
8.3.5.7 
Overall survival 
 
OS is defined as the duration of time from start of treatment to death due to any cause 
with censoring at last patient contact alive for patients who are lost to follow up or who do 
not experience the outcome of death during the study period. Public records (e.g. 
obituaries) may be used to ascertain dates of death for patients where such data is not 
available in the medical record unless the patient withdraws consent for follow-up. For 
patients who enroll in hospice care in whom the specific date of death cannot be 
determined, date of death will be recorded as the date the patient entered hospice. 
 
8.3.6 
Correlative studies 
8.3.6.1 
Correlative blood samples 
 
Peripheral blood correlative studies will be performed at the time points noted in the SoA 
in Appendix 12.1. At each time point, 50 mL of blood will be drawn for correlative studies. 
Peripheral blood samples will be immediately sent to the Human Immunology Core (HIC) 
at the University of Pennsylvania and peripheral blood mononuclear cells (PBMCs) will 
be isolated. Samples will undergo multi-parameter flow cytometry performed by Dr. 
Huang’s laboratory at the University of Pennsylvania. 

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8.3.6.2 
Tumor biopsy 
 
Archival tumor tissue, from diagnosis or more recent tumor biopsy, will be obtained to 
perform correlative studies. Next-generation sequencing will be obtained if not previously 
performed on archival tissue, if available, or re-biopsy should be performed as part of 
standard of care management to allow for next-generation sequencing. Samples will be 
analyzed by immunohistochemical staining (IHC) with markers including CD8, CD3, 
FoxP3, CK19, CD68, Ki-67, and PD-L1. Analysis will include counting the number of cells 
per 40X field staining positively for each marker with at least four fields examined for each 
marker. 
 
8.4 
Safety and Other Assessments 
8.4.1 
Toxicity evaluation 
 
All patients entered into the study and who are given at least one dose of XmAb20717 
will have detailed information collected on adverse events for the overall study safety 
analysis. All adverse events will be categorized and tabulated using CTCAE v. 5.0. 
 
8.5 
Adverse Events and Serious Adverse Events 
8.5.1 
Definition of Adverse Events (AE) 
 
An adverse event (AE) is any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention related. Intercurrent 
illnesses or injuries should be regarded as adverse events. 
 
A pre-existing condition should be recorded as an adverse event if the frequency, intensity 
or the character of the condition changes. 
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any of the 
following conditions is met: 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality. 
• The abnormality suggests a disease and/or organ toxicity. 
• The abnormality is of a degree that requires active management. 
 
8.5.2 
Definition of Serious Adverse Events (SAE) 
 
Serious Adverse Events (SAE) 
Adverse events are classified as serious or non-serious. A serious adverse event is any 
AE that, in the view of the investigator, is: 
• fatal 

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• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event when the event does not fit the other outcomes, but 
the event may jeopardize the patient and may require medical or surgical 
intervention (treatment) to prevent one of the other outcomes. 
 
Important medical events are those 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 noted above. For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered 
serious. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events. 
 
8.5.3 
Classification of an Adverse Event 
8.5.3.1 
Severity of Event 
 
All AE’s will be categorized and graded using CTCAE v. 5.0. 
 
 
8.5.3.2 
Relationship to Study Intervention 
 
All adverse events (AEs) must have their relationship to the study intervention assessed 
by the Investigator who examines and evaluates the participant based on temporal 
relationship and his/her clinical judgment. The degree of certainty about causality will be 
graded using the categories below. In a clinical trial, the study product must always be 
considered. 
 
• Definitely Related – There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. The clinical event, including 
an abnormal laboratory test result, occurs in a plausible time relationship to the 
study intervention administration and cannot be explained by concurrent disease 
or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically 
or phenomenologically definitive, with use of a satisfactory rechallenge procedure 
if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 

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laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other drugs 
or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., 
the event occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may rate 
only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as 
appropriate. 
• Unrelated – The AE is completely independent of the study intervention 
administration, and/or evidence exists that the event is definitely related to another 
etiology. There must be an alternative, definitive etiology documented by the 
clinician. 
 
8.5.3.3 
Expectedness 
 
The principal investigator will be responsible for determining expectedness; and the latest 
approved IB-RSI will be used. 
 
8.5.4 
Time Period and Frequency for Event Assessment and Follow-Up 
 
Safety will be assessed by monitoring and recording potential adverse effects using the 
CTCAE v. 5.0 at each study visit. Participants will be monitored by medical histories, 
physical examinations, and laboratory studies as outlined in Appendix 12.1 SoA. If 
CTCAE v. 5.0 grading does not exist for an adverse event, the severity of mild, moderate, 
severe, life-threatening, and death, corresponding to Grades 1-5, will be used whenever 
possible. 
 
At each contact with the patient, the investigator will seek information on adverse events 
by non-directive questioning and, as appropriate, by examination. Adverse events may 
also be detected when they are volunteered by the patient during the screening process 
or between visits, or through physical examination, laboratory test, or other assessments. 
Information on all adverse events will be recorded in the source documentation. To the 
extent possible, adverse events will be recorded as a diagnosis and symptoms used to 
make the diagnosis recorded within the diagnosis event. 
 
 
As much as possible, each adverse event or follow-up information will be evaluated to 
determine: 
1. Severity grade (CTCAE Grade 1-5) 
2. Duration (start and end dates) 
3. Relationship to the study treatment or process – Reasonable possibility that AE is 
related: No (unrelated/ not suspected) or Yes (a suspected adverse reaction). If 

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yes (suspected) - is the event possibly, probably or definitely related to the 
investigational treatment? 
4. Expectedness to study treatment or process – Unexpected – if the event severity 
and/or frequency is not described in the RSI section of the investigator brochure. 
5. Action taken with respect to study or investigational treatment or process (none, 
dose adjusted, temporarily interrupted, permanently discontinued, unknown, not 
applicable) 
6. Whether medication or therapy taken (no concomitant medication/non-drug 
therapy, concomitant medication/non-drug therapy) 
7. Whether the event is serious 
 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the 
study treatment, the interventions required to treat it, and the outcome. 
8.5.5 
Adverse Event Reporting 
Reporting Period 
Adverse events will be reported from the beginning of the reporting period (defined as 
time of first study treatment) until the end of the reporting period (defined as 30 days  after 
the last XmAb20717 infusion for patients in whom XmAb20717 treatment is permanently 
discontinued, initiation of another anti-cancer therapy, or withdrawal of consent by 
participant, whichever occurs first).  
 
Immune related adverse events will be reported from the time of first study treatment until 
90 days after the last XmAb20717 infusion (for patients in whom XmAb20717 treatment 
is permanently discontinued) or withdrawal of consent by participant, whichever occurs 
first.  
 
During the the screening period (prior to the beginning of the reporting period) and the follow-up 
period (after the end of the reporting period defined above), adverse events, including 
SAEs, that are unrelated to study treatment do not need to be reported.  
 
Investigator Reporting: Notifying Xencor 
Fatal drug-related SAEs should be reported to Xencor within the next business day after 
the day of awareness of the event.  
 
Life-threatening drug-related SAEs should be reported to Xencor within three business 
days of Principal Investigator’s determination of event and no later than five business 
days from the day of awareness of the event. 
 
Drug-related non-life-threatening and non-fatal SAEs should be reported to Xencor within 
seven (7) calendar days after the day of awareness of the event. 
 
All other reportable information (overdose, newly  diagnosed  cancer,  exposure  during  

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pregnancy  or  lactation,  non-drug  related  SAEs  and  cases  of  Potential  Drug-Induced  
Liver  Injury  where  the  subject  was exposed to the Xencor product) should be reported 
to Xencor within 10 calendar days after the day of awareness of the event 
 
For patients in screening (prior to the beginning of the reporting period) or those in follow-
up after the end of the reporting period defined in Reporting Period above, only SAEs 
potentially related to XmAb20717 or study procedures will be reported. 
 
Recurrent episodes, complications, or progression of the initial SAE must be reported to 
Xencor as a follow-up to the original episode within 2 business days of the investigator 
receiving the follow-up information. A SAE considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
 
Send the SAE report to the icon-mads@iconplc.com. 
 
New information regarding the SAE will be reported as it becomes available and in the 
same manner that the initial SAE (i.e. SAE form). The investigator must follow the event 
to resolution or until the event is deemed and documented irreversible, whichever is 
longer. 
 
All non-serious AEs should be compiled as an Excel spreadsheet derived from the clinical 
database quarterly (the first day of each quarter) and emailed to Xencor’s 
pharmacovigilance group (ma.pv@xencor.com) unless there is critical and important 
information that should be reported to Xencor as soon as possible. If an AE requires 
action by Xencor to prevent unreasonable risk of substantial harm to the public health, 
then notice of such event shall be given by telephone to Xencor and emailed to Xencor 
(ma.pv@xencor.com) as soon as possible.  
 
 
Investigator Reporting: Local Reporting Requirements 
The investigator will report AEs and SAEs to the IRB/EC of record and other local 
regulatory groups per the local requirements. 
 
8.5.6 
Serious Adverse Event Reporting 
 
The study sponsor will be responsible for notifying the Food and Drug Administration 
(FDA) of any unexpected serious adverse reactions (fatal or life-threatening suspected 
adverse reactions within 7 calendar days and all other serious adverse reactions within 
15 calendar days) per applicable regulations. In addition, the study sponsor must notify 
FDA and all participating investigators of potential serious risks, from XmAb20717 clinical 
trials or any other source, as per the applicable regulation. 
 
8.5.7 
Reporting Events to Participants 
 
If an event occurs that requires change to the study consent form, patients will be notified 
and re-consented prior to continued study participation. Otherwise, individual AEs and 

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SAEs will not be reported to other patients. 
 
8.5.8 
Events of Special Interest 
 
Not applicable. 
 
8.5.9 
Reporting of Pregnancy 
 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study 
drug or process may have interfered with the effectiveness of a contraceptive medication 
or method. When a pregnancy has been confirmed in a patient or patient’s female partner, 
and the fetus is exposed to study drug and/or process (maternally or paternally), the 
following procedures should be followed to ensure patient safety: 
 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation. 
Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications.  
The pregnancy should be reported to Xencor within 10 calendar days after the day of 
awareness of the event. 
 
 

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8.6 
Unanticipated Problems 
8.6.1 
Definition of Unanticipated Problems (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all the following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
Institutional Review Board (IRB)-approved research protocol and informed 
consent document; and (b) the characteristics of the participant population being 
studied; 
• Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
8.6.2 
Unanticipated Problem Reporting 
 
Unanticipated problems (UPs) such as: 
 
• 
Post-marketing withdrawal of a drug, device, or biologic used in a research 
protocol due to safety concerns. 
• 
FDA ban of a drug, device, or biologic used in a research protocol due to safety 
concerns. 
• 
Complaint of a participant when the complaint indicates unexpected risks, or the 
complaint cannot be resolved by the research team 
• 
Breach of confidentiality 
• 
Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the patient 
to remain on the study 
• 
Premature closure of a study (e.g., due safety, lack of efficacy, feasibility, financial 
reasons, etc.) 
 
should be reported by the investigator to the Sponsor, reviewing Institutional Review 
Board (IRB) and to the lead principal investigator (PI). The UP report will include the 
following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 

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• A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
 
• UPs that are serious adverse events (SAEs) will be reported as any other SAE. 
• Any other UP will be reported to the Sponsor and IRB within 10 business days of 
the investigator becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or 
designee), and the Office for Human Research Protections (OHRP) within 10 
business days of the IRB’s receipt of the report of the problem from the investigator. 
 
8.6.2.1 
Reporting Unanticipated Problems To Participants 
 
If unanticipated problem results in a change to the consent form, all patients on study will 
be re-consented. If unanticipated event results in closure of the study, patients on-study 
will be alerted on an individual basis. 
 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
 
Primary Efficacy Endpoint(s): Overall response rate (ORR) by investigator review using 
RECIST v. 1.1 (binary). The null hypothesis is an ORR of 5% and the one-sided 
alternative hypothesis is that the ORR will be greater than 5%. 
 
Secondary Endpoint(s): 
• Toxicity rates will be assessed as ordinal measures (e.g., Grade 1 
pneumonitis, Grade 2 pneumonitis, etc.) using CTCAE v. 5.0. Toxicity rates 
will also be assessed as a binary measure of proportion of patients 
experiencing each toxicity. 
• Overall response rate (ORR) using iRECIST criteria (binary variable) 
• Progression free survival (PFS) (time to event variable) 
• Duration of response (DOR) (time to event variable) 
• Overall survival (time to event variable) 
 
9.2 
Sample Size Determination 
 
Sample size determination is made on the basis of the primary outcome of ORR by 
RECIST v. 1.1. We will perform a Simon two-stage mini-max design. The null ORR is 5% 
based on a 5% ORR for standard-of-care second line therapy with FOLFOX and ORRs 
of 3 – 7% observed in phase II trials of single agent immune check point inhibitor therapy 
with PD-1 and PD-L1 inhibitors.6,8–10 The null hypothesis will be tested against a one- 
sided alternative. In the first stage, 13 patients evaluable for efficacy will be accrued. If no 

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responses are observed in these 13 patients, the study will be stopped for futility. 
Otherwise, 14 additional patients evaluable for efficacy will be accrued for a total of 27 
evaluable patients. If 4 or more responses are observed in 27 evaluable patients, then 
the null hypothesis will be rejected. This design yields a type I error rate of 0.05 and a 
power of 80% when the true ORR is 20%.27 
 
9.3 
Populations for Analyses 
 
9.3.1 
Efficacy Analysis 
 
To be eligible for efficacy endpoints (ORR, PFS, DOR, and OS), patients must have 
completed at least one cycle of therapy (two infusions). To be evaluable for ORR, PFS, 
and DOR patients must also have had their disease re-evaluated by appropriate cross- 
sectional imaging (CT or MRI) at least 4 weeks and no more than 12 weeks after their 
baseline imaging. Patients who do not meet criteria for the ORR efficacy analysis will be 
replaced. 
 
9.3.2 
Safety Analysis 
 
All patients entered into the study, who are given at least one dose of XmAb20717 will 
have detailed information collected on adverse events for the overall study safety analysis. 
 
9.4 
Statistical Analyses 
9.4.1 
General Approach 
 
The primary endpoint of ORR by RECIST v. 1.1 and other binary endpoints will be 
summarized as binomial proportions with 95% confidence intervals. This includes the 
secondary endpoint of ORR within subgroups of patients defined by receipt of prior 
immune checkpoint inhibitor therapy. Time to event endpoints including PFS, DOR, and 
OS will be analyzed using Kaplan Meier methods and will be summarized using medians 
with 95% confidence intervals. Adverse events will be summarized as binomial 
proportions with 95% confidence intervals. 
 
Baseline clinical and demographic characteristics will be summarized using mean and 
standard deviation for continuous variables and as a proportion of patients falling into 
each category for categorical variables. 
 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) 
 
As stated in section 9.2, the study will proceed via a Simon two-stage mini-max design. 
In the first stage, 13 patients evaluable for ORR will be accrued. If no responses are 
observed in these 13 patients, the study will be stopped for futility. Otherwise, 14 
additional patients evaluable for ORR will be accrued for a total of 27 evaluable patients. 
If 4 or more responses are observed in 27 evaluable patients, then the null hypothesis 
will be rejected. This methodology is based on using a one-sided alternative hypothesis 
for ORR compared to a null hypothesis ORR of 5% using a binomial exact test with a type I 

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error rate of 0.05. 
 
9.4.3 
Analysis of the Secondary Endpoint(s) 
 
Secondary endpoints will be summarized as noted in section 9.4.1 and will not undergo 
formal statistical testing. 
 
9.4.4 
Safety Analyses 
 
All adverse events will be categorized by CTCAE v. 5.0, tabulated as ordinal (Grade 1 
through Grade 5), and summarized as binomial proportions (proportion of patients 
experiencing each event). Adverse events leading to discontinuation of therapy, serious 
adverse events, and adverse events of Grade 3 or higher will also be presented as 
binomial proportions. 
 
9.4.5 
Baseline Descriptive Statistics 
 
Descriptive statistics will be performed as noted in section 9.4.1. 
 
9.4.6 
Planned Interim Analyses 
 
Planned interim analysis is described in section 9.4.2. 
 
9.4.7 
Sub-Group Analyses 
 
Any sub-group analyses performed will be exploratory in nature as the study will not be 
powered to assess differences in outcomes between sub-groups. This includes the 
secondary analysis examining ORR within subgroups of patients defined by prior receipt 
of immune checkpoint inhibitor therapy.  
 
9.4.8 
Tabulation of Individual Participant Data 
 
Individual participant outcome data may be presented in a de-identified fashion, for 
example, in the form of swimmer’s plots or waterfall plots to provide a visual summary of 
the depth and duration of clinical responses. 
 
9.4.9 
Exploratory Analyses 
 
Analysis of immune markers in tissue and blood will be a hypothesis-generating 
exploration of potential predictive biomarkers. 
 
Immunohistochemical markers (IHC) on tissue samples will be reported as number of 
cells staining for each marker per 40X field (with at least 4 fields examined, continuous 
variable) and as a proportion of examined cells that stain positive for the marker from the 
total number of cells examined (proportion). Individual IHC markers may also be reported 
on an ordinal scale (e.g. 1+, 2+, 3+, etc.). If RNA sequencing is performed, normalized 

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gene expression for genes of interest will be calculated using a stably expressed gene 
and reported as a continuous variable. Multi-parameter flow cytometry for immune cell 
markers will be reported as a proportion of mononuclear cells represented by each cell 
type (proportion) and as a count of each cell type per volume of blood (continuous 
variable). 
 
Logistic regression will be used to evaluate association of response status (binary) with 
baseline markers. Cox-proportional hazards regression models will be used to evaluate 
associations between exploratory markers and PFS, OS, and DOR. 
 
To evaluate changes in blood markers with treatment, pre- and post-treatment 
comparisons will be made using paired, two-tailed t-tests with type I error rate of 0.05 for 
variables that can be treated as continuous variables (e.g., cell counts per unit volume, 
proportion of cell staining positive for IHC marker, ordinal reporting of IHC marker). 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Informed Consent Process 
10.1.1.1 
Consent/Assent and Other Informational Documents Provided To 
Participants 
 
Consent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required prior 
to administering the study intervention. The following consent materials are submitted 
with this protocol: Patient Informed Consent Form. 
 
10.1.1.2 
Consent Procedures and Documentation 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Consent forms will be Institutional Review Board (IRB)-approved and the participant will 
be asked to read and review the document. The investigator will explain the research 
study to the participant and answer any questions that may arise. A verbal explanation 
will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The participants should have the opportunity to discuss the 
study with their family or surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants must be informed that participation is voluntary and 
that they may withdraw from the study at any time, without prejudice. A copy of the 
informed consent document will be given to the participants for their records. The 
informed consent process will be conducted and documented in the source document 
(including the date), and the form signed, before the participant undergoes any study- 
specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if 

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they decline to participate in this study. 
 
 
 
10.1.2 
Study Discontinuation and Closure 
 
This study may be temporarily suspended or prematurely terminated by the Sponsor or 
the PI if there is sufficient reasonable cause. Written notification, documenting the reason 
for study suspension or termination, will be provided by the suspending or terminating 
party to study participants, investigator, funding agency, the Investigational New Drug 
(IND) sponsor and regulatory authorities. If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality 
are addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
In terminating the study, the Sponsor and the Principal Investigator will assure that 
adequate consideration is given to the protection of the patients’ interests. 
 
10.1.3 
Confidentiality and Privacy 
 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor(s) and their interventions. This confidentiality is 
extended to cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, 
and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor. 
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of 
the Institutional Review Board (IRB), regulatory agencies or pharmaceutical company 
supplying study product may inspect all documents and records required to be maintained 

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by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the Abramson Cancer Center in the Velos 
clinical trial database. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems 
used by clinical sites and by the Abramson Cancer Center research staff will be secured 
and password protected. At the end of the study, all study databases will be de-identified 
and archived at the Abramson Cancer Center. 
 
10.1.4 
Future Use of Stored Specimens and Data 
 
Data collected for this study will be analyzed and stored at the Abramson Cancer Center. 
After the study is completed, the de-identified, archived data will continue to be stored at 
the Abramson Cancer Center for use by other researchers including those outside of the 
study. Permission to use the de-identified data upon completion of the study will be 
included in the informed consent. 
 
With the participant’s approval and as approved by local Institutional Review Boards 
(IRBs), de-identified biological samples will be stored at the Abramson Cancer Center. 
These samples could be used to research the causes of advanced biliary tract cancer, its 
complications, and to improve treatment. The Abramson Cancer Center will also be 
provided with a code-link that will allow linking the biological specimens with the 
phenotypic data from each participant, maintaining the blinding of the identity of the 
participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent 
to have biological specimens stored for future research. However, withdrawal of consent 
regarding biosample storage may not be possible after the study is completed. 
 
When the study is completed, access to study data and/or samples may be provided 
through the Abramson Cancer Center. 
 
10.1.5 
Safety Oversight 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site. This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and 

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implementation of a site data and safety-monitoring plan. Medical monitoring will include 
a regular assessment, at least every 6 months, of the number and type of serious adverse 
events by an independent clinician, Roger Cohen, MD. Additionally, the Medical Monitor 
will be consulted for protocol exceptions and deviations and as needed for decision- 
making regarding dose modifications, study eligibility, and any need to stop enrollment or 
the study for safety concerns. 
 
10.1.6 
Clinical Monitoring 
 
This study will be monitored in accordance with the Cancer Center’s Clinical Trials 
Scientific Review and Monitoring Committee (CTSRMC) Plan, approved by NCI during 
the Core Grant’s most recent review. This plan requires that the investigator submit a 
study-specific plan outlining how data will be reviewed. In addition, the CTSRMC plan 
calls for an internal audit by the Cancer Center’s Data Safety Committee twice yearly. 
 
The investigator will allocate adequate time for such monitoring activities. The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is 
given access to all the above noted study-related documents and study related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. 
 
10.1.7 
Quality Assurance and Quality Control 
 
All monitoring and audits are to be performed according to ICH GCP E6(R2). 
 
Each clinical site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion. An individualized quality 
management plan will be developed to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data 
or data anomalies will be communicated to the PI for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated, and specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)). 
 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, 
and inspection by local and regulatory authorities. 
 
10.1.8 
Data Handling and Record Keeping 
10.1.8.1 
Data Collection and Management Responsibilities 

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Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. All data requested on source documents must be recorded. All 
missing data must be explained. If a space on the source document is left blank because 
the procedure was not done, or the question was not asked, write “N/D”. If the item is not 
applicable to the individual case, write “N/A.”. All entries should be printed legibly in black 
ink. If any entry error has been made, to correct such an error, draw a single straight line 
through the incorrect entry and enter the correct data above it. All such changes must be 
initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For clarification of 
illegible or uncertain entries, print the clarification above the item, then initial and date it. 
 
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study. Data recorded in 
the electronic case report form (eCRF) derived from source documents should be 
consistent with the data recorded on the source documents. 
 
Clinical data (including adverse events (AEs), concomitant medications, and expected 
adverse reactions data) and clinical laboratory data will be entered into the Velos data 
management system a 21 CFR Part 11-compliant data capture system provided by the 
Abramson Cancer Center. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
Clinical and laboratory data will be entered into a 21 CFR Part 11-compliant electronic 
data capture system (EDC) that includes individual user account level password 
protection. This EDC (Velos version 9) supports programmable data entry validation rules 
and edit checks to identify data entry errors. 
 
10.1.8.2 
Study Records Retention 
 
Study documents should be retained for a minimum of 2 years after the last approval of 
a marketing application in an International Conference on Harmonization (ICH) region 
and until there are no pending or contemplated marketing applications in an ICH region 
or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of XmAb20717. These documents should be retained for a longer period, 
however, if required by local regulations. No records will be destroyed without the written 
consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform the 
investigator when these documents no longer need to be retained. 
 
10.1.9 
Protocol Deviations 
 
The PI and the study team should document all scenarios where the protocol is not 
followed and provide, in particular: 

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• Who deviated from the protocol 
• What was the deviation 
• When did the deviation occur 
• How did the deviation happen 
• What is the impact of the deviation 
• A root cause analysis of why the deviation occurred 
 
If the assessment results in a determination that any of the following are potentially 
affected, the deviation would be considered of significant impact: 
• having the potential to adversely affect patient safety; OR 
• increases risks to participants; OR 
• adversely affects the integrity of the data; OR 
• violates the rights and welfare of participants, OR 
• affects the patient’s willingness to participate in research. 
• there is a potential for an overall impact on the research that should be shared with 
the IRB for consideration and development of next best steps to address it 
 
10.1.10 
Publication and Data Sharing Policy 
 
This study will comply with the data sharing agreement. 
 
The Sponsor must approve all sharing of information/data prior to its occurrence. 
 
Neither the complete nor any part of the results of the study carried out under this protocol, 
nor any of the information provided by the sponsor for the purposes of performing the 
study, will be published or passed on to any third party without the consent of the Principal 
Investigator. Any investigator involved with this study is obligated to provide the Principal 
Investigator with complete test results and all data derived from the study. 
 
10.1.11 
Conflict of Interest Policy 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons 
who have a role in the design, conduct, analysis, publication, or any aspect of this trial 
will be disclosed and managed. Furthermore, persons who have a perceived conflict of 
interest will be required to have such conflicts managed in a way that is appropriate to 
their participation in the design and conduct of this trial. 
 
10.2 Additional Considerations 
 
Not applicable 
 
 

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10.3 Protocol Amendment History 
 
 
Version 
Date 
Description of Change 
Brief Rationale 
2.0 
01/26/2022 Section 1.1 and Section 7.1 
updated to reflect that study 
treatment will be discontinued at 
two years for patients who 
remain on therapy. For patients 
who complete two years of study 
treatment and experience 
disease progression after study 
treatment discontinuation, study 
treatment may be re-initiated 
Clarify study treatment 
duration. 
3.0 
04/05/2022 Added additional correlative 
blood draws.  Updated AE and 
SAE reporting to match CTA 
Monitor longer term changes 
in immune system. 
4.0 
02/25/2023 Changed exclusion criteria to 
allow prior immune checkpoint 
inhibitor therapy. Added 
secondary analysis examining 
ORR within subgroups of 
patients defined by receipt of 
prior immune checkpoint inhibitor 
therapy. Clarified inclusion 
criteria to note that tumor 
sequencing results not required 
to enroll on the study. Clarified 
that study procedures not 
performed due to SAEs are 
omitted and are not considered 
deviations. Updated definition of 
AE/SAE reporting period and 
clarified that events outside of 
this reporting period only need to 
be reported if possibly related to 
study interventions or 
procedures.  
Increasing population of 
patients receiving immune 
checkpoint inhibitor therapy 
as part of standard of care 
first-line therapy.  
Clarification of language 
surrounding inclusion criteria 
and contradictory language 
surrounding adverse event 
reporting.  
 
11 REFERENCES 
 
1. Yao KJ, Jabbour S, Parekh N, Lin Y, Moss RA. Increasing mortality in the United 
States from cholangiocarcinoma: an analysis of the National Center for Health 
Statistics Database. BMC Gastroenterol. 2016;16. doi:10.1186/s12876-016-0527-z 
 

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2. Bertuccio P, Malvezzi M, Carioli G, et al. Global trends in mortality from intrahepatic 
and extrahepatic cholangiocarcinoma. J Hepatol. 2019;71(1):104-114. 
doi:10.1016/j.jhep.2019.03.013 
 
3. Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX. New Horizons for Precision 
Medicine in Biliary Tract Cancers. Cancer Discov. 2017;7(9):943-962. 
doi:10.1158/2159-8290.CD-17-0245 
 
4. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine 
for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281. 
doi:10.1056/NEJMoa0908721 
 
5. Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, Cisplatin, and nab-Paclitaxel for the 
Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial. JAMA Oncol. 
2019;5(6):824-830. doi:10.1001/jamaoncol.2019.0270 
 
6. Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX 
chemotherapy versus active symptom control for advanced biliary tract 
cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet 
Oncol. 2021;22(5):690-701. doi:10.1016/S1470-2045(21)00027-9 
 
7. Lamarca A, Palmer DH, Watson HS, et al. ABC-06 | A randomised phase III, multi- 
centre, open-label study of active symptom control (ASC) alone or ASC with 
oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally 
advanced / metastatic biliary tract cancers (ABC) previously-treated with 
cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol. Accessed May 29, 
2021. http://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.4003 
 
8. Bang Y-J, Ueno M, Malka D, et al. Pembrolizumab (pembro) for advanced biliary 
adenocarcinoma: Results from the KEYNOTE-028 (KN028) and KEYNOTE-158 
(KN158) basket studies. J Clin Oncol. Accessed May 29, 2021. 
http://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.4079 
 
9. Yarchoan M, Cope L, Anders RA, et al. Abstract CT043: A multicenter randomized 
phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in 
biliary tract cancers (BTCs): A NCI Experimental Therapeutics Clinical Trials 
Network (ETCTN) study. Cancer Res. 2020;80(16 Supplement):CT043-CT043. 
doi:10.1158/1538-7445.AM2020-CT043 
 
10. Ioka T, Ueno M, Oh D-Y, et al. Evaluation of safety and tolerability of durvalumab 
(D) with or without tremelimumab (T) in patients (pts) with biliary tract cancer (BTC). 
J Clin Oncol. Accessed May 29, 2021. 
http://ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.387 
 
11. Klein O, Kee D, Nagrial A, et al. Evaluation of Combination Nivolumab and 
Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: 
Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 

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2020;6(9):1405-1409. doi:10.1001/jamaoncol.2020.2814 
 
12. Sahai V, Griffith KA, Beg MS, et al. A multicenter randomized phase II study of 
nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line 
therapy for patients with advanced unresectable biliary tract cancer (BilT-01). J Clin 
Oncol. 2020;38(15_suppl):4582-4582. doi:10.1200/JCO.2020.38.15_suppl.4582 
 
13. Oh D-Y, Lee K-H, Lee D-W, et al. Phase II study assessing tolerability, efficacy, and 
biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin 
(GemCis) in chemo-naïve advanced biliary tract cancer (aBTC). J Clin Oncol. 
2020;38(15_suppl):4520-4520. doi:10.1200/JCO.2020.38.15_suppl.4520 
 
14. Hickingbottom B, Clynes R, Desjarlais J, Li C, Ding Y. Preliminary safety and 
pharmacodynamic (PD) activity of XmAb20717, a PD-1 x CTLA-4 bispecificantibody, 
in a phase I dose escalation study of patients with selected advanced solid tumors. J 
Clin Oncol. 2020;38(15_suppl):e15001-e15001. 
doi:10.1200/JCO.2020.38.15_suppl.e15001 
 
15. Spiess C, Zhai Q, Carter PJ. Alternative molecular formats and therapeutic 
applications for bispecific antibodies. Mol Immunol. 2015;67(2, Part A):95-106. 
doi:10.1016/j.molimm.2015.01.003 
 
16. Blincyto(R) (Blinatumomab0 [Package Insert]. Amgen, Inc.; 2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2020/761049s005lbl.pdf 
 
17. Bavencio(R) (Avelumab) [Package Insert]. EMD Serono, Inc; 2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761049s006lbl.pdf 
 
18. Imfinizi(R) (Durvalumab) [Package Insert]. AstraZeneca Pharmaceuticals LP.; 2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761069s029lbl.pdf 
 
19. KEYTRUDA-Pembrolizumab Injection [Package Insert].; 2014. 
 
20. Libtayo(R) (Cemiplimab-Rwlc) [Package Insert]. Regeneron Pharmaceuticals, Inc.; 
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21. Opdivo(R) (Nivolumab) [Package Insert]. Bristol-Meyers Squibb Company; 2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf 
 
22. Tecentriq(R) (Atezolizumab) [Package Insert]. Genentech, Inc.; 2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s010lbl.pdf 
 
23. Yervoy(R) (Ipilimumab) [Package Insert]. Bristol-Meyers Squibb Company; 2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125377s073lbl.pdf 
 
24. National Comprehensive Cancer Network Clinical Practices Guidelines in 
Management of Immunotherapy-Related Toxicities. Version 3.2021. Published 

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online May 14, 2021. Accessed June 26, 2021. 
https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf 
 
25. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with 
immune checkpoint blockade: a comprehensive review. Eur J Cancer Oxf Engl 
1990. 2016;54:139-148. doi:10.1016/j.ejca.2015.11.016 
 
26. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria 
for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 
doi:10.1016/S1470-2045(17)30074-8 
27. Ivanova A. Simon’s Two-Stage design. Accessed July 9, 2021. 
http://cancer.unc.edu/biostatistics/program/ivanova/SimonsTwoStageDesign.aspx 

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12 APPENDIX 
12.1 
Schedule of Activities (SoA) 
 
All labs and study visits have a window of +/- 4 days. All imaging has a window of +/- 7 days 
 
Table 3: Schedule of Activities 
 
Study Phase 
Screening 
Cycle 1 (28 days) Cycles 
2+ 
(28 days) 
Post-treatment 
Day 
-28 - 0 
1 
8 
15 
1 
15 
EOT 
Safety 
follow- 
up1 
Follow-up2 
Administrative Procedures 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Demographics 
and 
medical 
history 
X 
Prior 
and 
concomitant 
medication review 
X 
X 
X 
X 
X 
Trial treatment administration 
X 
X 
X 
X 
Post-study anticancer therapy 
status 
X 
Survival status 
X 
Clinical Procedures/Assessments 
Review adverse events 
X 
X 
X 
X 
X 
X 
Full physical examination 
X 
Targeted physical examination 
X 
X 
X 
X 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
X 

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ECOG performance status 
X 
X 
X 
X 
X 
X 
Laboratory procedures and assessments: Analysis performed by LOCAL laboratory 
Pregnancy test - serum beta 
HCG 
X3 
CBC with differential 
X 
X 
X 
X 
X 
X 
Comprehensive 
metabolic 
panel 
X 
X 
X 
X 
X 
X 
TSH with reflex free T4 
X 
X 
X 
Tumor Markers: CA19-9, CEA4 X 
X 
X 
Tumor imaging (CT or MRI) 
X 
X5 
X 
Correlative 
studies 
blood 
collection 
X 
X 
X 
X6 
Tissue collection (archival or 
fresh biopsy if insufficient)7 
X 
 
1Safety follow up via phone call or office visit will occur at 30 and 90 days after treatment discontinuation to evaluate 
immune-related adverse events. 
2Follow up will be through review of the available medical record and/or phone calls every 6 months for up to 2 years. 
3Pregnancy testing is applicable to women of reproductive potential defined in section 8.2.11. 
4CA 19-9 should only be collected for subsequent blood draws if abnormal at baseline testing. CEA should be drawn only 
at baseline unless CA 19-9 normal and baseline CEA abnormal. 
5Tumor imaging should occur prior to cycle 3 day 1, cycle 5 day 1, and cycle 7 day 1, then every 12 weeks or every third 
cycle thereafter (imaging every 8 weeks for 24 weeks then every 12 weeks thereafter). Imaging should include CT of the 
chest and MRI or CT of the abdomen +/- pelvis as documented in section 8.3.1. 
6Correlative blood studies should be collected as indicated at cycle 1 day 1 prior to treatment, cycle 1 day 8, cycle 1 day 15, 
cycle 2 day 1, cycle 3 day 1, cycle 4 day 1, and cycle 5 day 1.  
7Tissue biopsy (either archival or fresh) is required for confirmation of diagnosis prior to enrollment in the study 

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12.2 National Comprehensive Cancer Network Management of Immunotherapy-related toxicities 
 
For a full reference of NCCN management guidelines for irAEs, see the NCCN Clinical Practice Guidelines in Oncology for 
the Management of Immunotherapy-Related Toxicities (Version 3.2021).24 
Table 4: Dermatologic Adverse Event Management Algorithm 
 
Adverse Event 
Grade 
Management 
Maculopapular Rash 
1 
Continue immunotherapy 
Topical emollient 
Oral antihistamine for pruritus 
Treatment with moderate potency topical steroids to affected areas 
2 
Continue immunotherapy 
Topical emollient 
Oral antihistamine for pruritus 
Treatment with moderate to high potency topical steroids to affected areas 
If unresponsive to topical, consider prednisone 0.5 mg/kg/day 
3 or 4 
Hold immunotherapy 
Treatment with high potency topical steroids to affected areas 
Prednisone 0.5 – 1 mg/kg/day (increase dose up to 2 mg/kg/day if no improvement) 
Urgent dermatology consultation, consider biopsy 
Consider inpatient care 
Pruritus 
1 
Continue immunotherapy 
Oral antihistamines 
Treatment with moderate potency topical steroids to affected areas or lidocaine 
patches for localized pruritus 
2 
Continue immunotherapy with intensified antipruritic therapy 
Oral antihistamines 
Consider gabapentinoids (gabapentin, pregabalin) 
Treatment with high potency topical steroids to affected areas 
Dermatology consultation 

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Adverse Event 
Grade 
Management 
3 
Hold immunotherapy 
Oral antihistamines 
Prednisone/methylprednisolone 0.5 – 1 mg/kg/day 
Consider gabapentinoids (gabapentin, pregabalin) 
Consider aprepitant or omalizumab for refractory cases 
Urgent dermatology consultation 
Bullous dermatitis 
1 
Hold immunotherapy 
High potency topical steroids to affected areas 
2 
Hold immunotherapy until < G1 
Prednisone/methylprednisolone 0.5 – 1 mg/kg/day 
If no improvement after 3 days, consider adding rituximab 
3 or 4 
Permanently discontinue immunotherapy 
Prednisone/methylprednisolone 1 – 2 mg/kg/day 
If no improvement after 3 days, consider adding rituximab or IVIG (1 g/kg/day in 
divided doses per package insert for 3 – 4 days) 
Inpatient care required 
Urgent dermatology, ophthalmology, and urology consultation 
SJS or TEN 
N/A 
Permanently discontinue immunotherapy 
Prednisone/methylprednisolone 1 – 2 mg/kg/day 
Consider IVIG (1 g/kg/day in divided doses per package insert for 3 – 4 days) 
Inpatient care required 
Urgent dermatology, ophthalmology, and urology consultation 
 
G1 = Grade 1; IVIG = intravenous immunoglobulin; N/A = Not Applicable; SJS = Stevens-Johnson syndrome; TEN = toxic 
epidermal necrolysis. 
 
 
Table 5: Gastrointestinal Adverse Event Management Algorithm 

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Adverse Event 
Grade 
Management 
Diarrhea or Colitis 
1 
Consider holding immunotherapy 
Loperamide or diphenoxylate/atropine for 2 – 3 days 
• If no improvement and not already done, obtain labs for infectious workup 
Hydration 
Close monitoring 
• If persistent or progressive symptoms, check lactoferrin/calprotectin 
o If positive, treat as G2 (below) 
o If negative and no infection, continue G1 management and add 
mesalamine, cholestyramine 
2 
Hold immunotherapy 
Prednisone/methylprednisolone (1 – 2 mg/kg/day) 
No response in 2 – 3 days, continue steroids, consider adding infliximab or 
vedolizumab within 2 weeks 
3 - 4 
G3: Discontinue anti-CTLA4; consider resuming anti-PD1/PDL1 after resolution of 
toxicity# 
G4: Permanently discontinue immunotherapy agent responsible for toxicity 
Consider inpatient care for provision of supportive care 
IV methylprednisolone (1 – 2 mg/kg/day) 
• No response in 2 days, continue steroids, strongly consider adding infliximab 
or vedolizumab within 2 weeks 
 
CTLA4= cytotoxic T-lymphocyte-associated protein; G = Grade; IV = intravenous; PD1 = programmed cell death protein 1; 
PDL1 = programmed cell death ligand 1. 
#If G3 toxicity occurs, XmAb20717 should be permanently discontinued. 
 
 
 
 
 

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Table 6: Hepatic Adverse Event Management Algorithm 
 
Adverse Event 
Grade 
Management 
Transaminitis 
without 
elevated bilirubin 
1 
< 3 × 
ULN 
Continue immunotherapy, consider holding immunotherapy for concerning lab value 
trend 
Assess transaminases and bilirubin with increased frequency 
2 
3 – 5 × 
ULN 
Hold immunotherapy 
Monitor LFTs every 3 – 5 days 
Consider prednisone 0.5 – 1 mg/kg/day 
3 
5 – 20 × 
ULN 
Hold immunotherapy 
Initiate prednisone 1 – 2 mg/kg/day; if steroid refractory or no improvement after 3 
days, consider adding mycophenolate 
Consider inpatient care 
Monitor liver enzymes every 1 – 5 days depending on the magnitude and rate of 
change 
Hepatology consultation 
Infliximab should not be used for hepatitis 
4 
> 20 × 
ULN 
Permanently discontinue immunotherapy 
Initiate prednisone/methylprednisolone 1 - 2 mg/kg/day; if steroid refractory or no 
improvement after 3 days, consider adding mycophenolate 
Inpatient care 
Monitor liver enzymes daily 
Hepatology consultation 
Consider liver biopsy if no contraindications 
Infliximab should not be used for hepatitis 
Grade > 1 transaminitis 
with bilirubin 1 - 3 × ULN 
(unless 
Gilbert’s 
syndrome) 
NA 
Hold immunotherapy 
Initiate prednisone/methylprednisolone 1 – 2 mg/kg/day 
Consider inpatient care 
Monitor liver enzymes and LFTs every 2 – 3 days 
Hepatology consultation 
If steroid refractory or no improvement after 3 days, consider adding mycophenolate 
Infliximab should not be used for hepatitis 

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Adverse Event 
Grade 
Management 
Grade > 1 transaminitis 
with bilirubin > 3 × ULN 
(unless 
Gilbert’s 
syndrome) 
N/A 
Permanently discontinue immunotherapy 
Initiate prednisone/methylprednisolone 1 - 2 mg/kg/day 
Inpatient care 
Monitor liver enzymes daily 
Hepatology consultation 
If steroid refractory or no improvement after 3 days, consider adding mycophenolate 
Infliximab should not be used for hepatitis 
 
LFT = liver function test; N/A = not applicable; ULN = upper limit of normal. 
 
Table 7: Pancreatic Event Management Algorithm 
 
Adverse Event 
Grade 
Management 
Elevation 
in 
amylase/lipase 
(asymptomatic) 
Mild ≤ 3 × ULN 
amylase 
and/or 
≤ 3 × ULN lipase 
If isolated elevation of enzymes without evidence of pancreatitis, continue 
immunotherapy 
Evaluate for pancreatitis 
• Clinical assessment 
• Consider abdominal CT with contrast 
• Consider MRCP 
If evidence of pancreatitis, manage according to pancreatitis algorithm 
(below) 
Consider other causes for elevated amylase/lipase 

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Moderate 
> 3 – 5 × 
ULN 
amylase 
and/or 
> 3 – 5 × 
ULN 
lipase 
If isolated elevation of enzymes without evidence of pancreatitis, consider 
continuing immunotherapy 
Evaluate for pancreatitis 
• Clinical assessment 
• If persistent moderate to severe amylase and/or lipase elevation, 
abdominal CT with contrast or MRCP 
Consider other causes for elevated amylase/lipase 
If evidence of pancreatitis, manage according to pancreatitis algorithm 
(below) 
Severe 
> 
5 
× 
ULN 
amylase 
and/or 
> 5 × ULN lipase 
If isolated elevation of enzymes without evidence of pancreatitis, consider 
continuing immunotherapy 
Evaluate for pancreatitis 
• Clinical assessment 
• If persistent moderate to severe amylase and/or lipase elevation, 
abdominal CT with contrast or MRCP 
Consider other causes for elevated amylase/lipase 
If evidence of pancreatitis, manage according to pancreatitis algorithm 
(below) 
Acute pancreatitis 
1 
Consider gastroenterology referral 
IV hydration 
Manage as per elevation in amylase/lipase (asymptomatic; above) 
2 
Hold immunotherapy 
Consider gastroenterology referral 
IV hydration 
Manage as per elevation in amylase/lipase (asymptomatic; above) 
3 
Hold immunotherapy 
Gastroenterology referral 
Prednisone/methylprednisolone 0.5 - 1 mg/kg/day 
IV hydration 

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4 
Permanently discontinue immunotherapy 
Gastroenterology referral 
IV hydration 
Prednisone/methylprednisolone 1 – 2 mg/kg/day 
 
CT =computed tomography; IV = intravenous; MRCP =magnetic resonance cholangiopancreatography; N/A = not 
applicable; ULN = upper limit of normal. 
 
 
 
 
 

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Table 8: Pulmonary Adverse Event Management Algorithm 
 
Adverse Event 
Grade 
Management 
Pneumonitis 
1 
Consider holding immunotherapy 
Reassess in 1 – 2 weeks 
• H&P 
• Pulse oximetry (resting and with ambulation) 
Consider chest CT with contrast 
• Consider repeat chest CT in 4 weeks or as clinically indicated for worsening 
symptoms 
2 
Hold immunotherapy 
Consider pulmonary consultation 
Consider infectious workup: 
• Nasal swab for potential viral pathogens 
• Sputum culture (including bacterial, fungal, and acid-fast bacilli), blood 
culture, and urine antigen test (pneumococcus, legionella) 
Consider bronchoscopy with BAL (send for institutional immunocompromised 
panel) and consider transbronchial lung biopsy if clinically feasible 
Consider chest CT with contrast 
• Repeat chest CT in 3 – 4 weeks 
Consider empiric antibiotics (including coverage of atypical pathogens) if infection 
has not yet been fully excluded 
Prednisone/methylprednisolone 1 – 2 mg/kg/day 
Monitor every 3 – 7 days with: 
• H&P 
• Pulse oximetry (resting and with ambulation) 
If no improvement after 48 – 72 hours of corticosteroids, treat as Grade 3 

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3 or 4 
Permanently discontinue immunotherapy 
Inpatient care 
Infectious workup: 
• Consider that patient may be immunocompromised 
• Nasal swab for potential viral pathogens 
• Sputum culture (including bacterial, fungal, and acid fast bacilli), blood 
culture, and urine culture 
Pulmonary and infectious disease consultation 
Bronchoscopy with BAL (send for institutional immunocompromised panel) if 
feasible to rule out infection and malignant lung infiltration and consideration of 
transbronchial lung biopsy if feasible and clinically indicated 
Consider empiric broad-spectrum antibiotics (including coverage for atypical 
pathogens) if infection has not yet been fully excluded 
Methylprednisolone 1 – 2 mg/kg/day. Assess response within 48 hours and plan 
taper over ≥ 6 weeks 
Consider adding any of the following if no improvement after 48 hours: 
• Infliximab 5 mg/kg IV, a second dose may be repeated 14 days later at the 
discretion of the treating provider 
• IVIG 
• Mycophenolate mofetil 1 – 1.5 g BID then taper in consultation with 
pulmonary service 
 
BAL = bronchoalveolar lavage; BID = twice a day; CT =computed tomography; H&P = history and physical; IV = intravenous; 
IVIG = intravenous immunoglobulin 
 
 
 
 
 

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Table 9: Renal Adverse Event Management Algorithm 
 
Adverse Event 
Grade 
Management 
Elevated 
serum 
creatinine/acute 
renal 
failure 
1 
Consider holding immunotherapy 
Follow creatinine and urine protein/creatinine ratio every 3 – 7 days 
Consider nephrology consult if creatinine remains unchanged over 2 weeks 
2 
Hold immunotherapy 
Follow creatinine and urine protein/creatinine ratio every 3 – 7 days 
Nephrology consultation, consider renal biopsy if feasible prior to starting steroids 
Start prednisone 0.5 – 1 mg/kg/day if other causes are ruled out 
For persistent G2 beyond 1 week, prednisone/methylprednisolone 1 – 2 mg/kg/day 
3 or 4 
Permanently discontinue immunotherapy 
Consider inpatient care 
Follow creatinine and urine protein/creatinine ratio every 3-7 days 
Nephrology consultation 
Consider renal biopsy if feasible prior to starting steroids 
Prednisone/methylprednisolone 1 – 2 mg/kg/day 
Consider adding one of the following if > G2 after 4-6 weeks of steroids: 
• Azathioprine 
• Cyclophosphamide (monthly) 
• Cyclosporine 
• Infliximab 
• Mycophenolate 
 
G = grade. 
 
 
 
 
 

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12.3 ECOG Performance Status Table 10: ECOG 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature e.g., light house work, 
office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair. 
5 
Dead 
 
 

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END OF DOCUMENT