A Phase 1 (First-In-Human [FIH]), Multi-Site, Dose Escalation and Expansion Study of WTX-330 in Adult Patients With Advanced or Metastatic Solid Tumors or Lymphoma
Phase: PHASE1
Conditions: Advanced or Metastatic Solid Tumors, Non-Hodgkin Lymphoma
Sponsor: Werewolf Therapeutics, Inc.

 
CLINICAL STUDY PROTOCOL 
A Phase 1 (First-In-Human [FIH]), Multi-Site, Dose Escalation and 
Expansion Study of WTX-330 in Adult Patients with Advanced or 
Metastatic Solid Tumors or Lymphoma 
Investigational Product: WTX-330 
Protocol Number: WTX-330x2101 
Sponsor: 
Werewolf Therapeutics, Inc. 
200 Talcott Avenue 
Watertown, MA 02472 
USA 
Telephone: 617-952-0555 
Version Number: 02 
Date: 06 April 2023 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Werewolf Therapeutics, Inc. (hereinafter, Werewolf), except to the extent that 
disclosure would be required by law and for the purpose of evaluating and/or conducting a 
clinical study for Werewolf. You are allowed to disclose the contents of this document only to 
your Institutional Review Board (IRB) and study personnel directly involved with conducting 
this protocol. Persons to whom the information is disclosed must be informed that the 
information is confidential and proprietary to Werewolf, and that it may not be further disclosed 
to third parties. 

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SIGNATURE PAGE 
STUDY TITLE: A Phase 1 (First-In-Human [FIH]), Multi-Site, Dose Escalation and 
Expansion Study of WTX-330 in Adult Patients with Advanced or Metastatic Solid Tumors 
or Lymphoma 
We, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
 
Randi Isaacs 
Chief Medical Officer 
Werewolf Therapeutics 
06-Apr-2023

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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Werewolf to study personnel under my supervision. I will discuss this material with them to 
ensure they are fully informed about the study product and study procedures. I will let them know 
that this information is confidential and proprietary to Werewolf and that it may not be further 
disclosed to third parties. I understand that the study may be terminated or enrollment suspended 
at any time by Werewolf, with or without cause, or by me if it becomes necessary to protect the 
best interests of the study patients. 
I agree to conduct this study in full accordance with United States (US) Food and Drug 
Administration (FDA) Regulations, Institutional Review Board (IRB)/Ethics Committee (EC) 
Regulations and International Council for Harmonisation (ICH) Guidelines for Good Clinical 
Practice (GCP). 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator Signature  
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator Printed Name 
 

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SYNOPSIS 
TITLE: A Phase 1 (First-In-Human [FIH]), Multi-Site, Dose Escalation and Expansion Study of 
WTX-330 in Adult Patients with Advanced or Metastatic Solid Tumors or Lymphoma 
BRIEF TITLE: A first-in-human study of WTX-330 to assess safety and determine the 
recommended dose in adult patients with advanced or metastatic solid tumors and lymphoma 
SPONSOR: Werewolf Therapeutics, Inc. 
CLINICAL PHASE: 1  
INVESTIGATION TYPE: Oncology 
STUDY TYPE: Dose escalation and expansion study 
PROTOCOL NUMBER: WTX-330x2101 
INVESTIGATIONAL PRODUCT: WTX-330 
STUDY PURPOSE AND RATIONALE: 
The recent development of immuno-oncology agents that enhance antitumor immunity is rapidly 
changing the treatment of cancer. However, these agents are not effective in all tumor types or in 
all patients with a certain tumor type. This gap represents an unmet medical need for novel 
immunotherapy approaches. 
Interleukin-12 (IL-12) is a potent, pleiotropic cytokine known to enhance immune-mediated 
killing of cancer cells. The mechanism of action of IL-12 includes stimulation of both innate and 
adaptive immune cells. Antigen-presenting cells (APCs) such as dendritic cells and macrophages 
produce IL-12 upon activation. Binding of IL-12 to its receptor expressed on multiple immune 
cell types activates the Janus kinase-signal transducer and activator of transcription (JAK/STAT) 
signaling pathway to induce changes in gene expression. IL-12 signaling activity induces 
interferon gamma (IFNγ) and together, these two cytokines produce a broad range of 
immunological activities including induction of T helper type 1 (Th1) cell differentiation; 
activation of cytotoxic natural killer (NK) and T cells; and inhibition or reprograming of 
immunosuppressive cells such as tumor-associated macrophages (TAM) and myeloid-derived 
suppressor cells (MDSCs). IL-12 also enhances antigen presentation by APCs, which is necessary 
to stimulate immune responses in tumors that have not naturally generated antitumor immunity. 
Numerous studies demonstrate that IL-12 has robust antitumor activity in a range of preclinical 
models and induces immune memory. These observations have generated significant interest in 
developing recombinant human IL-12 (rhIL-12) as a therapeutic agent for cancer. In early clinical 
studies, systemically administered rhIL-12 demonstrated clinical activity in several tumor types 
including renal cell carcinoma (RCC), melanoma, and non-Hodgkin lymphoma (NHL). However, 
systemic administration of rhIL-12 was shown to be toxic, resulting in death of 2 patients in a 
Phase 2 clinical study and multiple hospitalizations. Additional clinical studies using more 

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STUDY DESIGN: 
This is a Phase 1, FIH, multi-site study starting with dose escalation of WTX-330 (Part 1) followed 
by dose expansion of WTX-330 (Part 2) in two arms (A and B). 
Dose Escalation (Part 1) 
The dose escalation part of the study will be conducted in patients with relapsed/refractory (r/r) 
advanced and/or metastatic solid tumors. Patients with primary CNS malignancies are ineligible. 
Patients with castrate-resistant prostate cancer (CRPC) and non-Hodgkin lymphoma (NHL) will 
be eligible for Dose Expansion (see Arm B below) but are not eligible for Dose Escalation. During 
dose escalation, WTX-330 will be administered as a single agent on Days 1 and 15 (i.e., every 2 
weeks, Q2W) of 28-day treatment cycle. 
The starting dose of WTX-330 is 0.016 mg/kg. Selection of the starting dose in this FIH clinical 
study was informed by safety and PK data from non-Good Laboratory Practice (GLP) and GLP 
toxicological studies in cynomolgus monkeys, pharmacology studies in tumor-bearing mice, and 
the prior clinical experience with rhIL-12. A total of eight provisional dose levels are defined for 
the dose escalation. A dose level with a 50% lower dose than the starting dose is also included if 
the first dose level is not tolerated.  
To minimize the number of patients treated at potentially subtherapeutic dose levels, cohorts will 
enroll a minimum of 3 patients and up to 6 patients. In each dose cohort, a minimum of 3 patients 
are required to have completed the dose-limiting toxicity (DLT) observation period before 
initiating enrollment of the subsequent cohort. 
To help ensure patient safety, dosing of the first 2 patients at each dose level will be staggered by 
at least 7 days and dosing of the second and all following patients will be staggered by at least 2 
days. The DLT assessment period for a dose cohort must be completed and the data reviewed by 
the Dose Escalation Committee (DEC) prior to the recruitment of patients into the next dose 
cohort. The DEC is comprised of the study Investigators, the Sponsor’s medical representative(s) 
and independent functional experts as required. 
Patients may receive WTX-330 for as long as they continue to show clinical benefit, as assessed 
by the Investigator, or until disease progression or other treatment discontinuation criteria are met. 
No intrapatient dose escalation is allowed. 
A Bayesian Logistic Regression Model (BLRM) incorporating escalation with overdose control 
(EWOC) will be used to guide the dose escalation (Appendix F). Data from patients satisfying the 
requirements for inclusion in the dose-determining set (DDS) will be included in the model. After 
completion of a dose cohort, or at any time the BLRM is updated, a decision to escalate and the 
actual dose and schedule selected will be determined by the DEC based on a review of all available 
clinical, PK and laboratory data and on the recommendation of the BLRM regarding the highest 
admissible dose according to the EWOC principle. 
Dose escalation will continue until determination of the MTD and/or RDE. Once the MTD/RDE 
is identified, the Dose Expansion part of the study (Part 2) will open. Determination of the RDE 
and selection of an optimal dosage will be informed not only by clinical PK, PD, antitumor activity 
and safety data, but also by nonclinical pharmacology and toxicology data. 

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Dose Expansion (Part 2) 
Patients in Dose Expansion will have a confirmed diagnosis of a r/r locally advanced or metastatic 
solid tumor or lymphoma for which the patient has progressed or is intolerant of standard therapy, 
or for whom no standard therapy with proven benefit exists. Dose Expansion (Part 2) will be 
conducted in 2 arms that will enroll the following patient populations: 
• 
Arm A: Patients with indications for which a CPI is indicated/approved (e.g., cutaneous 
malignant melanoma, RCC, non-small cell lung cancer [NSCLC], head and neck squamous 
cell carcinoma [HNSCC], urothelial carcinoma, etc.) who have been treated with a CPI 
regimen and who demonstrate primary or secondary resistance to CPI therapy. Primary 
resistance is defined as disease progression or stable disease (SD) < 6 months as the best 
response after at least 6 weeks of exposure to inhibitors of PD-(L)1. Secondary resistance is 
defined as disease progression ≥ 6 months after initiation of PD-(L)1 inhibitors in patients 
who have received clinical benefit (i.e., CR or PR or SD > 6 months). Patients who 
discontinue CPI therapy for toxicity or other reasons and who don’t demonstrate primary or 
secondary resistance to CPIs as defined here are not eligible. Patients with Hodgkin 
lymphoma are also ineligible. 
• 
Arm B: Patients with tumor types for which CPI therapy is not indicated/approved (e.g., 
pancreatic cancer, microsatellite-stable [MSS] colorectal carcinoma, castrate-resistant 
prostate cancer [CRPC], NHL) and who are CPI naïve. Patients with NHL should have either 
follicular lymphoma or diffuse large B-cell lymphoma (DLBCL), though other subtypes of 
NHL including T-cell lymphomas may be considered after a discussion with the Sponsor. All 
patients with NHL must have received at least 2 prior systemic therapies. Patients with 
primary CNS malignancies are not eligible.  
Additional arms may be added in the Dose Expansion for specific indications of interest. 
Patients will remain on study treatment until they experience unacceptable toxicity, progressive 
disease per RECIST (Appendix D; Eisenhauer et al., 2009) or iRECIST (Appendix E) for solid 
tumors, or confirmed progressive disease for NHL (dose expansion part) according to Lugano 
classification (Cheson et al., 2014), and/or treatment discontinued at discretion of the Investigator, 
or the patient withdraws consent. 
The study consists of a screening period, a treatment period with either Dose Escalation (Part 1) 
or Dose Expansion (Part 2), an End-of-Treatment (EOT) visit, and a safety follow-up period. The 
Safety Follow-Up Visit should occur either 30 days after the last dose of study drug or prior to the 
start of a new cancer regimen, whichever comes first. Overall survival status will be evaluated 
every 12 weeks (+/- 2 weeks) for patients who are on Dose Expansion (Part 2). Patients will be 
contacted via telephone to evaluate overall survival until initiation of a new therapy or death, 
whichever comes first.  
The end of the study is defined as when 80% of patients have either discontinued the study or have 
completed follow-up. Throughout the study, patients will be assessed for efficacy, PK, PD and 
safety of WTX-330. 
 
 

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19. Active infection as determined by hepatitis B surface antigen and hepatitis B core antibody, 
or hepatitis B virus deoxyribonucleic acid (DNA) by quantitative polymerase chain reaction 
(qPCR) testing. 
20. Active infection as determined by hepatitis C virus (HCV) antibody or HCV RNA by qPCR 
testing. 
21. Pregnant or lactating. 
22. History of hypersensitivity to any of the study drug components. 
 
 
 

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KEY EFFICACY, PHARMACOKINETIC AND PHARMACODYNAMIC/BIOMARKER 
ASSESSMENTS: 
Efficacy Assessments 
Solid tumor responses will be evaluated based on RECIST 1.1 (Appendix D; Eisenhauer et al., 
2009) and iRECIST (Appendix E), whereas NHL responses will be assessed by Lugano 
classification (Cheson et al., 2014) at the times indicated in the Schedule of Assessments (SoA) 
(Appendix A). For solid tumors, disease assessments will include radiographic measurements of 
tumors in the chest, abdomen, pelvis, and at any other known sites of disease using computed 
tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography 
(PET)/CT. NHL will be evaluated with PET/CT. Intravenous (IV) and oral contrast should be used 
unless there is a clear contraindication such as decreased renal function or an allergy that cannot 
be addressed with standard prophylactic treatments. Baseline tumor assessments will be 
performed at Screening (i.e., within 28 days of Cycle 1 Day 1). Patients with CNS metastases must 
have brain imaging (MRI preferred; CT with contrast is acceptable if MRI imaging 
contraindicated) performed during Screening. On-study scans should be performed every 8 weeks 
(±7 days) from Cycle 1 Day 1 for the first 6 cycles and every 12 weeks (±7 days) thereafter, and 
include imaging of the chest, abdomen, pelvis, and any additional areas of disease identified at 
baseline, using the same modality as used for baseline imaging until progressive disease per 
RECIST 1.1 and iRECIST for solid tumors, or Lugano classification for NHL, withdrawal of 
consent, or initiation of a new anticancer therapy. 
Pharmacokinetic Assessments 
Plasma samples for WTX-330 PK assessments of the parent compound and free IL-12 will be 
obtained. Concentrations of WTX-330 and free IL-12 will be determined with a validated 
bioanalytical method. PK parameters such as AUC, maximum observed plasma concentration 
(Cmax) minimum observed plasma concentration (Cmin), time to maximum observed plasma 
concentration (Tmax), terminal-elimination half-life (t½), clearance, volume of distribution (Vd), 
and volume of distribution at steady state (Vss) will be determined. 
 

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SAFETY ASSESSMENTS 
The safety and tolerability profile of WTX-330 will be assessed by monitoring adverse events 
(AEs; including DLTs, serious AEs [SAEs], and AEs of special interest [AESIs]), physical 
examination findings (including ECOG performance status), clinical laboratory evaluations, vital 
sign measurements, and ECGs. AEs will be graded according to the NCI-CTCAE version 5.0. 
Cytokine release syndrome (CRS) will be graded by ASTCT consensus grading criteria. 
STATISTICAL ANALYSES: 
Primary (Dose Escalation) Analysis 
An adaptive 2-parameter BLRM incorporating EWOC will be used to guide the dose escalation 
(Appendix F). This model uses all the information currently available about the dose-DLT 
relationship of WTX-330 and is summarized in a prior distribution. For this study, nonclinical 
data informing the starting dose and the prior clinical experience with recombinant human IL-12 
are used to compute the prior distribution. This prior distribution is then updated after each cohort 
of patients is treated and incorporates all the DLT data available in the DDS. The posterior targeted 
toxicity to define the MTD will be between 16% and 33%. In addition, and according to the 
EWOC principle, any dose of WTX-330 that has a ≥ 25% chance of being in the excessive toxicity 
category is not considered for the next dose group. Dose escalation decisions will be made by the 
DEC based on the recommendations from the BLRM and all available clinical, safety, PK and PD 
data. 
Primary (Dose Expansion) Analysis 
For primary analysis of the Dose Expansion (Part 2) cohorts, a probability of success design for 
the ORR based on the best overall response (BOR) will be used. To model the primary analysis 
of the dose expansion cohorts, 2 independent Bayesian beta binomial designs with beta (0.05, 
0.95) prior distributions will be used. The response criteria for success are defined as follows: the 
study is considered successful in an extension arm if the posterior probability that the true response 
rate exceeds 10% is at least 90%. The final analysis will take place after the completion of the 
dose expansion cohorts when the last patient has had the final end-of-study visit. 
Safety Analyses 
Safety analyses will generally be descriptive and presented in tabular format with the appropriate 
summary statistics for the safety set (i.e., all patients who received at least 1 dose of WTX-330 
and had at least 1 post-baseline safety assessment). The safety set will be the primary population 
for all safety related endpoints except determination of the dose-DLT relationship. 
Efficacy Analyses 
All efficacy analyses will be performed for investigator‑assessed response criteria (per RECIST 
(Appendix D; Eisenhauer et al., 2009) and iRECIST (Appendix E) for solid tumors, or per Lugano 
classification (Cheson et al., 2014) for NHL [Dose Expansion part]). For NHL, the response will 
be analyzed for radiological response, metabolic response (PET/CT) and overall response: 
• 
ORR defined by achieving confirmed CR and/or PR will be presented by percentage rates and 
95% confidence intervals (CIs). For changes in tumor size, waterfall plots will be presented. 
For all response assessments, swimmer plots will be presented.