Phase II Study of XmAb23104 (Targeting PD-1 and ICOS), in Patients With Advanced Sarcoma
Phase: PHASE2
Conditions: Sarcoma
Sponsor: Memorial Sloan Kettering Cancer Center

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IRB Number: 22-195 A(3) 
Approval date: 04-Oct-2023 
MSK PROTOCOL COVER SHEET 
Phase II study of XmAb23104 (targeting PD-1 and ICOS), in Patients with Advanced Sarcoma 
Principal Investigator/Department: 
Ciara M. Kelly, MBBCh BAO, 
Assistant Attending, 
Sarcoma Medical Oncology Service, 
Department of medicine, 
Memorial Sloan Kettering Cancer Center, 
300 East 66th Street, 
New York, New York 10065. 
Phone: 646 888 4312 
Fax: 666 888 4252 
Email: kellyc1@mskcc.org 
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Table of ContentsMSK PROTOCOL COVER SHEET ................................................................. 1 
Principal Investigator/Department .................................................................................................... 1 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ........................................................................ 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................. 4 
3.0 
BACKGROUND AND RATIONALE ...................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................. 12 
4.1 
Design ................................................................................................................................ 12 
4.2 
Intervention ........................................................................................................................ 13 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS ........... 13 
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY ..................................................................... 15 
6.1 
Participant Inclusion Criteria ............................................................................................ 15 
6.2 
Participant Exclusion Criteria ........................................................................................... 16 
7.0 
RECRUITMENT PLAN ........................................................................................................ 17 
7.1 
Research Participant Registration .................................................................................... 17 
7.2 
Randomization ................................................................................................................... 18 
8.0 
INFORMED CONSENT PROCEDURES ............................................................................. 18 
9.0 
PRE-TREATMENT/INTERVENTION ................................................................................... 19 
10.0 
TREATMENT/INTERVENTION PLAN ................................................................................. 20 
11.0 
EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 21 
12.0 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................ 25 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY ................. 26 
14.0 
BIOSTATISTICS ................................................................................................................. 29 
15.0 
ADVERSE EVENTS/RISKS ............................................................................................... 31 
15.2 
Serious Adverse Event (SAE) Reporting .......................................................................... 33 
16.0 
PROTECTION OF HUMAN PARTICIPANTS ...................................................................... 41 
16.1 
Privacy ............................................................................................................................... 42 
16.2 
Data Management .............................................................................................................. 42 
16.3 
Quality Assurance ............................................................................................................. 42 
16.4 
Data and Safety Monitoring ............................................................................................... 42 
17.0 
REFERENCES .................................................................................................................... 44 
18.0 
APPENDICES ..................................................................................................................... 47 

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Tumor biopsy at week 7 
Research blood test at day 1 cycle 2, 3 
& end of treatment 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Sarcomas are a heterogenous group of mesenchymal malignancies, each with distinct pathologic 
features, unique molecular biology, and a varied immune microenvironment. The prognosis of 
unresectable or metastatic soft tissue sarcoma (STS) is poor, with a median overall survival (OS) of less 
than two years. Chemotherapy remains the standard of care first-line treatment for patients with 
advanced STS, providing a progression-free survival (PFS) of approximately 6 months. There is an 
unmet medical need for novel treatment approaches in patients with metastatic high-grade STS. 
Translational and clinical studies have documented that patients with certain high-grade STS subtypes, 
including undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), dedifferentiated 
liposarcoma (LPS), leiomyosarcoma (LMS), and angiosarcoma (AS), can respond to immune 
checkpoint blockade (ICB), although many patients remain refractory to PD- 1 or PD-L1 blockade. 
This phase II, open-label, single-center study will investigate the safety and efficacy of XmAb23104, an 
anti-PD-1 and ICOS antibody in patients with locally advanced or metastatic sarcoma. Patients on this 
study will receive treatment with XmAb23104 on day 1 and 15 of each 28-day cycle for up to 24 months 
depending on response and tolerability. 
In this phase II study, patients will be stratified into one of six cohorts based on sarcoma histologic 
subtypes to receive treatment: 1) Malignant solitary fibrous tumor (SFT), 2) Leiomyosarcoma (LMS), 3) 
Dedifferentiated chondrosarcoma (DDCS), 4) Undifferentiated pleomorphic sarcoma (UPS) or 
myxofibrosarcoma (MFS) 5) Translocation associated sarcoma: Sclerosing epithelioid fibrosarcoma 
(SEF) or Extraskeletal myxoid chondrosarcoma (ESMC), 6) Pecoma. Patients with UPS will be eligible if 
they have refractory to or relapsed after anti-PD-(L)1 therapy and demonstrated clinical benefit to 
immunecheckpoint inhibition [complete/partial response or stable disease >/=6 months]) Treatment with 
XmAb23104 will be continued until progression of disease, unacceptable toxicity, or completion of 24 
months of study therapy. The primary objective of this phase II study is to determine the proportion of 
patients who achieve partial response and complete response at 24 weeks. To assess the potential 
effect of XmAb23104 on selected biomarker expression, all patients will undergo mandatory research 
biopsies after 7 weeks for characterization of PD-1/PD-L1/ICOS expression, TILs, gene expression 
profiling, and characterization of T-cell receptor clonality in TILs (Figure 1). 
Figure 1: Study flowchart 
Assignment to a histology-specific cohort 
(5 per cohort; n= 30 total) 
XmAb23104 on day 1 & 15 q28 days 
1. SFT 
2. LMS 
3. DDCS 
4. UPS/MFS 
5. SEF or 
ESMC 
6. Pecoma 

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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 Primary Objective 
To evaluate the efficacy, as assessed by best objective response rate (partial response [PR] and 
complete response [CR]) at 24 weeks, as defined by RECIST v1.1, of XmAb23104 in patients with 
advanced sarcoma. 
2.2 Secondary Objectives 
1. To evaluate the safety and tolerability of XmAb23104 in patients with advanced sarcoma. 
2. To evaluate the efficacy, as assessed by the clinical benefit rate (stable disease [SD] for ≥ 16 
weeks + PR at 48 weeks + CR at 48 weeks), as defined by RECIST v1.1, of XmAb23104 in 
patients with advanced sarcoma. 
3. To assess the progression free survival (PFS) rate at 6 months, overall survival (OS) at 12 
months, median PFS, and median OS for patients treated with XmAb23104 in patients with 
advanced sarcoma. 
4. To assess the duration of response, as defined by RECIST v 1.1 of XmAb23104 in patients with 
advanced sarcoma. 
2.3 Exploratory Objectives 
1. To determine the baseline characteristics of sarcoma tumors (pre-treatment biopsy sample) 
evaluated in this study including level of PD-1/PD-L1/ICOS expression, presence of tumor 
infiltrating lymphocytes (TILs) and tumor antigens, gene expression profile and T-cell receptor 
clonality in TILs. 
2. To assess the potential effect of XmAb23104 on selected biomarker expression measured in 
post-treatment tumor tissue and the association between these biomarkers (baseline level of 
expression and the change in biomarker level of expression following treatment) and clinical 
outcome, including characterization of PD-1/PD-L1/ICOS expression, TILs, gene expression 
profiling, and characterization of T-cell receptor clonality in TILs. 
3. To evaluate the associations between selected biomarkers measured in serial peripheral blood 
and clinical efficacy, including immunophenotyping and functional analyses, evaluation of serum 
levels of chemokines, cytokines and other immune mediators, and characterization of T-cell 
receptor clonality in peripheral blood. 
End of treatment (progression or toxicity) 
Restaging imaging 
q 8 weeks x 56 wks, 
then q 8-12 weeks 

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3.0 
BACKGROUND AND RATIONALE 
Sarcomas: New therapies are desperately needed 
Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 80 
distinct subtypes. Approximately 13,000 cases of soft tissue and bone sarcomas are diagnosed annually 
in the US. Despite primary combined modality therapy, between 25-50% of patients develop recurrent 
and/or metastatic disease. Complete responses (CR) to chemotherapy for recurrent or metastatic 
sarcoma are rare, and the median survival in the metastatic setting is approximately 15-18 months. 
Standard cytotoxic chemotherapy agents such as doxorubicin, gemcitabine/docetaxel, and dacarbazine 
have response rates of 10-20%. The development of novel and effective therapies is desperately 
needed for patients with sarcomas. 
Immune Checkpoint Inhibition in sarcoma 
A limited number of immunotherapy sarcoma specific trials have been completed to date. The 
SARC028, phase II study examined pembrolizumab monotherapy in patients with advanced sarcoma. 
Clinical activity was observed in undifferentiated pleormorphic sarcoma (UPS) and dedifferentiated 
liposarcoma (DDLPS).6 The histology specific expansion cohorts in this study demonstrated responses 
in 9 (23%) of 40 patients with UPS, two of which were CRs (by RECIST v1.1) and in 4 (10%) of 39 
patients with DDLPS.7 The Alliance (A091401) phase II, non-comparative study, led by Sandra 
D’Angelo at MSKCC, randomized 80 patients to receive nivolumab alone or in combination with 
ipilimumab. The objective response rate was 16% in the combination arm while that in the monotherapy 
arm was 3%. Responses were again observed in UPS but clincal activity was also seen in other 
sarcoma subtypes such as angiosarcoma, leoimyosarcoma and myxofibrosarcoma.8 Results of the 
expansion phase of this study reported an objective response rate of 27% in the combination arm of the 
UPS cohort. UPS represents a genomically complex sarcoma with a higher mutational burden, a 
relatively high T-cell fraction and high levels of PD-1 and PD-L1 expression.9 
PD-L1 expression in association with immune-infiltrating cells and HLA class I expression was 
consistently identified in nearly 50% of patients with dedifferentiated chondrosarcomas which provides 
strong rationale for including these patients in clinical trials incorporating immune checkpoint inhibition.30 
An objective response rate of 54% was observed in patients with advanced alveolar soft part sarcoma 
receiving pembrolizumab in combination with axitinib while atezolizumab monotherapy demonstrated an 
objective response rate of 42% in this sarcoma subtype.32, 33 Sclerosing epithelioid fibrosarcoma is an 
aggressive variant of fibrosarcoma characterized by the EWSR1-CREB3L1/2 gene fusion. Standard 
chemotherapy options used to treat advanced sarcoma have limited activity in this subtype. Reports of 
response to immune checkpoint blockade in this subtype were recently published.34, 35 In a case series 
of patients with advanced SEF demonstrating response to immune checkpoint blockade both cases 
reported had evidence of relatively high frequencies of infiltrating CD8+ T-cells and tumor cell PD-L1 

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expression.35 Perivascular epithelioid cell tumors, otherwise known as Pecomas, are mesenchymal 
neoplasms composed of histologically and immunohistochemically distinctive epithelioid or spindle cells, 
which are immunoreactive for both smooth muscle and melanocytic markers. Pecomas constitute a 
genetically diverse group that includes neoplasms harboring TFE3 gene rearrangements and more 
commonly those with TSC2 mutations leading to elevated mechanistic/mammalian target of rapamycin 
complex activity. Preclinical studies have shown that programmed death 1 co-inhibitory receptor (PD-1) 
is upregulated on T cells in TSC associated tumors and that anti-PD1 therapy in a TSC2 deficient 
mouse model resulted in a 67% decrease in tumor growth (p<0.0001).36 
A phase II study evaluating durvalumab (anti‐ PD‐ L1) and tremelimumab (anti‐ CTLA‐ 4) resulted in 
objective responses in 5 (50%) of 10 patients with alveolar soft part sarcoma (ASPS).10 While limited by 
small numbers, these results highlight the potential importance of combinatorial immunotherapy 
strategies and sarcoma subtype selection for the future design of immunotherapy trials for sarcoma. To 
improve on clinical efficacy, there has been significant interest in combining checkpoint blockade 
antibodies with other systemic approaches such as chemotherapy, targeted therapy, radiation therapy 
and other immunotherapeutics which have been shown to stimulate immune cells, including CD4+ and 
CD8+ T cells,11, 12 natural killers cells,13 and dendritic cells.14 
Solitary fibrous tumor (SFT) comprises a histologic spectrum of rarely metastasizing fibroblastic 
mesenchymal neoplasms characterized by a gene fusion involving NAB2-STAT6. Advanced SFT are 
challenging to treat with limited effect therapeutic options available. Treatments that have demonstrated 
some activity in this disease include tyrosine kinase inhibitors, temodar and bevacizumab. 
Immunotherapy has not been widely explored in this subtype to date. However, there are anecdotal 
reports of activity with immunecheckpoint inhibition in this disease.44 
Combination Immunotherapy Approaches Targeting Different Aspects of the Immune Activation 
Cascade 
Responses to anti-PD-1 monotherapy rely primarily on the presence of pre-existing T-cell infiltrate that 
is inhibited by PD-1:PD-L1 interactions. Higher objective response rates have been observed when 
anti-PD-1 therapy has been combined with additional immune modulation aiming to recruit new antigen- 
specific T-cells into tumors. The power of a combination immunotherapy strategy in sarcoma, is 
reflected in the results of the Alliance A091401 previously discussed and a phase II study of the intra- 
tumoral injection of talimogene laherparepvec (T-VEC) in combination with pembrolizumab in patients 
with advanced sarcoma, led by Dr. Kelly. T-VEC and pembrolizumab modulate the immune system in 
complementary ways. T-VEC is an oncolytic immunotherapy designed to self-replicate within tumor 
cells, which subsequently causes their lysis, thereby increasing tumor-specific immune activation via the 
augmentation of antigen presentation and T-cell priming. Concurrently, pembrolizumab negates the 
downregulation of effector T-cell activity within peripheral tissue and tumors. The objective response 
rate observed in this study was 35%, one of the highest reported in a sarcoma-specific immunotherapy 
trial to date.15 These results have excited interest to explore novel combination immunotherapy 
strategies in sarcoma. Although a subset of sarcoma appears inflamed and responsive to immune 
checkpoint blockade with PD-1 targeted agents, novel immunotherapies and combinations likely will be 
needed for most subtypes. A variety of approaches—including targeting immune checkpoints other than 
PD-1 such as B7-H3, OX40, GITR, and ICOS; modulating tumor associated macrophage phenotype 
from tumor-promoting to tumor- suppressive status; using cellular based therapies, such as chimeric 
antigen and high-affinity T-cell receptors to deepen the adaptive immune response; and reinvigorating 
older approaches, such as vaccines and oncolytic virus-based treatments all merit exploration in 
sarcomas.16 
ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy 

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The inducible costimulator (ICOS or cluster of differentiation (CD278)) of T cells and its ligand (ICOSL) 
play important roles in memory and effector T cell development and specific humoral immune 
responses. ICOS is inducible and expressed following T-cell activation.17 This pathway has been shown 
to exert opposing effects on the various T cell subpopulations. Interactions between ICOS and ICOSL 
can potentiate immunosuppression mediated by some CD4+ T cell subsets, such as regulatory T cells 
(Tregs). This pathway can also promote anti-tumor T-cell effects when activated in Th1 and other Teff 
cells.18 This dual role in both anti-tumor and pro-tumor activities makes targeting the ICOS/ICOSL 
pathway attractive for enhancement of anti-tumor immune responses. Thus, a potential role for this 
pathway in improving the effectiveness of cancer immunotherapy is being investigated in early phase 
trials using agonistic or antagonistic antibodies administered alone or more often in combination with 
other immunotherapeutic treatments. 
ICOS targeted agents alone or in combination with anti-PD1 blockade and/or anti-CTLA4 
blockade 
In preclinical studies, ICOS agonistic monoclonal antibodies (mAbs) can potentiate the effects of anti- 
CTLA-4 therapy. In preclinical studies ICOS knockout mice responded poorly to anti-CTLA4 therapy 
which suggests that ICOS signaling is a crucial player in how CTLA4 blockade exerts anti-tumor 
effects.19 Treatment with ipilimumab has also been shown to increase the frequency of ICOS+ Th1-like 
CD4 effector cells in the tumor.20-22 In another study, a gene expression profile that included ICOS 
demonstrated that ICOS expression was associated with greater survival in metastatic melanoma 
patients.23 The combination of CTLA4 blockade and ICOS stimulation in melanoma and prostate mouse 
models demonstrated superior anti-tumor effects compared to anti-CTLA4 therapy alone.24 
PD-L1 blockade in tumor mouse models induced selectively the expansion of tumor-infiltrating CD4+ 
and CD8+ T-cell subsets, co-expressing both activating (ICOS) and inhibitory (LAG-3, PD-1) molecules 
(TAI cells). By therapeutically co-targeting these molecules on the TAI cell subsets in vivo by agonistic 
and antagonist antibodies, led to enhanced efficacy of PD-L1 blockade therapy as evidenced by an 
increased number of TAI cells within the tumor micro-environment and improved tumor protection.25 

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Figure 3. Targeting regulatory and/or effector T cells with ICOS agonistic or antagonistic antibodies. ICOS 
can be targeted by either agonist (in green) and antagonistic (in red) antibodies (Abs). ICOS agonists are 
usually administered in concomitance with anti-CTLA-4 or anti-PD-1 Abs, for their ability to synergistically 
inhibit the suppressive activity of regulatory T cells (Tregs) and to potentiate the anti-tumour activity of 
effector T cells (Teff), including CD4+ and CD8+ subpopulations. One main mechanism of action of ICOS 
antagonistic Abs is to inhibit Tregs by stimulating the antibody-dependent cell-mediated cytotoxicity 
(ADCC) mediated by natural killer (NK) cells. CTLA-4, cytotoxic T-lymphocyte Ag-4; PD-1, programmed 
celldeath-1. 
Early phase clinical trials testing ICOS agonist Abs in patients with advanced solid tumors have shown 
good safety profiles and promising anti-tumor activities, particularly when the compounds are given in 
combination with anti-PD-1 agents (pembrolizumab and nivolumab). Dose-limiting toxicities were not 
common occurrences, reinforcing these agents as promising new targets for combination cancer 
immunotherapy. The first-in-human trial, INDUCE-1 (NCT02723955), used an ICOS agonist Ab 
administered alone (part 1) or in combination with an anti-PD-1 antibody (pembrolizumab; part 2) in 
patients with advanced solid tumors and had promising results in terms of tolerability, toxicity profile and 
clinical activity.26 The ICONIC trial (NCT02904226) investigated the role of an ICOS agonist Ab (JTX- 
2011) given alone (mono arm) or in combination with an anti-PD-1 antibody (nivolumab; combo arm) in 
patients with relapsed/refractory tumors.27 Currently, the data shows this compound is safe, well 
tolerated and can generate anti-tumor responses in heavily pretreated gastric cancer and triple-negative 
breast cancer patients. Interestingly, peripheral blood CD4+ICOShi T cell subpopulations appear to be 
a promising biomarker of response.28 
ICOS expression in sarcoma 
Dufresne et al, recently examined the gene expression profiles of 93 immune checkpoint (ICP) 
membrane markers of immune cells in a series of 253 soft tissue sarcoma (synovial sarcoma, myxoid 

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liposarcoma, sarcoma with complex genomic signatures and gastrointestinal stromal tumors [GIST]) 
using Agilent Whole Human Genome Microarrays. Unsupervised hierarchical clustering of gene 
expression level was found to properly categorize patients according to their histological subgroup of 
sarcoma, indicating that each sarcoma subgroup is associated with a specific immune signature defined 
by its gene expression pattern. In general, synovial sarcoma had a consistently low level of expression 
for all ICPs conversely, the highest expression was in general reported for GIST and sarcomas with 
complex genomic signatures. The differential expression of each gene across sarcoma subgroups is 
highlighted in figure 4. The highest level of ICOS and PDCD1 expression was observed in sarcomas 
with complex genomic signatures which included UPS (n=30), LMS (n=24), DDLPS (n=11), MFS (n=7), 
pleomorphic LPS (n=6), and adult fibrosarcomas (n=3).29 
Figure 4. Expression level of the 93 ICP/MM genes across each sarcoma subtype. 
The gene expression value is displayed by bars representing the 25 and 75 percentile of expression level for each 
ICP/MM. Each sarcoma subtype is shown (green: GIST; blue: MLPS; red: SCG; orange: SS)- The Z-score is 
averaged for each gene within each sarcoma subgroup (red corresponding to the highest expression and blue the 
lowest one; from 2 to −2, respectively)- The significance displays the relationship between expression values 
across histological subtype given by multiple Bonferroni-adjusted ANOVA, ranked from high significance (top) to 
non-significant (bottom). Vertical dashed line indicates significance threshold (p = .05), 84 genes out of 93 (90%) 

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are differentially expressed in the different subtypes- The prognosis represents 
the impact of an ICP/MM gene expression on MFS. A positive prognostic impact (high expression correlated with 
longer MFS) and is represented in green. A negative impact (high expression correlated with shorter MFS) and is 
represented in red.- CT and FDA highlight genes whose protein is targeted in a Clinical Trial or by a Food and 
Drug Administration approved agent. 
XmAb23104: Simultaneous targeting of PD-1 and ICOS 
XmAb23104 is a humanized bispecific monoclonal antibody manufactured by Xencor that binds the 
immune checkpoint molecule PD1 and the costimulatory molecule ICOS. While XmAb23104 is expected 
to preferentially bind cells that simultaneously express ICOS and PD1, the anti-ICOS arm is believed to 
have immune agonist activity. Acting together, PD1 relieves exhausted T cells in the tumor 
microenvironment (TME), and ICOS costimulates T cells to enhance immune activation. Consistent 
with its intended mechanism of action and functional properties, XmAb23104 has been shown to 
interfere with binding of PDL1, PDL2 and ICOSL with PD1 and ICOS in a dose-dependent fashion. This 
was demonstrated by in vitro assays that involved treatment of HEK293T cells, which overexpress PD1 
and ICOS, with increasing doses of XmAb23104, followed by flow cytometry to assess the inhibition of 
binding of soluble PDL1, PDL2, and ICOSL. Furthermore, XmAb23104 dose dependently promoted IL-2 
and IFNγ release following stimulation of peripheral blood mononuclear cells (PBMC) with super-antigen 
Staphylococcal enterotoxin B (SEB). The mean EC10, EC20, EC30, EC50, EC80, and EC90 for 
XmAb23104-induced IL-2 release from SEB-stimulated human T cells was 44, 79, 125, 279, 1201, and 
3215 ng/mL, respectively. The mean EC10, EC20, EC30, EC50, EC80, and EC90 for XmAb23104- 
induced IFN-γ release from SEB-stimulated human T cells was 21, 34, 48, 81, 206, and 384 ng/mL, 
respectively. The same response was also demonstrated in SEB-stimulated cynomolgus monkey 
PBMCs. When incubated with human PBMCs, XmAb23104 did not induce cytokine (IFN-γ, TNF-α) or 
interleukin (IL-2, IL-4, IL-6, or IL-10) production. 
As of 03 November 2020, 46 subjects have been treated with XmAb23104 at dosages between 0.002 
and 10 mg/kg. At the 0.2 mg/kg dose level, 1 subject has received 24 doses, including one intra-subject 
dose escalation at Cycle 7, Day 15. 
The most common treatment-related treatment-emergent adverse event (TEAE) has been fatigue, 
observed in 10 subjects. In addition, 5 subjects experienced immunotherapy-related AEs (IRAEs) and 1 
subject experienced an infusion-related reaction (IRR). 
The mean half-life of XmAb23104 is approximately 9 days. Insufficient data are available at this time to 
accurately define efficacy and PD. 
Hypothesis and Rationale 
Based on the preclinical data, we hypothesize that combined anti-PD-1 and anti- ICOS therapy in 
advanced sarcoma with specific histological subtypes including LMS, DDLPS, dedifferentiated 
chondrosarcoma, ASPS, SEF and pecoma, will result in synergistic anti-tumor activity. 
The importance of ICOS engagement is supported by the superior activity of 5 mg/kg XmAb23104 (a 
dose with equivalent molar quantity of PD1 binding arms to that of the 3 mg/kg anti-PD1 dose) which 
significantly suppressed tumor growth in huPBMC engrafted mice in comparison to anti-PD1 
(XENP16432). Also, treatment with 0.3 mg/kg and 1.0 mg/kg XmAb23104 (doses with a lower molar 
quantity of PD1 compared to the 3.0 mg/kg anti-PD1) displayed anti-tumor activity that was comparable 
to that of anti-PD1 (XENP16432). 

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The impact of varying concentrations of nivolumab or pembrolizumab was also studied on the binding of 
XmAb23104 to PD1+ICOS+ cells. Monospecific anti-PD1 antibodies nivolumab and pembrolizumab are 
FDA approved for several oncology indications, and many subjects who are among the target 
populations for the XmAb23104 clinical trials may have received one of these agents immediately 
before enrolling in an XmAb23104 clinical trial. Given the relatively long half-lives of these antibodies, 
these subjects may continue to have detectable serum concentrations of nivolumab or pembrolizumab 
for a period of time after dosing has ceased. When the impact of pembrolizumab or nivolumab on the 
binding of XmAb23104 to PD1+ICOS+ HEK293T cells was estimated, pembrolizumab interfered with 
XmAb23104 binding in a dose-dependent manner. In contrast, nivolumab competed much less 
effectively with XmAb23104 for cell binding. Pembrolizumab has a terminal elimination half-life (t1/2) of 
22 days and a median steady state, maximum observed serum concentration (Cmax) and trough 
concentrations of 66.3 μg/mL and 27.6 μg/mL, respectively, when administered at a dose of 200 mg 
every 3 weeks. Some of the subjects who are eligible for this clinical trial of XmAb23104 may have been 
recently treated with approved anti-PD1 mAbs including pembrolizumab. Therefore, patients who have 
received pembrolizumab within 6 weeks of enrollment will not be eligible for this study. 
Identifying Predictive Biomarkers of Response to ICB 
Ultimately, the major challenge to harnessing immune checkpoint inhibitors in sarcomas is identifying 
patients who have the highest chance of benefit. To do this, lessons can be learned from other tumor 
types and applied to sarcomas. We believe the heterogeneity inherent in sarcomas can make them an 
ideal tumor type to validate a prospective biomarker for response to immune activating agents. It is 
unclear how best to predict which patients will benefit from ICB. While the initial phase I trial of 
nivolumab suggested tumors expressing PD-L1 by immunohistochemistry (IHC) may benefit more 
frequently from PD-1 blockade,35 more recent data from the combination ipilimumab plus nivolumab 
trial has cast doubt on the theory that PD-L1 expression is necessary for therapeutic benefit. Among 
patients that received combination therapy, responses were seen both in patients with PD-L1 
expression (6/13) or those without PD-L1 expression (9/22.) It is known that PD-L1 expression remains 
a dynamic marker that can change over time and under different conditions in the microenvironment. 
Tumor heterogeneity can also contribute varied PD-L1 expression.36 These data suggest either PD-L1 
expression may change as a result of therapy with immune checkpoint inhibitors or that other 
mechanisms underlie the response to immune checkpoint blockade. 
The Angiosarcoma project, a patient-partnered research initiative that obtained whole exome 
sequencing on 47 angiosarcoma tumors with matched normal tissue identified that angiosarcomas of 
the head, neck, face, and scalp (HNFS) were associated with a high tumor mutation burden (median 
20.7 mutations/Mb compared to 2.8 mutations/Mb in the remainder of the cohort) and a dominant 
ultraviolet damage mutational signature in 10 of 12 cases (COSMIC Signature 7). They report that 3 
patients with angiosarcoma of the HNFS received immune checkpoint blockade; 2 of whom experienced 
dramatic responses to immunotherapy after progressing on standard of care treatment.37 This suggests 
that a high TMB and a UV signature may be two biomarkers predictive of response to checkpoint 
blockade in sarcoma. 
In an in-depth analysis of 52 undifferentiated high-grade sarcomas with whole-genome sequencing, 
38 
Steele et al reported that in contrast to the majority of undifferentiated sarcomas with low TMB, a 
subgroup of these tumors (13%; n = 7) has a high TMB and low copy number alteration burden. 5 of 
these patients had an oncogenic mutation, copy-number loss, or promoter methylation of a Lynch 

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syndrome-associated gene either in the tumor or the germline associated with genomic signatures of 
mismatch repair deficiency. The other patient had a mutational signature (signature 30) strongly 
matching the base excision repair NTHL1 deficiency pattern, which was associated with a germline 
NTHL1 mutation and loss-of- heterozygosity of the wild type allele. The final patient with a high TMB 
had genomic signature 1, likely caused by spontaneous deamination of methylated cytosines and 
biallelic inactivation of the DNA glycosylase gene MBD4, which is a binding partner of the MMR protein 
MLH1. The better prognosis compared to the mutation-low sarcomas. Pathway analysis revealed 
significant enrichment for immune-related pathways in the mutation high compared with other samples. 
This analysis also highlights the importance of identifying specific genomic signatures in sarcoma as 
well as overall tumor mutation burden to predict potential immunogenicity of undifferentiated sarcomas. 
Recent studies have investigated the tumor microenvironment across a range of STS subtypes using 
publicly available gene expression profiles. Five distinct sarcoma immune classes (SICs) were 
proposed: immune desert (SIC A), vascularized (SIC C; high expression of endothelial-cell related 
genes), immune and tertiary lymphoid structure (TLS) high (SIC E), heterogenous but generally 
immune-low (SIC B), or heterogenous but generally immune high (SIC D). SIC E is characterized by the 
highest expression of genes specific to immune populations, such as T cells, CD8+ T cells, NK cells, 
and cytotoxic lymphocytes. SIC E were also high in the expression of the lymphoid-structures- 
associated B-cell-specific chemokine CXCL12, whereas PD-L1 was heterogeneously expressed across 
SICs. SICs D and E had high expression of genes associated with T cell or myeloid cell chemotaxis, T 
cell activation and survival, MHC class I, regulatory gene signatures, as well as immune-checkpoint- 
related genes. Patients with SIC D or E had the highest overall survival among 496 patients with 
survival data available. When survival was stratified by the dominant immune cell type, the B lineage 
signature was associated with survival on a multivariable analysis.39 
Using the SIC classification, 47 patients treated with pembrolizumab were analyzed both before and 
after treatment to determine the association between SIC and outcome. SIC E patients (DDLPS and 
UPS patients) had the highest overall response rate (50%; 5 of 10), followed by SIC D (DDLPS and 
UPS; 25%; 3 of 12) and SIC C (Synovial sarcoma, LMS, UPS and DDLPS; 22%; 2 of 9). There were no 
responders in SIC A or B (5 and 11 patients, respectively), which included DDLPS, synovial sarcoma, 
LMS, and UPS patients.39 Thus, stratification of patients by sarcoma immune class could accurately 
predict response to immune checkpoint blockade and the presence of tertiary lymphoid structures was 
associated with response. 
This trial will obtain pre- and on-treatment biospecimens to further explore predictors of response to 
XmAb23104 including tumor biopsies and peripheral blood. Aside from PD-L1 and ICOSL expression in 
tumor and infiltrating immune cells, unique gene expression profiles can potentially be utilized to predict 
responses to treatment. Additionally, utilizing deep sequencing with the targeted gene panel on MSK- 
IMPACT we will attempt to correlate specific genomic alterations, as well as TMB, and microsatellite 
instability status with clinical outcome to therapy on this study. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
The study is an open-label, single institution phase II trial of XmAb23104 in patients with locally 

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advanced or metastatic sarcoma. Patients will receive the recommended phase II dose of XmAb23104 
monotherapy on day 1 and 15 of each 28-day cycle. Patients will continue XmAb23104 (day 1 & 15, q 
28 days) for up to 24 months depending on their response and tolerability to treatment. Treatment will 
be continued until progressive disease (PD) or toxicity or a total of 24 months of study therapy has been 
completed. 
4.2 
Intervention 
Thirty patients will be enrolled in this study. Patients will be stratified based on sarcoma histological 
subtype into one of 6 cohorts with 5 patients per cohort including SFT, LMS, DDCS, UPS/MFS, SEF 
or ESMC, and pecoma. Study involves XmAb23104 monotherapy. The cycle will be 28 days at 
length. Participants will be given the recommended phase II dose of XmAb23104 (10 mg/kg) 
intravenously on days 1 and 15 of each 28-day cycle. XmAb23104 will be administered by IV 
infusion at a constant rate over 1 hour. The treatment with XmAb23104 will continue until 
unacceptable toxicity, disease progression, or the completion of 24 months. Physical examinations 
and pre-dose clinical evaluations may be performed up to 24 hours prior to a scheduled infusion of 
XmAb23104. Radiographic assessment by RECIST v1.1 will occur at baseline, after the first two 
treatment cycles, and every 8 weeks for the first 56 weeks of study treatment, followed by every 8- 
12 weeks thereafter at the discretion of the treating investigator. Mandatory tumor biopsies will be 
performed at baseline and week 7. 
5. 0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS 
5.1 XmAb23104 
5.1.1 Availability 
Xencor will provide investigational supply of XmAb23104 to patients enrolled on this protocol 
free of charge for the duration of the study. A complete description of the drug, its clinical 
pharmacology, contraindications and adverse reactions are available in the investigator’s 
brochure. MSK will be cross-referencing Xencor’s IND for XmAb23104. 
5.1.2 Mechanism of Action 
XmAb23104 is a humanized bispecific antibody that binds the immune checkpoint molecule PD1 and 
the costimulatory molecule ICOS. XmAb23104 is expected to preferentially bind cells that 
simultaneously express ICOS and PD1. To generate XmAb23104, Xencor humanized, and affinity- 
optimized anti-PD1 and anti-ICOS antibodies and combined them in a single bispecific molecule. 
XmAb23104 is produced as a 3-chain scFv-Fab-Fc antibody (Figure 5), in which the single-chain Fv 
(scFv) domain targets PD1 and the antigen-binding fragment of an antibody (Fab) domain targets ICOS. 
XmAb23104 has an Fc region that has been engineered to remove binding to Fc gamma receptors 
(FcγRs), with the intent of preventing activation and/or depletion of T cells via engagement of 

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XmAb23104 by FcγR-expressing cells. The FcRn affinity has been increased via amino acid 
engineering to improve serum half-life relative to antibodies containing native IgG Fc domains. 
Figure 5: Schematic of XmAb23104 PD1 × ICOS Bispecific Monoclonal Antibody 
Fab = fragment, antigen binding; Fc = fragment, crystallizable; FcγR = Fc gamma receptor; FcRn = Fc neonatal receptor; 
scFv = single-chain variable fragment (immunoglobulin fusion protein). 
5.1.3 Formulation and Storage 
XmAb23104 is a sterile liquid product supplied in single-use glass vials filled with 10.0 mL at a 
concentration of 10.0 mg/mL in 20 mM acetate, 250 mM sorbitol at pH 5.5. It should be stored under 
refrigeration at 2°C to 8°C, protected from light. 
5.1.4 Administration 
XmAb23104 is administered in a dose of 10mg/kg over 60 minutes (+15 minutes) every 2 weeks. The 
full calculated dose should be administered based on the patient’s actual baseline weight measurement 
in kilograms. Following the first dose, subsequent doses will only be modified if the patient’s weight 
changes by more than 10% from the baseline weight, at which point it will be recalculated using the 
current weight. See the pharmacy manual for specific dosing information. 
XmAb23104 should be infused through a dedicated peripheral IV (PIV) 
XmAb23104 may be infused through central lines, including PICCs, PORTs and mid-lines. 
The drug should be infused over 1 hour. For patients >120 kg, bag 1 and bag 2 would each be infused 

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over 30 minutes for a total of 1 hour. 
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY 
6.1 
Participant Inclusion Criteria 
• 
Male or female age ≥ 18 years at the time of informed consent 
• 
Be capable, willing, and able to provide written informed consent/assent 
• 
Be willing to comply with clinical trial instructions and requirements, including mandatory biopsies at 
baseline and on-treatment where feasible 
• 
Patients must have progressed on or be intolerant of at least one prior standard systemic therapy 
where available. If a patient declines standard systemic therapy they will be considered eligible. 
• 
Patients must have a histologically confirmed locally advanced/metastatic sarcoma with select 
histological subtypes including: 
o i) malignant solitary fibrous tumor (SFT) 
o ii) leiomyosarcoma (LMS) 
o iii) dedifferentiated chondrosarcoma 
o iv) undifferentiated pleomorphic sarcoa/myxofibrosarcoma (Patients with UPS/MFS will be 
eligible if they have refractory to or relapsed after anti-PD-(L)1 therapy and demonstrated 
clinical benefit to immunecheckpoint inhibition [complete/partial response or stable disease 
>/=6 months]) 
o v) sclerosing epithelioid fibrosarcoma (SEF) or extraskeletal myxoid chondrosarcoma 
(ESMC) 
o vi) pecoma. 
• 
Adequate performance status: ECOG 0 or 1/KPS 100-70% 
• 
Expected life expectancy >3 months 
• 
Presence of measurable disease per RECIST v1.1. 
o Target lesion(s) must not be chosen from a previously irradiated field unless there has 
been radiographically and/or pathologically documented tumor progression in that lesion 
prior to enrollment. 
• 
Adequate organ function determined within 10 days of treatment initiation 
o Platelet count > 100 x 109/L 
o Hemoglobin level > 8.0 g/dL 
o Absolute neutrophil count > 1.0 x 109/L 
o AST at screening < 3 x ULN for subjects without known liver involvement by tumor; or < 5 x 
ULN for subjects with known liver involvement by tumor 
o ALT at screening < 3 x ULN for subjects without known liver involvement by tumor; or < 5 x 
ULN for subjects with known liver involvement by tumor 
o Bilirubin  1.5 × ULN (unless prior diagnosis and documentation of ongoing hemolysis or 
Gilbert’s syndrome has been made) 
o Estimated creatinine clearance (CL) > 30 mL/min calculated by the Cockcroft-Gault or 
modification of diet in renal disease formulas 
• 
Male subjects must agree to use contraception and refrain from donating sperm during the treatment 
period and for at least 8 weeks after the last dose of XmAb23104 
• 
Female subjects of childbearing potential must agree to use a highly effective method of birth control 
during and for 8 weeks after completion of study. Women are considered to be of childbearing 
potential unless it is documented that they are over the age of 60 OR postmenopausal by history 

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with no menses for 1 year and confirmed by FSH OR have a history of hysterectomy and/or bilateral 
oophorectomy OR have a history of bilateral tubal ligation. Highly effective methods of birth control 
include hormonal birth control (oral, intravaginal, transdermal, implantable, or intrauterine device 
[IUD]), IUDs (non-hormonal), vasectomy (in male partner), or any double-barrier methods 
(combination of male condom and spermicide with either cap, diaphragm, or sponge). 
6.2 
Participant Exclusion Criteria 
• 
History of unstable or deteriorating cardiovascular disease within the previous 6 months prior to 
screening including but not limited to the following: 
o Unstable angina or myocardial infarction 
o CVA/stroke 
o Congestive heart failure (New York Heart Association [NYHA] Class III or IV 
o Uncontrolled clinically significant arrhythmias 
• 
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 
Patients with previously treated brain metastases or carcinomatous meningitis may participate 
provided they are stable (without evidence of progression by imaging for at least four weeks prior to 
the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases on imaging performed during study screening, and 
are not using steroids for at least 14 days prior to trial treatment 
• 
Current use of immunosuppressive medication, EXCEPT for the following: 
o intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection) 
o Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent 
o Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 
• 
Evidence of clinically significant immunosuppression such as the following: 
o Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease 
o Concurrent opportunistic infection 
o Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 
10 mg/day of prednisone or equivalent within 2 months prior to enrollment 
• 
History or evidence of symptomatic autoimmune disease (e.g., pneumonitis, glomerulonephritis, 
vasculitis, or other), or history of active autoimmune disease that has required systemic treatment 
(i.e., use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of 
autoimmune diseases) in past 2 years prior to enrollment. Replacement therapy (e.g., thyroxine for 
hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency) is not considered a form of systemic treatment for autoimmune disease 
• 
A life threatening (Grade 4) immune related adverse event related to prior immunotherapy. 
• 
Failure to recover from any immune related adverse event from prior anti-cancer therapy to grade ≤ 
1, with the exception of alopecia or endocrinopathies that are managed and stable on hormone 
replacement therapy. 
• 
Failure to recover from any other toxicity (other than immune-related toxicity) related to previous 
anticancer treatment to Grade ≤ 2 except for alopecia and peripheral neuropathy related to prior 
chemotherapy. 
• 
Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) disease that is not 
controlled 
HIV positive patients will be considered eligible if: 

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• 
Established ART for at least four weeks and have an HIV viral load less than 400 
copies/mL prior to enrollment 
• 
CD4+ T-cell (CD4+) counts ≥ 350 cells/uL 
• 
No opportunistic infection within the past 12 months 
• 
Patients known to be positive for active Hepatitis B (HBsAg reactive with detectable HBV DNA), or 
Hepatitis C (HCV RNA (qualitative) is detected) 
o Patients with chronic hepatitis B (positive HBsAg and/or HBcAb and negative HBV DNA by PCR) 
are eligible for this study if they are on suppressive anti-viral therapy and deemed safe by a 
gastroenterologist 
o Patient who is HCV Ab positive but HCV RNA negative due to prior treatment or natural 
resolution will be considered eligible. 
• 
Has a known history of active TB (Bacillus Tuberculosis) 
• 
Women who are pregnant or breastfeeding 
• 
Patients expecting to conceive or father children within the projected duration of the trial, starting 
with the pre-screening or screening visit through 120 days after the last dose of study treatment(s) 
• 
Prior organ transplantation including allogenic stem-cell transplantation 
• 
Active infection requiring systemic therapy 
• 
Known prior severe hypersensitivity to investigational product or any component in its formulations, 
including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5 Grade ≥ 
3) 
• 
Prior treatment with an investigational anti-ICOS therapy 
• 
Treatment with a PD-1 or PD-L1 antibody within 8 weeks of the start of study therapy. 
• 
Treatment with any other anticancer therapy within 3 weeks of the start of study drug (ie, other 
immunotherapy, chemotherapy, radiation therapy, etc.). 
• 
Treatment with antibiotics within 14 days prior to first dose of study drug 
• 
Receipt of a live-virus vaccine within 30 days prior to first dose of study drug (vaccines that do not 
contain live virus are permitted). 
• 
Presence of any other active malignancy requiring systemic therapy that may influence the outcome 
of this study. 
7.0 
RECRUITMENT PLAN 
7.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain informed 
consent, by following procedures defined in section entitled Informed Consent Procedures. During the 
registration process registering individuals will be required to complete a protocol specific Eligibility 
Checklist. The individual signing the Eligibility Checklist is confirming whether the participant is eligible 
to enroll in the study. Study staff are responsible for ensuring that all institutional requirements 
necessary to enroll a participant to the study have been completed. 
The clinical trial will be listed on the clinicaltrials.gov website. Patients will be identified through internal 
referrals and external referrals by Medical and Surgical Oncologists, nationally and internationally. 
Patients will be recruited through the Sarcoma Disease Management Team. The Sarcoma Service and 

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the Sarcoma Disease Management Team each hold weekly interdepartmental meetings to identify study 
participants for open clinical trials. A patient’s sarcoma histological subtype will always be confirmed by 
a MSK pathologist prior to being deemed fully eligible for this study. We will also discuss the trial and 
patient recruitment with several Sarcoma patient support groups. The principal investigator will be 
available to all patients for further questions and information through a contact number, which will be 
provided on the consent form. All eligible patients, regardless of sex and race, will be approached for 
participation. The investigators are aware of the NIH policy concerning inclusion of women and 
minorities in clinical research populations. 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center. (MSKCC). If 
the investigator is a member of the treatment team, s/he will screen their patient’s medical records 
for suitable research study participants and discuss the study and their potential for enrolling in the 
research study. Potential subjects contacted by their treating physician will be referred to the 
investigator/research staff of the study. 
The principal investigator may also screen the medical records of patients with whom they do not have a 
treatment relationship for the limited purpose of identifying patients who would be eligible to enroll in the 
study and to record appropriate contact information in order to approach these patients regarding the 
possibility of enrolling in the study. 
During the initial conversation between the investigator/research staff and the patient, the patient may 
be asked to provide certain health information that is necessary to the recruitment and enrollment 
process. The investigator/research staff may also review portions of their medical records at MSKCC in 
order to further assess eligibility. They will use the information provided by the patient and/or medical 
record to confirm that the patient is eligible and to contact the patient regarding study enrollment. If the 
patient turns out to be ineligible for the research study, the research staff will destroy all information 
collected on the patient during the initial conversation and medical records review, except for any 
information that must be maintained for screening log purposes. 
In most cases, the initial contact with the prospective subject will be conducted either by the treatment 
team, investigator or the research staff working in consultation with the treatment team. The recruitment 
process outlined presents no more than minimal risk to the privacy of the patients who are screened and 
minimal PHI will be maintained as part of a screening log. For these reasons, we seek a (partial) limited 
waiver of authorization for the purposes of (1) reviewing medical records to identify potential research 
subjects and obtain information relevant to the enrollment process; (2) conversing with patients 
regarding possible enrollment; (3) handling of PHI contained within those records and provided by the 
potential subjects; and (4) maintaining information in a screening log of patients approached (if 
applicable). 
7.2 
Randomization 
No randomization will be performed. 
8.0 
INFORMED CONSENT PROCEDURES 

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Before protocol-specified procedures are carried out, consenting professionals will explain full details of 
the protocol and study procedures as well as the risks involved to participants prior to their inclusion in 
the study. Participants will also be informed that they are free to withdraw from the study at any time. All 
participants must sign an IRB/PB-approved consent form indicating their consent to participate. This 
consent form meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to withdraw from 
participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully explain 
the aspects of patient privacy concerning research specific information. In addition to signing the IRB 
Informed Consent, all patients must agree to the Research Authorization component of the informed 
consent form. Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
9.0 
PRE-TREATMENT/INTERVENTION 
All aspects of the screening evaluation must be completed prior to entering the study, unless otherwise 
noted. The following must be completed within 28 days of starting treatment: 
• 
Confirmation of disease: documented presence of metastatic and/or locally advanced sarcoma with 
RECIST v1.1 measurable disease using standard baseline imaging with CT scan of the chest (with 
or without contrast), abdomen and pelvis (with contrast where renal function permits) and all other 
known sites of disease and MRI if applicable. 
• 
Signed informed consent for study participation 
• 
Full medical history including all active conditions 
• 
Review of concomitant medications including any prior medications taken 
• 
Physical exam (including height and weight) 
• 
Vital signs (pulse, blood pressure, temperature, respiratory rate, and oxygen saturation). Note: 
height may be documented at any time prior to registration 
• 
ECOG performance status 
• 
Complete blood count with differential 
• 
Comprehensive metabolic panel (sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, total protein, albumin, total bilirubin, total protein, AST, ALT, alkaline phosphatase, 
calcium), magnesium, and phosphorus 
• 
Amylase, lipase, CK, and LDH 
• 
PT (or INR) and aPTT 
• 
Thyroid function tests (TSH, T4 free, T3) 
• 
Hepatitis B surface antigen and core antibody, and Hepatitis C antibody, with reflex PCR test if 
positive 
• 
Urinalysis (dipstick) 

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• 
Serum β-HCG or urine pregnancy test for women of child-bearing potential. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test is required 
• 
12-lead electrocardiogram (ECG) 
• 
CT scan of the chest (with or without contrast), abdomen and pelvis (with or without contrast) or MRI 
and CT scan or MRI of brain, if applicable. 
• 
All patients enrolled in this study will undergo a new baseline biopsy where feasible 
10.0 
TREATMENT/INTERVENTION PLAN 
10.1 
Treatment plan 
o All patients will be administered the XmAb23104 monotherapy intravenously, as an outpatient, on 
days 1 and 15 of each 28-day cycle for a total of 24 months. 
o For each cycle, XmAb23104 will be administered at the recommended phase 2 dose, 10mg/kg once 
every two weeks. 
• 
Supportive medications will be administered according to institutional guidelines 
• 
Granulocyte colony stimulating factor (G-CSF) administration will be permitted at the discretion of 
institutional policy and/or the study investigator 
• 
Physical exam, including vital signs and weight measurement, and toxicity assessments will occur 
on day 1 and 15 of each treatment cycle and at the end of treatment visit 
• 
Radiographic assessment by RECIST v1.1 will occur at baseline, after the first two treatment cycles, 
and every 8 weeks for the first 56 weeks of study treatment, followed by every 8-12 weeks thereafter 
at the discretion of the treating investigator 
• 
Mandatory tumor biopsies will be performed at baseline and week 7 
• 
Peripheral blood analyses will be obtained at baseline, day 1 of cycle 2 and 3, and at the end of 
treatment 
• 
The end of treatment visit should be within 30 days (+ 7 days) of the last administered dose of study 
therapy 
• 
Survival status will be confirmed every 12 weeks (± 28 days) following the end of treatment visit until 
death, the patient withdraws consent, or 12 months after the end of treatment, whichever occurs 
first. 
10.2 Dose Delay Criteria 
Because of the potential for clinically meaningful XmAb23104 related AEs requiring early recognition 
and prompt intervention, management algorithms have been developed for suspected AEs of selected 
categories, see Appendices A and B. Tumor assessments should continue per protocol schedule, even 
if dosing is delayed. 
If dosing is delayed and the criteria to resume treatment are subsequently met, the subject should 
restart treatment one week later or at the discretion of the investigator once criteria are met. If treatment 
is delayed or interrupted for > 8 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Appendices A and B or unless the principal investigator determines that 
resumption of the drug will provide further clinical benefit. 

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XmAb23104 should be permanently discontinued if any AE, laboratory abnormality, or intercurrent 
illness occurs which, in the judgment of the investigator, presents a substantial clinical risk to the patient 
with continued XmAb23104 dosing. 
A delay in treatment due to holidays, weather, or other circumstances will be permitted up to 7 days and 
not considered a protocol violation. Tumor assessments should continue per protocol schedule, even if 
dosing is delayed. 
10.3 Dose Modifications 
No dose modification of XmAb23104 will be permitted. Permanent discontinuation criteria for 
XmAb23104 are outlined in the study appendix. 
11.0 
EVALUATION DURING TREATMENT/INTERVENTION 
11.1 Schedule of Assessments/Study Calendar 
Table 1. Study Calendar 
Screening 
Treatment 
Follow up 
Screening 
Cycle 1 
Cycle 2 
Cycle 3+ 
End of 
treatment 
(EOT)10 
Follow up 
Intervention 
28 Days 
prior to 
the 
treatment 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
30 days 
after last 
dose (+7 
days) 
Every 12 
weeks 
Informed consent 
X 
Medical history 
X 
Concurrent 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
XmAb231041 
X 
X 
X 
X 
X 
X 
Adverse event 
assessment 
X 
X 
X 
X 
X 
X 
X 

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Physical exam2 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
Routine laboratory 
tests3 
X 
X 
X 
X 
X 
X 
X 
X10 
Thyroid function 
tests4 
X 
X 
X 
X 
X10 
HBV, HCV 
serology (reflex 
PCR if +ve)5 
X 
Serum pregnancy 
test6 
X 
X 
X 
X 
X10 
Urinalysis 
X 
X10 
EKG 
X 
X 
CT/MRI7 
X 
X 
Research blood 
tests8 
X 
X 
X 
X 
Research biopsy9 
X 
X 
Survival status11 
X 
1. XmAb23104 will be administered via intravenous infusion at assigned dose. The XmAb23104 dosing window for 
Cycle 1 Day 15 will be ±1 day and ±3 days for Cycle 2 and higher. XmAb23104 will be administered as a 1-hour (- 
5 min / + 15 min) IV infusion. Supine blood pressure observation period and pulse rate, body temperature, 
respiratory rate. On days of XmAb23104 infusions, vital signs should be taken pre-infusion and 30 minutes after 
start of infusion (±10 min), at the end of infusion (±5 min), and 30 and 60 minutes after end of infusion (±10 min), 
then hourly (±10 min) after end of infusion for the remainder of the required. All vital signs during infusion should 
be taken with subject in the same position. Subjects will be observed for at least 4 hours following the first 3 
infusions. The observation period and vital signs assessments may be decreased to 2 hours if there are no 
infusion reactions for 3 consecutive infusions. 
2. Physical exam includes vital signs (pulse, blood pressure, temperature, respiratory rate, and oxygen saturation), 
height (required at baseline/screening assessment) and weight, and determination of ECOG status. 
3. Routine laboratory tests include comprehensive metabolic panel (sodium, potassium, magnesium, phosphorus, 
chloride, bicarbonate, BUN, creatinine, glucose, total protein, albumin, total bilirubin, AST, ALT, alkaline 
phosphatase), and amylase, and lipase to be performed prior to each dose of treatment. In addition, CK, LDH, PT 
(or INR) and aPPT should be tested during screening and at EOT only. 
4. Thyroid function tests include TSH, T3, and FT4. All will be collected at baseline and EOT visits. TSH and free T4 
is required at baseline and before each cycle 
5. Hepatitis B surface antigen and core antibody, and Hepatitis C antibody, with reflex PCR test if positive 
6. Serum β-HCG (Female subject of childbearing potential should have a negative serum pregnancy at screening 
and within 72 hours prior to first dose of both study drugs, the start of every cycle and at the off-study visit. 
7. Standard imaging studies for RECIST 1.1 assessment will be performed at baseline, week 8 and every 8 weeks 
subsequently (± 7 days window) for 56 weeks following which imaging may be performed every 8-12 weeks at the 
discretion of the treating investigator. Imaging will include CT of chest (with or without contrast) , CT of 
abdomen/pelvis (with contrast where renal function permits) and/or MRI alternatively (with and without contrast) of 
an affected area if deemed necessary by the study investigator. 
8. Research blood tests will be collected at baseline, day 1 cycle 2, 3, 4, 6 and at the end of treatment. 
9. All study participants will undergo mandatory tumor biopsies at baseline and week 7 (+/-7 days) where feasible 
and safe to do so. Effort will be made to choose the same site on re-biopsy when clinically feasible. 
10. Subjects who are permanently discontinued from receiving investigational product will return for End of Treatment 
visit 30 days after last dose or prior to initiation of unless consent is withdrawn, the subject is lost to follow-up, or 

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he/she begins another treatment. If patient begins another treatment, EOT Labs are to be collected prior to 
initiation of next treatment. 
11. Survival status and initiation of new anti-cancer therapy will be collected every 12 weeks (± 28 days) following the 
end of treatment visit until death, the patient withdraws consent, or 12 months after the end of treatment, 
whichever occurs first. This information may be obtained in person/via phone/electronically/medical record review. 
11.2 Tumor and Blood Samples for Correlative Analysis 
11.2.1 Tumor Biopsies 
Tumor biopsies for research purposes will be done at baseline and at 7 weeks after treatment where 
feasible and safe to do so. The same tumor site will be biopsied at each time point, if feasible. Cores will be 
obtained with 18-gauge needles where appropriate and be of at least 1 cm in length. Cores should be 
representative of tumor and targeted to the de-differentiated component in the case of dedifferentiated 
liposarcoma (DD-LPS) and dedifferentiated chondrosarcoma. 
The quality, viability, and tumor content of biopsies will be confirmed by the on-call clinical pathologist at the 
time of retrieval. The goal will be to extract 6 cores, with a minimum of one formalin-fixed, for later paraffin 
embedding (FFPE), one fresh (stored in RPMI media on ice), and one flash frozen in liquid nitrogen and 
transported on dry ice. If it is not possible to obtain 6 cores the sample type will be prioritized as follows: 
1. FFPE 
2. Fresh (stored in RPMI) 
3. Flash frozen 
4. Fresh (stored in RPMI) 
5. Flash frozen 
6. Flash frozen 
If any extra cores are obtained, they will be flash frozen with liquid nitrogen. Samples will be labeled using 
an adherent, liquid nitrogen proof label with the following information: 
1. Procurement date 
2. Study IRB number 
3. Study patient number 
4. Time point (baseline/pre-treatment, on-treatment (week 8), progression (optional)) 
5. Anatomical biopsy site 
Each FFPE sample is to be placed in a pathology sample container pre-filled with formalin and delivered to 
the MSK pathology lab. Each fresh sample is to be placed in a 50ml Falcon tube with 20 ml of RPMI media, 
labeled and the cryovial placed in a sample bag and the sample bag placed within the ice. 
Each flash frozen sample is to be placed within an individual cryovial, labeled, and the vial immediately 
placed in liquid nitrogen for 2 minutes or longer to snap-freeze the tissue. These vials can be transported in 
either liquid nitrogen or in dry ice. The fresh and flash frozen samples are to be transported to the Immune 
Monitoring Facility as detailed below in section 11.2.2 
11.2.2 Research Blood Sample Collection 

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Peripheral blood samples for research will be obtained at baseline, day 1 cycle 2, 3, 4, 6 and at the end of 
treatment. At each research blood collection time point the following samples will be collected: 
• 4x8ml of peripheral venous blood will be collected in CPT tubes. Invert all tubes several times immediately 
after collection to ensure mixing with anticoagulant. 
Specimens will be placed in a biohazard bag and transportedat room temperature. Samples will be labeled 
with the following information without obstructing the visualization of drawn blood volume: 
• 
Procurement date 
• 
Study IRB number 
• 
Study patient number 
• 
Patient medical record number 
• 
Time point (baseline or week-X) 
1. Research blood samples and tumor biopsy samples, along with completed requisition forms, are to be 
transported to the Immune Monitoring Facility located at the MSKCC Zuckerman Research Center (408 
E. 69th St, New York, NY 10021), Room Z-1513. Place into sample drop-off bin located OUTSIDE of Z- 
1513. At least 24h advanced notification should be provided using the Outlook shared blood delivery 
calendar (zzCAL_LAB_Clinical_Trials/Shared Calendar) and be sure to include clinical site location and 
contact information from which samples are arriving on the calendar notice. 
a. Rosemarie Ramsawak ramsawar@mskcc.org 
b. Phillip Wong wongp@mskcc.org 
Samples must be delivered after collection between the hours of 9 am-4 pm to a member of the lab. 
11.3 Biomarker Analysis 
11.3.1 Density of Immune Infiltrate and Immune Regulatory Biomarker Expression 
IHC will be used to assess the number and composition of immune infiltrates to define the immune cell 
subsets present within the tumor before and after exposure to study therapy. PD-L1 and ICOS expression 
within the tumor and on immune cells before and after exposure to study therapy will also be determined. 
IHC assays will be performed using, but are not limited to, the following markers: CD3, CD4, CD8, CD25, 
CD28 CD45RA, CD68, CD69, CD163, CD206, CCR7, IDO-1, PD-L1, PD-1, CD137, FOXP3, LAG-3, TIM-3, 
and ICOS. 
11.3.2 Tumor Biopsy gene expression profiling 
Fresh tumor biopsy will be examined for RNA gene and protein expression by NanoString technology 
(nCounter® RNA: Protein, PanCancer Immune Profiling Panel) and/or qRT-PCR to detect expression of 
immune related genes. This panel includes 770 immune related genes including: 109 genes related to cell 
surface markers for 24 different immune cell types and populations, 30 genes for commonly studied 
cancer/testis (CT) antigens, over 500 genes for measuring immune response and 40 reference genes. 
In the course of this research it is possible that some patients whose tumors are analyzed through 
investigational “next-generation” profiling in a research (non-CLIA) environment will be found to have 

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somatic or germline mutations in genes that are known to be associated with an increased risk of cancer or 
other diseases. It will be stated in the consent that the participants will not receive any specific results from 
research tests. The consent will tell participants that if they wish to have genetic testing done for personal 
reasons than they should make an appointment with the MSK Clinical Genetics Service. 
If in the course of this research a research finding is obtained that, in the opinion of the investigator, may be 
critical to the preventive care of the participant or their family, the investigator can communicate that finding 
to the IRB Genomic Advisory Panel (GAP). The finding will be reviewed by the GAP to determine whether 
the incidental finding should be discussed with the participant. For MSK, in the event that the GAP 
determines that the finding should be discussed with the participant, and the participant has consented to 
be re-contacted, then the treating/consenting physician shall be contacted by the panel and asked to refer 
the participant to the Clinical Genetics Service for further discussion of the research finding. 
11.3.3 Next generation sequencing for T-cell receptor clonality in TILs 
Samples will be analyzed using high throughput sequencing of the variable -chain of the T cell receptor 
(TCR) to characterize the expansion and clonality of the T-cell repertoire in TILs. 
11.3.4 Peripheral Blood Immunophenotyping, Functional Analyses, and Cytokine/Chemokine Analysis 
Samples will be analyzed by flow cytometry to study the effects of XmAb23104 monotherapy on various 
peripheral blood immune cell subsets including, but not limited to T cell subsets (activated, memory and 
regulatory T cells). To explore whether targeting PD1 and ICOS will restore T cell activation and function, 
peripheral blood mononuclear cells (PBMCs) will be isolated and cryopreserved. Assays of the functional 
status of effector T cells will be performed, including, but not limited to assays for interferon-gamma (IFN-γ) 
and granzyme B. 
Baseline and on-treatment serum levels of chemokines, cytokines and other immune mediators will be 
assessed by techniques that may include, but are not limited to, ELISA or multiplex assays. Analytes may 
include, but are not limited to IFN-γ, IL-12, IL-10, soluble MICA, C-reactive protein, soluble PD-1, ICOS and 
soluble PD-L1. 
12.0 CRITERIA FOR REMOVAL FROM STUDY 
In the absence of serious toxicity or complications, all patients will continue treatment. In the absence of 
treatment delays due to AEs, treatment may continue until one of the following criteria applies: 
• 
Disease progression 
• 
Development of an inter-current medical condition or need for concomitant treatment that precludes 
further participation in the trial 
• 
Unacceptable toxicity or any AE that precludes further participation in the trial. 
• 
The investigator removes the patient from the trial in the best interests of the patient 
• 
Patient death 
• 
Study completion or discontinuation for any reason 
• 
Patient withdraws consent to continued participation in the trial or is lost to follow up 

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Due to the mechanism of action, patients may experience growth in existing tumors or the appearance of 
new tumors prior to maximal clinical benefit of XmAb23104. The patient may be allowed to continue study 
treatment after initial RECIST 1.1 defined progression if they are assessed by the treating physician to be 
deriving clinical benefit and tolerating study treatment and have no signs of symptoms indicating clinically 
significant progression of disease and no decline in ECOG performance status. Patients who are treated 
beyond progression will be re-consented and adequately informed of all FDA-approved therapy, and 
potential clinical benefit, that the patient may be foregoing in order to continue receiving the investigational 
product at the time of radiographic progression. Such patients should discontinue study therapy upon 
further evidence of progression at the discretion of the treating investigator. 
Subjects who are permanently discontinued from receiving investigational product will return for end of 
treatment visit, unless consent is withdrawn, the subject is lost to follow-up, or he/she begins another 
treatment. All subjects will be followed for survival by phone (if not actively following at MSKCC) every 3 
months for up to 12 months. After the end of treatment, each patient will be followed for 30 days for AE 
monitoring. SAE reporting is required for 30-days after the participant’s last investigational treatment or 
intervention. Any events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. If consent is withdrawn, the subject will not receive any further investigational 
product or further study observation. 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY 
13.1 Criteria for Therapeutic Response/Outcome Assessment 
13.1.1 Categorization of Tumor Lesions 
• Measurable Lesions: must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
o 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm) 
o 10 mm caliper measurement by clinical exam (when superficial) 
o Malignant lymph nodes are 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). 
• 
Non-measurable Lesions: all other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis). Lesions 
considered truly non-measurable including leptomeningeal disease, ascites, pleural/pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques. 
• 
Target Lesions: all lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per 
organ) representative of all involved organs should be identified as target lesions. 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. 
• 
Non-target Lesions: it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”) 

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13.1.2.1 
Evaluation of Target Lesions 
• 
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 (the sum may not be “0” 
if there are target nodes. 
• 
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 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 
progression.) 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum of diameters while on study. 
13.1.2.2 
Evaluation of Non-target Lesions 
• 
Complete Response: disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (< 10 mm short axis) 
• 
Non-complete response/Non-progressive disease: persistence of 1 or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits. 
• 
Progressive Disease: unequivocal progression of existing non-target lesions will be defined as 
the overall level of substantial worsening in non-target disease such that, even in presence of 
SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. In the absence of measurable disease, change in non-measurable 
disease comparable in magnitude to the increase that would be required to declare PD for 
measurable disease. Examples include an increase in a pleural effusion from “trace” to “large,” 
an increase in lymphangitic disease from localized to widespread. 
13.1.4 Appearance of New Lesions 
The appearance of new lesions is considered PD according to RECIST v 1.1 guidelines. Considering 
the unique response kinetics that have been observed with immunotherapy, new lesions may not 
represent true disease progression. In the absence of rapid clinical deterioration, subjects may continue 
to receive study treatment. 
13.1.5 Evaluation of Overall Response 
Table 2 provides overall responses for all possible combinations of tumor responses in target and non- 
target lesions with or without the appearance of new lesions. 
Table 2: Evaluation of Overall Response 

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13.2 Criteria for Study Endpoint Evaluability 
Patients evaluable for efficacy analysis will include all patients treated with XmAb23104 who are 
assessable for response. Patients who have no assessment of response post-baseline will not be 
considered evaluable for response unless they missed the assessment due to progression of disease, 
death or treatment-related toxicities, in which case they will be considered non-responders for that time 
point. Patients with at least one post-baseline assessment who are not assessed at 24 weeks for 
reasons other than progression of disease, death, or excessive-toxicity, will be evaluated based on their 
last imaging assessment. Patients who are not evaluable (excluding those who died, had progression of 
disease, stopped study treatment due to treatment-related toxicity, or those with at least one post- 
baseline assessment) may be replaced. The anticipated replacement rate is ≤ 5%. Patients evaluable 
for safety analysis will include all patients who have received at least one dose of with XmAb23104. 

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14.0 
BIOSTATISTICS 
This is a single-center, open label, phase II trial to evaluate the XmAb23104 monotherapy. Confirmed 
response rate over the first 24 weeks of treatment is our primary endpoint. All treatment decisions and 
the evaluation of the primary endpoint will be based on RECIST v1.1. Patients will be stratified into one 
of 6 cohorts based on sarcoma histological subtype. There will be 5 patients in each cohort. 
14.1.1 Primary Endpoint 
To evaluate the efficacy, as assessed by best objective response rate (ORR; partial response [PR] and 
complete response [CR]) at 24 weeks, as defined by RECIST v1.1, of XmAb23104 in patients with 
advanced sarcoma. ORR will be calculated as a proportion with a two-sided 95% confidence interval 
provided. 
14.1.2 Hypothesis 
We are testing the hypothesis of an objective response rate with XmAb23104 being at most 5% 
(clinically inactive) versus an objective response rate of at least 25% (clinically active). 
14.1.3 Design Characteristics and Endpoint Assessment 
This study will enroll a total of 30 evaluable patients. Demonstration of at least 4 objective responses will 
be considered as having sufficient evidence of promising activity in this population. This design 
yields 96% power to detect a true objective response rate of at least 25%, with a 0.06 significance level 
(1-sided test) if the true objective response rate is 5%. 
The statistical consideration for this study will be for all 30 patients enrolled to one of 6 disease-specific 
cohorts: SFT, LMS, dedifferentiated chondrosarcoma, UPS/MFS, translocation associated sarcoma 
including SEF or extraskeletal myxoid chondrosarcoma (ESMC) and Pecoma. As each histologic 
subtype may respond differently to treatment with XmAb23104, 5 patients per histology-specific cohort 
will be enrolled, for a total of 30 patients. The sample size of 30 was chosen to allow the opportunity to 
detect a significant difference in ORR within each sarcoma subtype under investigation and because of 
budget constraints. All 6 cohorts will be evaluated together for the primary and secondary endpoints. If a 
signal of efficacy is found within a specific histologic subtype as opposed to others, expansion of this 
cohort or a larger phase II study may be considered, depending on discussions between the study 
investigators and the sponsor based on both efficacy data and correlatives results. A signal of efficacy in 
a given sarcoma subtype, for the purpose of determining appropriateness of expanding the study will be 
considered as either of the following: 1) two objective responses or 2) a single objective response in 
combination with correlative data where available to support a positive therapeutic effect or manipulation 
of the immune microenvironment. 
If a two-stage design were implemented, the study might be terminated early for a presumed lack of 
efficacy that may be driven by one or two histologic subtypes, especially if the accrual rate for different 
histologies differs. As sarcoma represents a heterogenous group of diseases with unique biologies, the 
response to dual-immune checkpoint blockade may be different in each histologic cohort. Response to 
single-agent anti-PD-1 therapy varies by subtype, these have been relatively small early phase trials 
and results have not been consistent or uniform across studies. 

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We hypothesize that XmAb23104 will yield an ORR of 25% if clinically active versus 5% if clinically 
inactive in advanced sarcoma. 
Based on the available clinical trial data, we would connsider an ORR of 25% at 24 weeks to be 
promising and 5% ORR to be not promising. The study will be claimed to be positive if 4 or more of the 
30 evaluable patients demonstrate a confirmed objective response at 24 weeks. This design has a type 
I error rate of 0.06 and a power of 96%. 
The primary efficacy dataset will include all patients who received at least one dose of study therapy 
and are assessable for response. Patients who have no assessment of response post-baseline will not 
be considered evaluable for response unless they missed the assessment due to progression of 
disease, death or treatment-related toxicities, in which case they will be considered non-responders for 
that time point. 
The study is expected to complete accrual in 30 months. Accrual is expected to vary based on 
histological sarcoma subtype, likely 1 patient every 2 months for the cohorts enrolling leiomyosarcoma 
and dedifferentiated liposarcoma and 1 patient every 4-6 months for cohorts enrolling all other subtypes. 
The accrual rate will be monitored closely and every 6 months consideration will be made to potentially 
stop enrolling a specific sarcoma subtype and expand enrollment of another sarcoma subtype based on 
accrual patterns observed. 
14.1.4 Secondary Endpoints 
• 
To evaluate the safety and tolerability of XmAb23104 in patients with advanced sarcoma. 
Adverse events will be recorded using NCICTCAE v5.0 criteria and the adverse event rate to study 
treatment will be determined. Categorical data analysis will be used to summarize the adverse event 
rate and maximum severity during treatment for each patient and AE classification 
The safety analysis dataset will include all patients treated with at least one dose of XmAb23104. 
• 
To evaluate the efficacy, as assessed by the clinical benefit rate(stable disease [SD] for ≥ 16 weeks 
+ PR at 48 weeks + CR at 48 weeks) , as defined by RECIST v1.1, of XmAb23104 in patients with 
advanced sarcoma. Patients who don’t have the 48-week assessment due to reasons other than 
progression, excessive toxicity, or death, will be included in the calculation of 48-week CBR by 
carrying forward the last assessment before 48 weeks, 
• 
To assess the progression free survival (PFS) rate at 6 months, overall survival (OS) at 12 months, 
median PFS, and median OS for patients treated with XmAb23104 in patients with advanced 
sarcoma 
• 
To assess the duration of response, as defined by RECIST v 1.1 of XmAb23104 in patients with 
advanced sarcoma. 
Kaplan-Meier methodology will be used to evaluate time to event endpoints: PFS (time from treatment start 
date to the earliest of either disease progression or death from any cause), OS (time from treatment start 
date to death from any cause) and duration of response (time from first response to disease progression). 
CBR will be calculated as a proportion with a two-sided 95% confidence interval provided. 

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14.1.5 Exploratory Endpoints 
• 
To determine the baseline characteristics of sarcoma tumors (pre-treatment biopsy sample) 
evaluated in this study including level of PD-1/PD-L1/ICOS expression, presence of tumor infiltrating 
lymphocytes (TILs) and tumor antigens, gene expression profile and T-cell receptor clonality in TILs. 
• 
To assess the potential effect of XmAb23104 on selected biomarker expression measured in post- 
treatment tumor tissue and the association between these biomarkers (baseline level of expression 
and the change in biomarker level of expression following treatment) and clinical outcome, including 
characterization of PD-1/PD-L1/ICOS expression, TILs, gene expression profiling, and 
characterization of T-cell receptor clonality in TILs. 
• 
To evaluate the associations between selected biomarkers measured in serial peripheral blood and 
clinical efficacy, including immunophenotyping and functional analyses, evaluation of serum levels of 
chemokines, cytokines and other immune mediators, and characterization of T-cell receptor clonality 
in peripheral blood 
All patients enrolled on this study will undergo mandatory treatment biopsies both before and after initiation 
of study therapy. The correlative analyses are exploratory in nature and are not powered to detect specific 
hypotheses. Results will be used to identify biomarkers of interest that have the potential to define benefit 
from study treatment. 
Summary statistics will be used to describe changes over time observed in tumor tissue biopsies (baseline 
and on-treatment) and serial peripheral blood samples (at baseline, day 1 cycle 2, 3, 4, 6 and at the end of 
treatment). In addition, the time course of biomarker measurements will be investigated graphically, by 
summary plots or individual patient plots; their trends over time will be categorized either by visual 
inspection (if there are clear trend groups such as monotonically increasing or monotonically decreasing) or 
by pattern recognition methods such as K-means clustering. The associations with the observed trend 
categories in selected biomarkers will be evaluated for association with clinical outcome such as response, 
if there are a reasonable number of events for each outcome, using Fisher’s exact test, and progression 
free survival using log rank test. 
15.0 
ADVERSE EVENTS/RISKS 
15.1.1 Definition of an Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation patient, 
temporally associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 
medicinal product. For marketed medicinal products, this also includes failure to produce expected 
benefits, abuse, or misuse. 
All AEs, either reported by the patient or observed by study staff, will be recorded for up to 30 days after 

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end of treatment or until a new antineoplastic regimen has been initiated. AEs will be summarized by 
preferred term, system organ class, NCI CTCAE version 5.0 grade of severity, and relationship to each 
study drug. 
Examples of events meeting the definition of an AE include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or grade of the condition 
• 
New conditions detected or diagnosed after study treatment administration even though it may 
have been present prior to the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication (overdose per se will not be reported as an AE/SAE). 
Events that do not meet the definition of an AE include: 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the 
procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease or condition present or detected at the 
start of the study that do not worsen. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s condition. 
Any clinically significant safety assessments that are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the patient's condition, are not to be 
reported as AEs or SAEs. 
15.1.2 Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or other safety 
assessments (e.g., ECGs, radiological scans, vital signs measurements) including those that worsen 
from baseline, and events felt to be clinically significant in the medical and scientific judgment of the 
investigator are to be recorded as an AE or SAE, in accordance with the protocol. 
15.1.3 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
Disease Related Events are events (serious or non-serious) anticipated to occur in the study population 
due to the underlying disease. These could include overall disease progression or pain or discomfort 
caused by growing tumors. Such events do not meet the definition of an Adverse Event unless 
assessed to be more severe than expected for the patient’s condition. An event which is part of the 
natural course of the disease under study (i.e., disease progression) does not need to be reported as an 
SAE. Deaths and hospitalizations related to disease (other than for study procedures) during the study 
period and 90 days after completion must be reported as SAEs. 
Disease Related Events that would qualify as an Adverse Event or Serious Adverse Event, include any 

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event based on the underlying disease that is worse than expected as assessed by the investigator for 
the patient’s condition if the investigator believes there is a causal relationship between the 
investigational product/study treatment/protocol required therapies and disease worsening. 
15.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
SAE reporting is required as soon as the participant starts investigational treatment/intervention. SAE 
reporting is required for 30-days after the participant’s last investigational treatment/intervention. Any 
event that occur after the 30-day period that is unexpected and at least possibly related to protocol 
treatment must be reported. 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention and is 
related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per IRB SOP 
RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted within 5 calendar 
days of the event. All other SAEs must be submitted within 30 calendar days of the event. 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 

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15.2.1 External SAE Reporting 
The MSK SAE report should be completed as per above instructions. If appropriate, the report will be 
forwarded to the FDA by the IND Office. Regardless of suspected causality (e.g., relationship to study 
drug or study procedures), all SAEs occurring after the participant initiates treatment through 30 days 
after the last dose of study drug must be reported to Xencor (or designee) within 24 hours of learning of 
its occurrence, unless otherwise specified by the Protocol. Information regarding maternal exposure to 
the Study Drug during pregnancy, and information regarding paternal exposure to the Study Drug (in 
accordance with MSK pregnant partner policy) will be reported to Xencor according to the reporting 
timelines below. 
• Procedures for Reporting SAEs/AEs and Exposure to Study Drug During Pregnancy to 
Xencor/designee 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the IMP may have 
interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see 
below). Hospitalization for normal delivery of a healthy newborn should not be considered an 
SAE. All notifications of pregnancy should be documented and reported through 30 days 
following cessation of study treatment (or through 28 days following cessation of study 
treatment, if the subject initiates new anticancer therapy) whether or not there is an associated 
AE or SAE. 
Each pregnancy must be reported by the Investigator to Xencor using an initial 
pregnancy report form within 24 hours after becoming aware of the pregnancy. The Investigator 
must follow-up and document the course and the outcome of all pregnancies even if the subject 
was withdrawn from the clinical study or if the clinical study has finished. The follow-up period 
will be deemed to have ended when the health status of the child has been determined on its 
birth. 
All outcomes of pregnancy must be reported by the Investigator Xencor on the 
pregnancy outcome report form within 30 days after he/she has gained knowledge of the normal 
delivery or elective abortion. 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (eg, maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, birth defect) and reported within 24 hours of awareness in accordance with 
the procedure for reporting SAEs. 
o Initial Reporting: 
• 
Upon learning of an SAE temporally associated with the Study Drug or exposure to Study 
Drug during pregnancy, which is required to be reported pursuant to Applicable Law, 
Institution or Principal Investigator shall complete and submit an Adverse Event Report Form 
to Xennor or its designee within twenty-four (24) hours of learning of the event, via email to 
icon-mads@iconplc.com. 

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• 
If critical or outstanding information is missing from the Adverse Event Report Form or 
additional clarification is needed, Xencor or its designee shall submit a Data Clarification 
Form (“DCF”) to the Institution or Principal Investigator. 
o Follow-up Reporting: 
• 
When new information regarding an initially reported SAE temporally associated with the Study 
Drug or maternal or paternal exposure to Study Drug during pregnancy becomes available, the 
Institution or Principal Investigator shall provide such follow-up information on a new or updated 
Adverse Event Report Form within five (5) business days of learning of the new information, via 
icon-mads@iconplc.com. 
o Form: 
• 
All adverse event information is reported to Xencor/designee on the Principal 
Investigator’s/Institution’s Adverse Event Report Form. The Principal Investigator does not 
provide medical records (e.g., discharge summary) to Incyte, unless specifically requested. 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur 
prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences of potential 
drug-induced liver injury (DILI), meeting the defined criteria, must be reported as SAEs). 
15.3 Possible Toxicity 
15.3.1 XmAb23104 
To date, XmAb23104 has been evaluated in a single Phase 1 dose-escalation trial (XmAb23104-01) in 
adults with advanced solid tumors. This trial is ongoing, and a recommended Phase 2 dose of 10 mg/kg 
was established; an MTD was not reached. 
As of the data cutoff date of 01 November 2021, a total of 75 patients have been enrolled and treated in 
the XmAb23104-01 study. Doses of XmAb23104 have ranged from 0.002 – 15.0 mg/kg. 
Four subjects were eligible and opted to intra-subject dose escalate; 1 subject from 0.2 mg/kg to 0.6 
mg/kg, 1 subject from 0.6 mg/kg to 1.8 mg/kg, 1 subject from 5.4 mg/kg to 10 mg/kg and a single 
subject escalated twice, once from 1.8 mg/kg to 5.4 mg/kg and finally up to 10 mg/kg. Three subjects 
received 10 mg/kg XmAb23104 monotherapy in the expansion phase of the study, and 10 subjects 
received 10 mg/kg XmAb23104 in combination with 1 mg/kg ipilimumab. 
Sixty-seven (89.3%) subjects had at least 1 treatment-emergent adverse event (TEAE); the most 
common was fatigue, observed in 17 (22.7%) subjects. In addition, 9 (12.0%) subjects experienced 
immunotherapy-related AEs (IRAEs) and 1 (1.3%) subject experienced an infusion-related reaction 
(IRR). 
The mean half-life of XmAb23104 is approximately 10.6 days. Insufficient data are available at this time 
to accurately define efficacy and PD. 
The safety findings based on the 75 subjects treated in the XmAb23104-01 study have shown 
acceptable toxicity. 

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Study XmAb23104-01 is a Phase 1, FIH, multiple-dose, ascending dose-escalation (Part A) and cohort 
expansion (Part B) study. The primary objectives of XmAb23104-01 are to (1) evaluate the safety and 
tolerability of XmAb23104 with and without ipilimumab in subjects with selected advanced solid tumors 
who have progressed after treatment with standard/approved therapies or have no appropriate available 
therapies, and (2) identify the MTD and/or RD/schedule for XmAb23104 administered by IV dosing on 
Days 1 and 15 of each 28-day cycle in subjects with selected advanced solid tumors. 
As of the clinical database cutoff of 01 November 2021, sixty-two subjects have been treated at 
dosages of < 10, 10, and 15 mg/kg in escalation (Part A). Thirteen subjects have received 10 mg/kg 
XmAb23104 with or without 1 mg/kg ipilimumab in expansion (Part B). 
Of the 75 subjects dosed with study drug, 21 (28%) subjects experienced a total of 33 TE-SAEs. The 
most frequent TE-SAEs were from the following system organ classes (SOCs): Gastrointestinal 
disorders in 6 (8.0%) subjects, Renal and urinary disorders in 4 (5.3%) subjects, and Investigations and 
Respiratory, thoracic and mediastinal disorders in 3 (4.0%) subjects. 
As of 01 November, 2021, there were 2 cases of serious adverse reactions (SARs; assessed by the 
sponsor as possibly related to the IMP) reported in 2 (2.7%) subjects in the XmAb23104-01 study. 
These events included a Grade 3 Hyperbilirubinemia reported in a subject at 1.8 mg/kg dose, and 
asymptomatic Grade 4 Lipase increased in a subject at 0.6 mg/kg dose, both of which resolved. No fatal 
or life-threatening SARs were reported. 
At least 1 TEAE occurred in 89.3% of subjects. The most commonly observed TEAEs were fatigue (18 
subjects, 24.0%), nausea (18 subjects, 24.0%), vomiting (15 subjects, 20.0%), diarrhea (14 subjects, 
18.7%), pyrexia (13 subjects, 17.3%), and anemia (12 subjects, 16.0%) [see Appendix A, Table 14]. • 
Treatment-related AEs (TRAEs) are shown in Table 3. By patient, the most common events were 
diarrhea (9 subjects, 12%), fatigue (7 subjects, 9.3%), decreased appetite (7 subjects, 9.3%), pyrexia (7 
subjects, 9.3%), and vomiting (6 subjects, 8.0%) • Grade ≥ 3 TRAE occurred in 8 (10.7%) subjects. The 
most common Grade ≥ 3 TRAEs were lipase increased and diarrhea, each seen in 2 (2.7%) subjects. • 
There were 15 IRAEs, as determined by the investigator, occurring in 9 subjects reported thus far in the 
study. No individual IRAE occurred in more than 1 subject. 
Table 3. Treatment-Related Adverse Events by Preferred Term in Decreasing Frequency (Safety 
Population) 

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. 
15.3.2 Infusion related Reactions 
One subject experienced a Grade 2 IRR 30 minutes into the Cycle 2, Day 1 infusion. They were treated 
with IV antihistamine, solumedrol, and IV fluids, with resolution of the event. On subsequent doses, the 
patient was premedicated with diphenhydramine, ranitidine, and acetaminophen, with no further IRR 
events. Infusion reactions have also been commonly seen with monovalent therapeutic antibodies. 
Infusion reactions to XmAb23104 will be managed as specified in detail in the clinical protocol and/or as 
deemed appropriate by investigators, including discontinuation of further infusions, if necessary. 
Primary prophylaxis with acetaminophen and an H2-blocker should be strongly considered for 
participants who have had previous systemic reactions to protein product infusions or when 
recommended according to institutional policy. Secondary prophylaxis is recommended for participants 
who have experienced IRRs to XmAb23104. Participants who experience life- threatening IRRs should 
not be retreated with XmAb23104. 
Refer to appendix A for guidance on management of suspected infusion reactions. 
15.3.2 Immune-Related Adverse Events (irAE) 

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XmAb23104 is a bispecific humanized mAb that has been designed to restore T-cell immune function, 
similar to other PD-1 inhibitors that have been extensively studied. Therefore, safety experience with 
other drugs should be considered when administering XmAb23104. Potentially serious irAEs include: 
• 
Pneumonitis 
• 
Hepatitis 
• 
Colitis 
• 
Nephritis 
• 
Endocrinopathies (thyroiditis, hypophysitis, type I diabetes) 
• 
Encephalitis 
• 
Myocarditis 
• 
Skin reactions (including SJS/TEN) 
• 
Rejection of organ transplants 
• 
Other reactions (including arthritis, uveitis, Gulian-Barre syndrome, myasthenia gravis, vasculitis, 
pancreatitis, and hemolytic anemia) 
There were 15 irAEs occurring in 9 subjects reported thus far in the XmAb23104-01 study (see 
Table 4). Patients will be evaluated for signs and symptoms of irAEs prior to administration of each 
dose of study drug. Refer to appendix B for guidance on management of immune mediated adverse 
events. 
Table 4 Immune-Related TEAEs by Preferred Term in Decreasing Frequency 

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15.3.1.3 Immunagenicity 
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody 
formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed 
incidence of ADA positivity in an assay may be influenced by several factors, including assay 
methodology, sample handling, timing of sample collection, concomitant medications, and underlying 
disease. 
Using a validated electro chemiluminescent assay, anti-XmAb23104 antibodies were induced or 
boosted in 50 of 69 subjects (72.5%) at any time after treatment. Four of those subjects had preexisting 
antibodies that were boosted after exposure to XmAb23104. There was an apparent impact on 
XmAb23104 drug exposure on 2 out of 49 subjects who were screened positive (4.0%) and both were at 
low-dose (≤ 0.06 mg/kg) cohorts with PK data available and concurrent with confirmed binding ADA, all 
of which emerged at C1D15 or later with titer greater than 1:5000. Among all subjects treated as of the 
data cutoff, 1 experienced an infusion-related reaction (Grade 2); this subject was ADA positive. The 
neutralizing capacity of the antibodies has not been evaluated. 
15.3.1.3 Drug Interactions 
There are no known drug interactions with XmAb23104, and drug interaction studies have not been 
conducted. Careful attention is warranted in combination studies since immune-related toxicities may 
potentially be exacerbated when XmAb23104 is combined with other immunoactive agents. 
Immunosuppression in excess of physiologic maintenance corticosteroid doses (> 10 mg of prednisone 
or equivalent) within 14 days of first dose and throughout the treatment period of the study (with the 
exception of acute treatment for an AE). 
Live vaccines within 28 days before first administration of study drug, throughout the treatment period of 
the study, and for a duration of 90 days after the last dose of study drug. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, chicken pox/zoster, yellow fever, 
rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed. 
15.3.1.6 Contraindications 
Patients with known hypersensitivity to recombinant proteins or any excipient contained in the 
XmAb23104 drug formulation that cannot be controlled with routine supportive measures should not 
receive XmAb23104. 
15.3.1.7 Mutagenicity 
XmAb23104 should not be used in females who are pregnant or breastfeeding. XmAb23104 is not 
expected to be mutagenic; however, carcinogenicity studies have not been conducted, and male 
participants should use barrier contraception (i.e., condom) while receiving XmAb23104. 
16.0 
PROTECTION OF HUMAN PARTICIPANTS 

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16.1 
Privacy 
MSK’s Privacy Office may allow the use and disclosure of protected health information pursuant to a 
completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals/entities described in the Research Authorization form. A 
Research Authorization form must be approved by the IRB and Privacy Board (IRB/PB). The consent 
indicates that individualized de identified information collected for the purposes of this study may be 
shared with other qualified researchers. Only researchers who have received approval from MSK will be 
allowed to access this information which will not include protected health information, such as the 
participant’s name, except for dates. It is also stated in the Research Authorization that their research 
data may be shared with others at the time of study publication. 
16.2 
Data Management 
A Clinical Research Coordinator (CRC) will be assigned to the study. The responsibilities of the CRC 
include project compliance, data collection, abstraction and entry, data reporting, regulatory monitoring, 
problem resolution and prioritization, and coordinate the activities of the protocol study team. The data 
collected for this study will be entered into a secure Medidata database. Source documentation will be 
available to support the computerized patient record. Final data sets for publication are required to be 
locked and stored centrally for potential future access requests from outside entities. 
16.3 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be monitored 
periodically throughout the study period and potential problems will be brought to the attention of the 
study team for discussion and action. Random-sample data quality and protocol compliance audits will 
be conducted by the study team, at a minimum of two times per year, more frequently if indicated. 
16.4 
Data and Safety Monitoring 
The Data and Safety Monitoring Plan utilized for this study must align with the MSK DSM Plan, where 
applicable.The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were approved by 
the National Cancer Institute in August 2018. The plans address the new policies set forth by the NCI in 
the document entitled “Policy of the National Cancer Institute for Data and Safety Monitoring of Clinical 
Trials.” 
There are several different mechanisms by which clinical studies are monitored for data, safety and 
quality. At a departmental/PI level there exists procedures for quality control by the research team(s). 
Institutional processes in place for quality assurance include protocol monitoring, compliance and data 
verification audits, staff education on clinical research QA and two institutional committees that are 
responsible for monitoring the activities of our clinical trials programs. The committees: Data and Safety 
Monitoring Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Deputy Physician-in-Chief, Clinical Research. 
During the protocol development and review process, each protocol will be assessed for its level of risk 
and degree of monitoring required. 
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials. The DSMB/C 

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have oversight over the following trials: 
• MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
• External studies where MSK is the data coordinating center 
• Low risk studies identified as requiring DSMB/C review 
The DSMC will initiate review following the enrollment of the first participant/or by the end of the year 
one if no accruals and will continue for the study lifecycle until there are no participants under active 
therapy and the protocol has closed to accrual. The DSMB will initiate review once the protocol is open 
to accrual. 

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17.0 
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Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas. Cancers. 
2020;12(7). 
35. Doshi SD, Oza J, Remotti H, Remotti F, Moy MP, Schwartz GK, et al. Clinical Benefit From 
Immune Checkpoint Blockade in Sclerosing Epithelioid Fibrosarcoma: A Translocation- 
Associated Sarcoma. JCO Precision Oncology. 2021(5):1-5. 
36. Liu HJ, Lizotte PH, Du H, Speranza MC, Lam HC, Vaughan S, et al. TSC2-deficient tumors 
have evidence of T cell exhaustion and respond to anti-PD-1/anti-CTLA-4 immunotherapy. JCI 
insight. 2018;3(8). 
37. Painter CA, Jain E, Tomson BN, et al. The Angiosarcoma Project: enabling genomic and 
clinical discoveries in a rare cancer through patient-partnered research. Nat Med. 
2020;26(2):181-187. 
38. Steele CD, Tarabichi M, Oukrif D, et al. Undifferentiated Sarcomas Develop through 
Distinct Evolutionary Pathways. Cancer Cell. 2019;35(3):441-456 e448. 
39. Petitprez F, de Reynies A, Keung EZ, et al. B cells are associated with survival and 
immunotherapy response in sarcoma. Nature. 2020;577(7791):556-560. 
40. Steddon B, Strauss S, Whelan J, et al. Gemcitabine and docetaxel versus doxorubicin as 
first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue 
sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 2017 
Oct;18(10):1397-1410. 
41. Shreyaskumar Patel, Margaret von Mehren, Damon R Reed, et al. Overall survival and 
histology-specific subgroup analyses from a phase 3, randomized controlled study of 
trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma. 
Cancer. 2019 Aug 1;125(15):2610-2620. 
42. Winette T A van der Graaf , Jean-Yves Blay, Sant P Chawla, et al. Pazopanib for 
metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled 
phase 3 trial. Lancet. 2012 May 19;379(9829):1879-86. 
43. Patrick Schöffski, Sant Chawla, , Robert G Maki, et al. Eribulin versus dacarbazine in 
previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, 
open-label, multicentre, phase 3 trial. Lancet. 2016 Apr 16;387(10028):1629-37. 

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44. James T. Boothe, G. Thomas Budd, Matthew B. Smolkin, Patrick C. Ma. Durable Near- 
Complete Response to Anti-PD-1 Checkpoint Immunotherapy in a Refractory Malignant 
Solitary Fibrous Tumor of the Pleura. Case Rep Oncol. 2017 Sep-Dec; 10(3): 998–1005. 
18.0 
APPENDICES 
18.1 Appendix A Guidelines for Management of Suspected Infusion Reactions 
Infusion or hypersensitivity reactions may be observed with administration of any foreign protein. 
Premedication with an antipyretic (e.g., acetaminophen/paracetamol) and a histamine blocker (e.g., 
diphenhydramine) should be considered for participants who have had previous systemic reactions to 
protein product infusions or when recommended by institutional policy. Routine prophylaxis is not 
required. Guidelines for management of suspected infusion reactions are provided in Appendix A 
Table 2 below. 
Infusion-related reactions and cytokine release syndrome will be toxicity graded according to the 
NCI-CTCAE, Version 5. 
Table 1: 
Grading of Infusion Reactions/Cytokine Release Syndrome 
Advers 
e 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Infusion 
related 
reaction 
Mild transient 
reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or 
infusion 
interruption 
indicated but 
responds 
promptly to 
symptomatic 
treatment (eg, 
antihistamines, 
NSAIDS, 
narcotics,IV 
fluids); 
prophylactic 
medications 
indicated for ≤ 24 
h 
Prolonged (eg, not 
rapidly 
responsive to 
symptomatic 
medication and/or 
brief interruption 
of infusion); 
recurrence of 
symptoms 
followinginitial 
improvement; 
hospitalization 
indicated for 
clinical sequelae 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 

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Cytokine 
release 
syndrome 
Mild reaction; 
infusion 
interruptionnot 
indicated; 
intervention not 
indicated 
Therapy or 
infusion 
interruption 
indicated but 
responds 
promptly to 
symptomatic 
treatment (eg, 
antihistamines, 
NSAIDS, 
narcotics,IV 
fluids); 
prophylactic 
medications 
indicated for ≤ 24 
h 
Prolonged (ie, not 
rapidly 
responsive to 
symptomatic 
medication and/or 
brief interruption 
of infusion); 
recurrence of 
symptoms 
followinginitial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae 
(eg, renal 
impairment, 
pulmonary 
infiltrates) 
Life-threatening; 
consequences; 
pressor or 
ventilatory 
supportindicated 
h = hours; IV = intravenous; NSAIDS = nonsteroidal anti-inflammatory drugs. 
REMARK: An acute infusion-related reaction may occur with an agent that causes cytokine release (eg, 
monoclonalantibodies or other biological agents). Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug fever); Arthralgia (joint pain); 
Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); 
Headache; 
Hypertension; 
Hypotension; 
Myalgia 
(muscle 
pain); 
Nausea; 
Pruritis/itching; 
Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Urticaria (hives, welts, wheals); 
Vomiting. 

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The following are treatment guidelines for XmAb23104 treatment-related infusion-relatedreactions: 
Table 2: 
XmAb23104 Infusion Reaction Dose Modification and Treatment Guidelines 
NCI-CTCAE Grade 
Treatmen 
t 
Premedication at 
Subsequent 
Dosing 
Grade 1 
• Increase monitoring of vital signs as medically 
indicateduntil the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Mild reaction; 
infusioninterruption 
not indicated; 
intervention 
not indicated 
Grade 2 
• Stop Infusion. 
Participant may be 
premedicated 1.5 h (± 30 
minutes) prior to infusion 
ofdrug with: 
• Diphenhydramine 25-50 
mgiv 
• Acetaminophen 650 mg po 
• Corticosteroids 
(dexamethasone 10 mg 
iv orequivalent) 
Requires therapy or 
o Additional appropriate medical therapy may 
infusion interruption 
includebut is not limited to: 
butresponds promptly 
o IV fluids 
to symptomatic 
o Antihistamines 
treatment (eg, 
o NSAIDs 
antihistamines, 
o Acetaminophen 
NSAIDs, narcotics, IV 
o Narcotics 
fluids); prophylactic 
• Increase monitoring of vital signs as medically 
medications indicated 
indicateduntil the participant is deemed medically 
for ≤ 24 h. 
stable in the opinion of the investigator. 
• If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/h. to 50 
mL/h.). Otherwise dosing will be held until symptoms 
resolve andthe participant should be premedicated 
for the next 
scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequatepremedication should be permanently 
discontinued from further study drug treatment 
Grades 3 or 4 
• Stop Infusion. 
No subsequent dosing 
Grade 3: 
• Additional appropriate medical therapy may include 
but isnot limited to: 
o Epinephrine** 
o IV fluids 
o Antihistamines 
o NSAIDs 
o Acetaminophen 
o Narcotics 
o Oxygen 
o Pressors 
o Corticosteroids 
• Increase monitoring of vital signs as medically 
indicateduntil the participant is deemed medically 
stable in the opinion of the investigator. 
• Hospitalization may be indicated. 
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicatedfor other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
** In cases of anaphylaxis, epinephrine should be 
Life-threatening; 
usedimmediately. 
pressor or 
Participant is permanently discontinued from further study 
ventilatorsupport 
drugtreatment. 
indicated 
IV/iv = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events;NSAID 
= nonsteroidal anti-inflammatory drugs; po = oral. 

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Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. For further information, please refer to the CTCAE v5 at http://ctep.cancer.gov 
18.2 Appendix B Procedures for Participants Exhibiting Immune-Related Adverse Events 
Adverse events of a potential immunologic etiology, or irAEs, may be defined as AEs of unknown etiology, 
associated with drug exposure and consistent with an immune phenomenon. Immune-related AEs may be 
predicted based on the nature of the compounds, their mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action. Special attention should be paid to AEs that may be 
suggestive of potential irAEs. An irAE can occur shortly after the first dose or several months after the last dose 
of treatment. 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other 
etiologic causes before labeling an AE as an irAE. 
Recommendations for management of specific immune-mediated AEs known to be associated with other PD-1 
inhibitors (e.g., pembrolizumab, nivolumab) are detailed in Appendix B Table (below). Algorithms for evaluation 
of selected immune toxicities that have previously been attributed to PD-1 inhibitors and management 
guidelines for irAEs not detailed elsewhere in the Protocol should follow the ASCO or ESMO Clinical Practice 
Guidelines (Brahmer et al 2018, Haanen et al 2017). 
Table 1. Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where XmAb23104 has been withheld, they can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv5) 
Action Taken with 
XmAb23104 
irAE 
Manageme 
nt with 
Corticoster 
oid and/or 
Other 
Therapies 
Monitor and Follow-up 
Pneumonitis 
Grade 2 
Withhold 
Administer 
corticostero 
ids (initial 
dose of 1-2 
mg/kg 
prednisone 
or 
equivalent) 
followed by 
taper 
Monitor participants for signs andsymptoms 
of pneumonitis 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiatecorticosteroid treatment 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis 
Grade 2 
Withhold 
Administer 
corticostero 
ids (initial 
dose of 1-2 
Monitor participants for signs andsymptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 

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Grade 3 
Withhold 
XmAb23104 
mg/kg 
prednisone 
or 
equivalent) 
followed by 
taper 
and ileus). 
Participants with Grade ≥ 2 diarrhea 
suspecting colitis shouldconsider GI 
consultation and performing endoscopy to 
rule outcolitis. 
Participants with diarrhea/colitis should be 
advised to drink liberalquantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation without 
elevated bilirubin 
or Increased 
bilirubin alone 
Grade 2 
Withhold 
Administer 
corticosteroid 
s 
(initial dose 
of 0.5- 
1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable) 
Grade 3 or 4, or 
/findings 
consistent 
with DILI (Grade 2 
AST/ALT and 
total 
bilirubin > 2 × 
ULN) 
Permanently 
discontinue 
Administer 
corticosteroid 
s 
(initial dose 
of 1-2 
mg/kg 
prednisone 
or equivalent) 
followed by 
taper 
Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv5) 
Action Taken with 
XmAb23104 
irAE 
Manageme 
nt with 
Corticoster 
oid and/or 
Other 
Therapies 
Monitor and Follow-up 
AST / ALT 
elevation with 
bilirubin >1.5 × 
ULN (unless 
Gilbert’s 
syndrome) 
Grade > 1 
Permanently 
discontinue 
Adminis 
ter 
corticost 
eroids 
(initial 
dose of 
2 mg/kg 
prednis 
one or 
equivale 
nt) 
followed by 
taper 
Monitor with liver function tests(consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable) 

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T1DM or 
Hyperglycemia 
Newly onset 
T1DMor 
Grade 3 or 4 
hyperglycemi 
a associated 
with evidence 
of -cell 
failure 
Withhold 
Initiate 
insulin 
replacem 
ent 
therapy 
for 
participant 
s with 
T1DM 
Administer 
anti- 
hyperglyce 
mic in 
participant 
s with 
hyperglyce 
mia 
Monitor participants for hyperglycemia or 
other signs andsymptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer 
corticosteroi 
ds and 
initiate 
hormonal 
replacemen 
ts as 
clinically 
indicated. 
Monitor for signs and symptomsof 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1 
Hyperthyroidism 
Grade 2 
Continue 
Treat 
with non- 
selective 
beta- 
blockers 
(eg, 
proprano 
lol) or 
thionami 
des as 
appropri 
ate 
Monitor for signs and symptomsof thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue 
Initiate 
thyroid 
replaceme 
nt 
hormones 
(eg, 
levothyrox 
ine or 
liothyronin 
e) per 
standard 
of care 
Monitor for signs and symptomsof thyroid 
disorders. 
Nephritis and 
Renal dysfunction 
Grade 2 
Withhold 
Administer 
corticostero 
ids 
(prednison 
e 1-2 
mg/kg or 
equivalent) 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 

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followed by 
taper. 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on 
severity of 
AE 
administer 
corticoster 
oids 
Ensure adequate evaluation to confirm 
etiology and/or excludeother causes 
Grade 3 or 4 
Permanently 
discontinue 
Immune- 
related 
AEs 
Toxicity Grade 
orConditions 
(CTCAEv5) 
Action Taken with 
XmAb23104 
irAE 
Manageme 
nt with 
Corticoster 
oid and/or 
Other 
Therapies 
Monitor and Follow-up 
All other 
Intolerable/ 
Withhold 
Based on 
type and 
severity of 
AE 
administer 
corticostero 
ids 
Ensure adequate evaluation to confirm 
immune-related 
persistentGrade 2 
etiology and/or excludeother causes 
AEs 
Grade 3 
Withhold or discontinue 
based onthe type of 
event. 
Events that require 
discontinuation include 
and not limited to: 
Guillain-Barré 
Syndrome, encephalitis 
Grade 4 or 
Permanently 
recurrentGrade 3 
discontinue 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common 
Terminology Criteria for Adverse Events; DILI = drug-induced liver injury; irAE = immune-related adverse event;IV 
= intravenous; T1DM = type 1 diabetes mellitus; ULN = upper limit of normal. 
1 Withhold or permanently discontinue XmAb23104 is at the discretion of the investigator or treating physician. 
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of XmAb23104 is 
required, the drugs may be resumed when AE resolves to Grade ≤ 2 and is controlled with hormonal 
replacementtherapy or achieved metabolic control (in case of T1DM).